25
Who Owns You
Blackwell Public PhilosophyEdited by Michael Boylan Marymount University
In a world of 24‐hour news cycles and increasingly specialized knowledge the Blackwell Public Philosophy series takes seriously the idea that there is a need and demand for engaging and thoughtful discussion of topics of broad public impor-tance Philosophy itself is historically grounded in the public square bringing people together to try to understand the various issues that shape their lives and give them meaning This ldquolove of wisdomrdquomdashthe essence of philosophymdashlies at the heart of the series Written in an accessible jargon‐free manner by internationally renowned authors each book is an invitation to the world beyond newsflashes and sound bites and into public wisdom
1 Permission to Steal Revealing the Roots of Corporate Scandal by Lisa H Newton
2 Doubting Darwin Creationist Designs on Evolution by Sahotra Sarkar
3 The Extinction of Desire A Tale of Enlightenment by Michael Boylan
4 Torture and the Ticking Bomb by Bob Brecher
5 In Defense of Dolphins The New Moral Frontier by Thomas I White
6 Terrorism and Counter‐Terrorism Ethics and Liberal Democracy by Seumas Miller
7 Who Owns You The Corporate Gold Rush to Patent Your Genes by David Koepsell
8 Animalkind What We Owe to Animals by Jean Kazez
9 In the Name of God The Evolutionary Origins of Religious Ethics and Violence by John Teehan
10 The Secular Outlook In Defense of Moral and Political Secularism by Paul Cliteur
11 Freedom of Religion and the Secular State by Russell Blackford
12 As Free and as Just as Possible The Theory of Marxian Liberalism by Jeffrey Reiman
13 Happy‐People‐Pills For All by Mark Walker
14 Life Liberty and the Pursuit of Dao by Sam Crane
15 The Justification of Religious Violence by Steve Clarke
16 Who Owns You Science Innovation and the Gene Patent Wars by David Koepsell
Who Owns You
Science Innovation and the Gene Patent Wars
SECoND EDITIoN
David Koepsell
This second edition first published 2015copy 2015 John Wiley amp Sons Ltd
Edition history John Wiley amp Sons Ltd (1e 2009)
Registered OfficeJohn Wiley amp Sons Ltd The Atrium Southern Gate Chichester West Sussex Po19 8SQ UK
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For details of our global editorial offices for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at wwwwileycomwiley‐blackwell
The right of David Koepsell to be identified as the author of this work has been asserted in accordance with the UK Copyright Designs and Patents Act 1988
All rights reserved No part of this publication may be reproduced stored in a retrieval system or transmitted in any form or by any means electronic mechanical photocopying recording or otherwise except as permitted by the UK Copyright Designs and Patents Act 1988 without the prior permission of the publisher
Wiley also publishes its books in a variety of electronic formats Some content that appears in print may not be available in electronic books
Designations used by companies to distinguish their products are often claimed as trademarks All brand names and product names used in this book are trade names service marks trademarks or registered trademarks of their respective owners The publisher is not associated with any product or vendor mentioned in this book
Limit of LiabilityDisclaimer of Warranty While the publisher and author have used their best efforts in preparing this book they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose It is sold on the understanding that the publisher is not engaged in rendering professional services and neither the publisher nor the author shall be liable for damages arising herefrom If professional advice or other expert assistance is required the services of a competent professional should be sought
Library of Congress Cataloging‐in‐Publication DataKoepsell David R (David Richard) authorWho owns you science innovation and the gene patent wars David Koepsell ndash Second edition p cm Previous edition has subtitle the corporate gold-rush to patent your genes Includes bibliographical references and index ISBN 978-1-118-94850-7 (pbk)I Title [DNLM 1 Genetics Medicalndashlegislation amp jurisprudence 2 Patents as Topicndashlegislation amp jurisprudence 3 ownershipndashethics QZ 324] K1519B54 34604prime86ndashdc23 2014048341A catalogue record for this book is available from the British Library
Cover image copy esenkartal
Set in 10513pt Minion by SPi Publisher Services Pondicherry India
2 2015
To Alexandro
Contents
Acknowledgments viii
Preface to the Second Edition x
Foreword xiv
Introduction xxiv
1 Individual and Collective Rights in Genomic Data Preliminary Issues 1
2 Ethics and Ontology A Brief Discourse on Method 21
3 The Science of Genes 30
4 DNA Species Individuals and Persons 52
5 Legal Dimensions in Gene Ownership 69
6 BRCA1 and 2 The Myriad Case and Beyond 88
7 Are Genes Intellectual Property 101
8 DNA and The Commons 119
9 Pragmatic Considerations of Gene Ownership 137
10 Nature Genes and the Scientific Commons A Social Ontology of Invention 155
11 So Who Owns You Some Conclusions About Genes Property and Personhood 165
Notes 182
Index 194
Acknowledgments
Many thanks must be given to those whom I have spoken to about the issues discussed herein since the first edition and who helped inform the updates including Tania Simoncelli Luigi Palombi Joanna Rudnick Dan Ravicher Kevin Noonan James Watson and numerous online commenters who helped point out errors and hone my arguments Thank you also to my colleagues at Delft University of Technology where I have worked the past 6 years and continued discussing and sharpening my approach to the ideas in this book and others
I remain grateful to the Yale Interdisciplinary Bioethics Center for appointing me as their Donaghue Initiative Fellow in Research Ethics 2006ndash2007 I drafted a significant portion of this book during that appoint-ment and had the chance to hash out many of these issues with the staff affiliated faculty and others who participated in events that year Special thanks to all the good people at Yale including especially Robert Levine Julius Landwirth Carol Pollard Autumn Ridenour and Jonathan Moser Thanks also to the folks at the New Haven dog park for keeping my dear departed Buttercup and me company during my residency at Yale Many thanks to my wife Vanessa who gave me significant scientific guidance and lots of encouragement as I worked out these issues and drafted the original book and who helped redraft Chapter 3 for this edition Thanks to my 3‐year‐old daughter Amelia whose appearance brought new purpose to my life and my work My parents Eva Hwa and Richard Koepsell provided commentary and feedback on early drafts of chapters and I am as always grateful for their continuing encouragement My dear friend Peter Hare who passed away in 2008 also kept me company bought me lunches and encouraged my work while at Yale hellip I am grateful for his guidance and friendship and will miss him dearly Thanks to Barry Smith who has remained a helpful and encouraging mentor as I pursue the sometimes
Acknowledgments ix
frustrating but often fruitful path of philosophy Thank you also to Denise Riley who helped dig up obscure articles and arranged almost all the research for my initial trip to Yale that hatched the first edition Finally many thanks to anyone I have forgotten including all those who have given me probing questions puzzling scenarios and further guidance in the talks I have given on this fascinating subject over the past 8 years
David KoepsellAugust 14 2014
Mexico City Mexico
Preface to the Second Edition
A lot has happened in nearly every respect since I first decided to try to delve into philosophical issues of gene patenting nearly a decade ago I have learned much the world has changed and I have changed I would very much like to think I have played a role in that change though chances are things would have changed in almost exactly the same way without my small contribution When the first edition came out patenting genes was still a regular part of biotech and only months after the first edition appeared did a surprising and now‐landmark lawsuit alter that significantly Little did I realize the nature of the forces that would be involved in what I had originally assumed was no more than an academic exercise but which became a matter of weighty and heated public debate and finally judicial action
I first became interested in the subject of gene patents when I began reading up on the topic my future wife was researching pharmacogenom-ics To grasp what she did I first needed to study the science and in so doing I also studied the history of that science Along the way I read about the Human Genome Project and learned about the practice of gene patenting that it spawned Having had some experience and interest in general issues of the philosophy of intellectual property (see my 1997 PhD thesis turned 2000 book The Ontology of Cyberspace) my ears perked up when I first read about the notion of patenting genes So I dived into the research and thinking in my ordinary style of philosophical work Although I sometimes teach ethics my primary field is ontology and it is from an ontological approach that I start with everything in philosophy Thus I began to try to get a grip on the nature of the existence of the underlying objects some of which are ldquobrute factsrdquo (molecules exist with or without social institutions or intentionality) and some of which are social objects (like laws rights and other parts of ldquosocial realityrdquo existing only because of
Preface to the Second Edition xi
collective intentionality) The book was an attempt to lay all this out and to connect it together into a theory that is somehow connected to notions of ldquojusticerdquo which I argued bridges the worlds of brute facts and social objects
The conclusions I reached were I thought pretty neat Specifically I worked out an ontology of ldquothe commonsrdquo that I had never heard expressed before and one that connected nicely with the objects involved to show why artifacts and nature ought to be treated differently and how to decide what constitutes an artifact and what constitutes nature and a defense of the viewpoint that unmodified genes were clearly not artifacts It seemed all the more relevant and interesting even perhaps somewhat important in light of the then ongoing practice of gene patenting I was much too focused on the ontological arguments and their seeming relevance to real‐world practices than I was to the scientific and legal terminology with which I was engaging and this was an error When the book was released minor errors I made in using technical terminology from both the science and the law were latched onto by a couple critical reviewers from the Intellectual Property law and teaching worlds and urged as a basis to ignore my substantive arguments They were right to call out the errors and I have attempted to correct them in this edition Regardless the underlying argu-ments I had set forth would become shortly echoed nearly precisely in the lawsuit that the American Civil Liberties Union (ACLU) spearheaded against Myriad Corp over the BRCA1amp2 gene patents
For a brief period of time partly due to lucky timing I was thrust head-long into the public debates about gene patenting with the Myriad case leading the headlines Given numerous opportunities to engage publicly with the issues and ideas I had previously assumed were only academic musings unlikely to alter public policy and given feedback and counterar-guments in those same venues the general arguments could be more finely honed This edition attempts to coalesce them
Perhaps more importantly in the intervening years since I began my musings about the nature of genes artifacts nature and patents I came to learn the very personal impact that gene patents have on peoplersquos lives Because the ACLU chose to sue over the patents on BRCA1amp2 genes there was a ready‐made large and passionate community (mostly women) whose heredity put them at risk of breast and ovarian cancers but who were basically forced into paying monopolistic prices for the only test available for the gene which was patented by Myriad Corp Breast cancer and the threat of inherited tendencies for breast cancer are real They are not legal
xii Preface to the Second Edition
sophistry they are not philosophical musing They kill people or alter their lives irrevocably
I began researching and considering the effects of gene patents believing they were potentially a threat to the conduct of science whose foundational objects I argued were part of a commons‐by‐necessity but I realized after my book came out that real lives were being harmed by patents on genes The Myriad case brought together the theoretical with the actual for me and the dynamics of both the case and the loud and sometimes angry public debate raised my awareness not only about this particular subject but also the power and responsibility of academic research in the sphere of public policy Suddenly ideas seemed more important had relevance outside the academy and could perhaps make a difference in peoplesrsquo lives I began to interact with the activists who were fighting to liberate genes to stop com-panies like Myriad in the courts and engage not just in the philosophical arguments but in those fights I joined with authors of amicus (friend of the court) briefs interviewed and interacted with BRCA1amp2 mutation‐positive women who were actively pursuing an end to a practice that I had only pre-viously considered to be an interesting metaphysical conundrum I also debated Intellectual Property (IP) attorneys and others primarily with backgrounds in biotech industries and learning better the nature of their arguments I came to understand that most of them including Kevin Noonan who once called me a ldquoliarrdquo on his blog but who has now drafted the foreword to this edition that they too generally have the best intentions Many like Dr Noonan truly expect that without gene patents as they existed until recently the sort of innovation we need in biomedical technol-ogies would not occur as it should
Throughout the course of the litigation in Myriad I remained engaged continued to speak to hone my arguments adding to my list of criteria for something to be a creation (artifact) capable of patent ldquodesignrdquo (as well as intention and being man‐made) and finally rejoicing when the decision of the Supreme Court came out as close to what I believed and argued was right as possible I had seen an academic idea mature and bloom into public policy real law enforceable justice While I realistically believe that the first edition of this book had only a very minor role in what finally happened I am proud to have played some part to have foreseen the issues to argue them honestly from what I think is a rational and logical standpoint and see that the world can be changed by ideas
Preface to the Second Edition xiii
There remain issues to discuss and not everything about gene patents has been resolved by Myriad Some still argue that cDNA ought not to be patent‐eligible (in fact I still think it should be under the criteria I have set forth though there are also arguments to be made that it is not somehow ldquodesignedrdquo by man) Moreover we should expect patent attorneys to do their creative best to continue to pursue patents on as much of the genome as they can within the constraints of Myriad Finally Myriad Corp has not given up They are still suing potential competitors under theories of infringement of parts of their patents that might have survived the ACLUrsquos case against them We shall see how they are eventually resolved and what the future holds for companies like theirs who profited mightily from gene patents for decades I describe as much of this recent legal history as possible in this edition
This book is meant to be a definitive version sewing up the past five years since the first edition emerged and so much changed in the world summa-rizing that recent history and refining the arguments I originally made correcting errors and describing where we are where we yet may be and why gene patents as they once were ought never to be again
David KoepsellAugust 14 2014
Mexico City Mexico
Foreword
David and I have had a friendly disagreement about the subject (and even the title) of this book ever since it was first published and I am happy that he asked me to write this Foreword to the Second Edition The issues David raises in the pages to follow continue to be relevant to a discussion of philosophy and patent law with events that have occurred since the first edition justifying (indeed demanding) this update
Without getting into the deep waters of philosophy (Davidrsquos meacutetier not mine) as we have discussed the issues in the book David contends that he takes a deontological approach and has characterized mine as a utilitarian one Accepting that dichotomy I understand the difference to be that David is operating from ldquofirst principlesrdquo about the rules society should impose on human activity and specifically on what the law permits individuals to ldquoownrdquo with regard to genes and more broadly naturally occurring substances I disagree with that approach on several levels perhaps the most germane of which is that if we posit rules we need to impose a rule‐giver and the potential for improvident rules (if not outright abuse of the privilege) makes me wary in some ways I subscribe to Lani Gruinierrsquos suspicions about the effects of the ldquotyranny of the majorityrdquo in this regard
Part of that tyranny is also the tyranny of unintended or intentional ignorance The issue heremdashldquogenerdquo patentingmdashis one at the intersection of molecular biology and modern genetics on the one hand and patent law (an area notorious for its arcane minutiae) I used to joke with my col-leagues about the effect of trying to explain my position to a lay audience of any type and how I distrusted those who advocated that all that was needed was to ldquoeducaterdquo the public the press and policy makers The problem for proponents of gene patenting has been that opponents have gotten the better part of the debate not by making a reasoned philosophical argument such as the one you will find in these pages but instead by making an
Foreword xv
emotional plea to individuals afraid that corporate America was trying to ldquostealrdquo their genes which has proven very effective This process began with an Op‐Ed piece in The New York Times by Michael Crichton wherein he posited a scenario where a patent holder knocks on your door one day and demands payment for the use of ldquoherrdquo patented gene that resides in your liver (Not coincidentally Dr Crichton had just published a novel on the perils of genetic engineering and corporate ownership of human genes complete with an essay as an addendum containing his arguments against the practice And it should be noted that a constant theme in his novels was a mistrust of technology and particularly the ability of humans to use it without dire consequences) Academics like my friend Lori Andrews at Illinois Institute of Technology (IIT)‐Kent School of Law joined in this theme which was picked up eventually by most popular press outlets and became regrettably the canonical narrative on gene patenting culminating in the American Civil Liberties Unionrsquos (ACLUrsquos) ldquoKeep Your Hands Off My Genesrdquo slogan and logo I hope that this essay provides some antidote to this argument which is founded on the literal fear that someone can ldquoownrdquo you (David assures me that his title is allegorical and that he acknowledges that in all countries that have banned slavery no one can ldquoownrdquo another human being or a part of them See the 13th Amendment I assure you that the ACLU has no such illusions about the intended consequences of their ownership rhetoric)
My philosophy is that the principle we should follow is the greatest good to the greatest number while not infringing on individual rights without (at least) compensation As regards patent law this principle is translated into rules that foster the broadest disclosure of technology possible in return for exclusive patent rights and robust‐enough enforcement rights for patents that they provide sufficient certainty to promote investment so his technology is commercialized to benefit the greatest number In my role as a biotechnology patent attorney I have seen how risky investment in biotechnology can be (indeed the evidence is overwhelming that for all its successes biotechrsquos history is littered with the remains of companies that have failed) and how important it is to have a sound patent system of predictable rights go support that investment
The evidence in support of ldquogene patentingrdquo and more broadly natural products patenting is strong the biotechnology industry has promoted innovation in the form of new drugs and diagnostics assays for a genera-tion This may continue despite the recent restrictions on patent protection
xvi Foreword
for genes and natural products (including patent‐restricting decisions in Mayo Collaborative Labs v Prometheus Labs and Assoc of Molecular Pathologists v Myriad Genetics and recently promulgated US Patent and Trademark Office Guidances on Subject Matter Eligibility) In fact these very restrictions suggest that we would benefit from an appreciation of the facts surrounding the past thirty years of gene patenting to understand why these restrictions are not only wrongheaded but dangerous for future innovation
These include debunking several myths First the concern that patents on specific human genes in some way inhibit innovation in basic genetic research is entirely unfounded One reason is that the genetic information itself is not patented while isolated DNA is encompassed by gene patent claims and described in those claims by its sequence the sequence itself is unpatented information that can be used freely for any purpose (eg inter-rogating genetic databases from other species or even human DNA inter alia to find related genes in those databases) Indeed the innovative benefits to gene patenting are evident in at least two ways First scientific publication databases reveal that there have been more than 11 000 scientific papers published on the BRCA1 and BRCA2 genes since the patents claiming them were granted This outcome refutes the prediction that gene patenting would create a ldquotragedy of the anticommonsrdquo where scientific research would be stifled by patenting (see Heller amp Eisenberg 1998 ldquoCan Patents Deter Innovation The Anticommons in Biomedical Researchrdquo Science 280 698ndash701)) a conclusion supported by the overwhelming majority of studies done on this subject (see for example Walsh et al 2003 ldquoScience and the Law Working Through the Patent Problemrdquo Science 299 1020 Walsh et al 2005 ldquoScience and Law View from the Bench Patents and Material Transfersrdquo Science 309 2002ndash03)
In addition policies that the US Patent and Trademark Office adopted in 2001 required applicants to disclose a practical utility for the product of a gene claimed in a patent These requirements were imposed at a time when the standards for scientific journal publication were much less stringent so that identifying a gene by the extent of genetic similarity between the ldquonewrdquo gene and previously discovered genes was enough for publication But it was not enough for a patent which has been held to be ldquonot a hunting license It is not a reward for the search but compensation for its successful conclusionrdquo Thus genes encoding proteins having no known use or biological activity cannot be patented because to do so would allow the
Foreword xvii
gene to be within the exclusive patent right undeservedly the public would not have received its quid pro quo of a useful invention in return for patent exclusivity All such genes not having patent protection are in the public domain (from which they cannot be retrieved for future patenting) and for humans these constitute the vast majority of genes identified inter alia by the Human Genome Project
The role for patenting genes and the related genetic diagnostic methods using this genetic information in the successes of the biotechnology era are evident The industry has produced hundreds of biologic drugs (at an ever‐increasing rate) that have provided effective treatment for a variety of illnesses and decoding the human genome has enabled researchers to iden-tify genes like the BRCA1 and BRCA2 genes that can be used in predictive genetic diagnostic tests Even the much‐maligned Myriad Genetics has played a positive role in the development and prevalence of genetic diagnostic testing It must be remembered that in 1997 (when Myriadrsquos BRCA gene patents were granted) genetic testing was in its infancy and companies like Myriad were under the burden of convincing payers that the tests did the one thing that all insurers public or private require of such tests save them money in the long run by identifying patients with a high probability of becoming ill and costing the insurers much more for treatment than the costs of prophylaxis Moreover Myriad and like com-panies needed to convince doctors that the testing was worthwhile and to establish a network of genetic counselors who could explain to healthy women that they were at much greater risk of developing breast or ovarian cancer than normal under circumstances that resulted in empowerment from the information and not abject fear And in 1997 genetic sequencing technology was not as developed as it is now and the mechanisms and tech-niques needed to minimize or eliminate the occurrence of false positives or negatives had not been conclusively established All these burdens were ones borne by Myriad and these activities produced the world we have today
It is possible as some have argued that BRCA tests may have been devel-oped independently by individual researchers in the absence of patent pro-tection However it is almost certain that such researchers would have been located in medical centers in urban environments Under these circum-stances women living in or near cities such as New York Boston Philadelphia Cleveland Chicago Houston Denver Los Angeles San Francisco Portland and Seattle might have had access to these tests But what of women in
xviii Foreword
Appalachia or the Four Corners region in the Southwest or more generally in rural or other relatively remote locations Would Yale University for example have had any incentive to provide access to the BRCA tests to these women in these far‐off locations Or to provide genetic counseling where the women lived Or to lobby state Medicare administrators or private insurance commissioners to cover the test I think that unlikely Myriad Genetics did all of this as well as perform outreach to the obstetrics and gynecology doctors throughout the United States so that these primary care doctors were aware of the tests Myriad did not ace from altruism but as part of their business plan in order to expand the number of patients who received the test and thus maximize the companyrsquos revenue While it may be counterintuitive to some these circumstances may have been the most effective way not only to pro-mulgate the BRCA tests but also to facilitate acceptance of genetic diagnostic testing for other diseases showing that in this instance Adam Smith rather than Karl Marx provided the most practical solution to the problem of estab-lishing genetic diagnostic testing as a recognized component of a physicianrsquos diagnostic armamentarium
Fortunately the significance and impact of recent US court decisions (spe-cifically the Myriad case) is much less than it would have been ten to thirty years ago Due to patent term rules most patents (and applications) on iso-lated DNA filed in the heyday of the Human Genome Project (approxi-mately 1998ndash2001) are near the end of their actual or potential term indeed a recent study shows that the number of granted patents having at least one claim reciting an isolate DNA comprising a gene peaked in 1999 and has been dropping since 2005 (Graff et al 2013 ldquoNot quite a myriad of gene pat-entsrdquo Nature Biotechnology 31 404ndash410)) These recent decisions in the United States have not harmed the biotechnology industry because they retained patent eligibility for species of DNA that show evidence of the ldquohand of manrdquo and do not occur in nature These include enzymatically pro-duced copies (cDNA) of cellular messenger RNA and should also encom-pass the tools of the recombinant geneticist (eg including recombinant vectors for cloning and expressing genes in heterologous cells) Most impor-tantly the US Supreme Court did not overturn its Diamond v Chakrabarty decision wherein recombinant cells were determined to be patent eligible
Thus in many ways the question of patent eligibility for human genes is a philosophical one However that does not mean that how we think about patent eligibility for isolated DNA is irrelevant to important questions regarding the usefulness of patents for promoting progress and innovation
Foreword xix
Indeed the most pernicious effects of the current trend in the zeitgeist against patenting has been not that genes have become harder to patent but rather that the ability to patent other natural products has been called into question It is the extension of these recent decisions on isolated DNA to all natural products that poses the greatest threat to innovation This threat can be illustrated by a thought experiment for which of these substances should patent protection be withheld
bull A petrochemical with excellent lubrication qualities isolated in pure form and used as improved motor oil
bull Vitamin B12 isolated from beef muscle formulated into a medicament used to cure anemia in children
bull The drug penicillin isolated from a mixture of naturally produced chemicals made by a mold and formulated as a drug to cure syphilis (which is otherwise eventually fatal)
bull Human urinary erythropoietin formulated to treat anemia in kidney dialysis patients
bull The gene responsible for Gaucherrsquos disease a lipid storage disease wherein the gene is used to make the missing protein that is administered to children and that cures an otherwise incurable and fatal disease
The current answer is that none of them are patent‐eligible per se (although there may be ways to claim them that could pass eligibility muster that remains to be seen) Judge Sweet the US District Court judge who first ruled that isolated DNA was not patent‐eligible did so using language carefully crafted to avoid encompassing all natural products into his decision Specifically Judge Sweet distinguished isolated DNA as the ldquophysical embodiments of genetic informationrdquo a property limited to DNA and not shared by other natural products (While an enzymatic protein could be characterized as the physical embodiment of catalysis of a particular chemical reaction that formulation has much less appeal and inherent rationale than Judge Sweetrsquos regarding DNA) Instead of this careful formu-lation the broader language employed by the Supreme Court as well as the broader rationale the Court used in finding genomic DNA unpatentable has made it easier to employ that fractured logic to render patent‐ineligible naturally occurring molecules other than DNA
I would be remiss not to mention the rather comical (but persistent) efforts of former Acting Solicitor General Neal Katyal who included in the
xx Foreword
US Governmentrsquos amicus brief to the Federal Circuit the distinction engine he called a ldquomagic microscoperdquo embodying the concept that if you are able to visualize a natural product (like a genomic DNA molecule) using this mythical microscope then the natural product would not be patent‐eligible whereas if you could not (eg a cDNA molecule) then the natural product could be eligible for patenting Fortunately the disdain with which the Federal Circuit greeted this fantasy (particularly from Judge Moore) prompted its quick abandonment as are argumentative distinction as the case moved forward Nonetheless both the courts and the US Patent and Trademark Office have adopted this standard de facto even as it becomes the theory that dare not speak its name in legal circles
The philosophical point here is that these substances and natural products generally have been deemed patent‐ineligible categorically which while consistent with (and perhaps even mandated by) the deon-tological approach imposes a distinction that cannot be flexibly applied to the individual circumstances Without such flexibility the law is con-strained to use one criterion that the substance can be found in some form in nature to decide patent eligibility instead of making the deter-mination of whether permitting patenting exclusivity satisfies the cri-teria that the invention ldquopromotes progressrdquo as the US Constitution requires and has a benefit to the public that outweighs any categorical disabilities
The potential that using this standard for determining patent eligibility will result in negative practical outcomes that no one in this debate desires is illustrated by a 2012 Report from the National Institutes of Health Natural Product Branch regarding statistics relating to the number of FDA approvals (a total of 1355) for new drugs falling into the following categories
Drug typesource Number
Biological (B) 203Natural product (N) 55Natural product (botanical) (NB) 149Derived from a natural product (ND) 298Totally synthetic (S) 393Total synthesisnatural product (S) 176Vaccine (S) 81
Foreword xxi
These statistics illustrate the consequences of a general ban on patenting naturally derived products of the 1355 drugs approved between 1981 and 2010
bull Fifty percent of all small‐molecule drugs approved between 2000 and 2010 are natural products
bull About 75 of antibacterial drugs are natural products or derived from natural products
bull Almost 80 of small‐molecule anticancer drugs were natural products or derivatives
In addition only 15 of drugs approved during this time frame were so‐called biologic drugs which are also putatively patent‐ineligible This the problems caused by the current interpretation of the law excluding natural product drugs from patent eligibility will be exacerbated in view of reports from every study showing that the percentage of drugs that are biologic drugs has been growing and will be the predominant type of drug devel-oped in the 2011ndash2030 time period
Another ldquothought experimentrdquo illustrating the practical illogic (David can provide his philosophical justifications in the body of the text) of broad natural products patent ineligibility is as follows Suppose a researcher finds a molecule produced by the human body that causes blood pressure homeo-stasis that is lack of this molecule causes or contributes to the disease of high blood pressure The logical consequence of the current natural prod-uct patent ineligibility standards would be that the closer a drug molecule is to the structure of the molecule as it occurs in the body the less patent‐eli-gible it would be Practically speaking there would be no incentive to modify the molecule to confer patent eligibility on the altered molecule because of the unpredictability of such changes on the molecule such as its biological activity half‐life stability antigenicity or other biological prop-erties And there would be even less incentive to develop the molecule as a drug because without patent protection the available regulatory exclusiv-ities would not pass economic muster to sufficiently defray the large development costs (some of which prevent drugs neither safe nor effica-cious from being sold and thus provide their own justification)
There is one further pernicious outcome that can be predicted to arise from a ban on natural products patents (including patents on isolated DNA and genetic diagnostic methods based on such isolated DNA) Natural
xxii Foreword
products are almost by nature complex and an ldquoactive principlerdquo isolated from nature is beneficial because it is isolated Kodak ran an advertisement in the journal Nature in the 1970s showing a scientist in a lab coat holding a 250‐ml flask and standing next to several bushels of green peppers wherein the content of the flask was the purified ldquoessence of green pepperrdquo equivalent to that substance contained in all the peppers in all the bushels and bushels that the scientist was standing beside But this very complexity makes it possible for the ldquoactive principlerdquo (either as a chemical compound or as a diagnostic genetic sequence) to be ldquohidden in plain sightrdquo in ways that may be particularly refractory to reverse engineering
For example even using somewhat dated ldquogene chiprdquo technology genetically diagnostic markers could be encrypted onto a microchip comprising 10 000 unique sequences wherein a computer‐readable bar code would be used to identify the positions of diagnostically relevant sequences on the chip This form of encryption which can be random and confounded by the presence of positive and negative control sequences as well as variable numbers and lengths of sequences specific for the gene (or more likely genes) of interest would be very difficult if not impossible to reverse‐engineer Even if reverse engineering could be done it would be difficult and expensive to undertake and thus make it more likely that the innovator would be able to avoid com-petition (ie it would provide unlimited exclusivity to its purveyor not con-strained by patent term or burdened by the requirement that the invention be disclosed with the specificity required by the Patent Act) While the possi-bility that this type of chip could be made exists with or without patents the absence of patent protection could tip the scales in favor of the extra effort needed and risk entailed in nondisclosure if the reward of extended ldquomonopolyrdquo is great enough But particularly for genetic diagnostic inven-tions the benefits of developing a proprietary database for which a corpora-tion could provide the economic and marketing wherewithal to expeditiously produce would result in a ldquoworst of both worldsrdquo outcome unlimited exclu-sivity based on undisclosed proprietary information that not only is difficult to replicate but whose existence would inhibit competition After all if a company had such a database its outcome for any particular patientrsquos test would be more accurate (and might identify disease riskndashassociated genetic variants not available elsewhere) and this would provide little incentive for a physician to choose an alternative provider to perform the test (and even more malevolently could create a system where the wealthy could afford the best diagnostic testing while the less affluent would be restricted to the more
Foreword xxiii
limited assays offered by companies without access to the ldquoinnovatorrsquosrdquo proprietary database information)
The other aspect of foreclosing patents for certain substances or technology areas categorically is that it upsets a carefully crafted dynamic that has worked extremely well during the biotech era between ldquotruerdquo innovators (typically university professors or small start‐up biotechnology companies) and more established companies capable of commercializing innovation Pundits who worry that permitting patenting will harm innovation miss an important point innovation will happen particularly in universities research institutes and like places because human nature demands it and regardless of whether patent protection is available The intelligent ape in us wants to know and the disparity between how univer-sity professors and patent lawyers are paid should establish how powerful the need to know can be Patenting and the impetus for patenting provided for example by the BayhndashDole Act in the United States prevents the fruits of these inventive efforts from mere predation by commercial concerns The benefits that can be had from a system where private commercializa-tion is encouraged are tempered by the types of corporate shenanigans that raise cogent criticisms of the system But perhaps it is mere human nature that people (in the corporate as well as individual sense) will want to expro-priate technology rather than pay for it and patenting prohibits (or at least retards) this outcome (if not these tendencies) Thus paradoxically limiting patent rights does not free innovation but rather makes it more likely to be kept captive by the entities capable of using such innovation to make a commercial product that is not from the power of building a better mouse-trap but by being able to outcompete smaller innovators merely by their greater economic prowess and resources Conversely patents provide a way for the innovators to protect their innovations and compel corporations to license their inventions producing revenue that can be used to fund future research endeavors This useful cycle has resulted in the successes of the biotechnology era and is something that we abandon at our peril
Thus in my view patents are a useful tool for achieving these societally ben-eficial goals promoting innovation and commercialization and protecting and supporting individuals who use the patent system to protect the products of their labors from being expropriated by others David provides a cogent and honest counterpoint to these thoughts Enjoy reading them
Kevin E NoonanChicago Illinois 2014
Who Owns You
Blackwell Public PhilosophyEdited by Michael Boylan Marymount University
In a world of 24‐hour news cycles and increasingly specialized knowledge the Blackwell Public Philosophy series takes seriously the idea that there is a need and demand for engaging and thoughtful discussion of topics of broad public impor-tance Philosophy itself is historically grounded in the public square bringing people together to try to understand the various issues that shape their lives and give them meaning This ldquolove of wisdomrdquomdashthe essence of philosophymdashlies at the heart of the series Written in an accessible jargon‐free manner by internationally renowned authors each book is an invitation to the world beyond newsflashes and sound bites and into public wisdom
1 Permission to Steal Revealing the Roots of Corporate Scandal by Lisa H Newton
2 Doubting Darwin Creationist Designs on Evolution by Sahotra Sarkar
3 The Extinction of Desire A Tale of Enlightenment by Michael Boylan
4 Torture and the Ticking Bomb by Bob Brecher
5 In Defense of Dolphins The New Moral Frontier by Thomas I White
6 Terrorism and Counter‐Terrorism Ethics and Liberal Democracy by Seumas Miller
7 Who Owns You The Corporate Gold Rush to Patent Your Genes by David Koepsell
8 Animalkind What We Owe to Animals by Jean Kazez
9 In the Name of God The Evolutionary Origins of Religious Ethics and Violence by John Teehan
10 The Secular Outlook In Defense of Moral and Political Secularism by Paul Cliteur
11 Freedom of Religion and the Secular State by Russell Blackford
12 As Free and as Just as Possible The Theory of Marxian Liberalism by Jeffrey Reiman
13 Happy‐People‐Pills For All by Mark Walker
14 Life Liberty and the Pursuit of Dao by Sam Crane
15 The Justification of Religious Violence by Steve Clarke
16 Who Owns You Science Innovation and the Gene Patent Wars by David Koepsell
Who Owns You
Science Innovation and the Gene Patent Wars
SECoND EDITIoN
David Koepsell
This second edition first published 2015copy 2015 John Wiley amp Sons Ltd
Edition history John Wiley amp Sons Ltd (1e 2009)
Registered OfficeJohn Wiley amp Sons Ltd The Atrium Southern Gate Chichester West Sussex Po19 8SQ UK
Editorial Offices350 Main Street Malden MA 02148‐5020 USA9600 Garsington Road oxford oX4 2DQ UKThe Atrium Southern Gate Chichester West Sussex Po19 8SQ UK
For details of our global editorial offices for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at wwwwileycomwiley‐blackwell
The right of David Koepsell to be identified as the author of this work has been asserted in accordance with the UK Copyright Designs and Patents Act 1988
All rights reserved No part of this publication may be reproduced stored in a retrieval system or transmitted in any form or by any means electronic mechanical photocopying recording or otherwise except as permitted by the UK Copyright Designs and Patents Act 1988 without the prior permission of the publisher
Wiley also publishes its books in a variety of electronic formats Some content that appears in print may not be available in electronic books
Designations used by companies to distinguish their products are often claimed as trademarks All brand names and product names used in this book are trade names service marks trademarks or registered trademarks of their respective owners The publisher is not associated with any product or vendor mentioned in this book
Limit of LiabilityDisclaimer of Warranty While the publisher and author have used their best efforts in preparing this book they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose It is sold on the understanding that the publisher is not engaged in rendering professional services and neither the publisher nor the author shall be liable for damages arising herefrom If professional advice or other expert assistance is required the services of a competent professional should be sought
Library of Congress Cataloging‐in‐Publication DataKoepsell David R (David Richard) authorWho owns you science innovation and the gene patent wars David Koepsell ndash Second edition p cm Previous edition has subtitle the corporate gold-rush to patent your genes Includes bibliographical references and index ISBN 978-1-118-94850-7 (pbk)I Title [DNLM 1 Genetics Medicalndashlegislation amp jurisprudence 2 Patents as Topicndashlegislation amp jurisprudence 3 ownershipndashethics QZ 324] K1519B54 34604prime86ndashdc23 2014048341A catalogue record for this book is available from the British Library
Cover image copy esenkartal
Set in 10513pt Minion by SPi Publisher Services Pondicherry India
2 2015
To Alexandro
Contents
Acknowledgments viii
Preface to the Second Edition x
Foreword xiv
Introduction xxiv
1 Individual and Collective Rights in Genomic Data Preliminary Issues 1
2 Ethics and Ontology A Brief Discourse on Method 21
3 The Science of Genes 30
4 DNA Species Individuals and Persons 52
5 Legal Dimensions in Gene Ownership 69
6 BRCA1 and 2 The Myriad Case and Beyond 88
7 Are Genes Intellectual Property 101
8 DNA and The Commons 119
9 Pragmatic Considerations of Gene Ownership 137
10 Nature Genes and the Scientific Commons A Social Ontology of Invention 155
11 So Who Owns You Some Conclusions About Genes Property and Personhood 165
Notes 182
Index 194
Acknowledgments
Many thanks must be given to those whom I have spoken to about the issues discussed herein since the first edition and who helped inform the updates including Tania Simoncelli Luigi Palombi Joanna Rudnick Dan Ravicher Kevin Noonan James Watson and numerous online commenters who helped point out errors and hone my arguments Thank you also to my colleagues at Delft University of Technology where I have worked the past 6 years and continued discussing and sharpening my approach to the ideas in this book and others
I remain grateful to the Yale Interdisciplinary Bioethics Center for appointing me as their Donaghue Initiative Fellow in Research Ethics 2006ndash2007 I drafted a significant portion of this book during that appoint-ment and had the chance to hash out many of these issues with the staff affiliated faculty and others who participated in events that year Special thanks to all the good people at Yale including especially Robert Levine Julius Landwirth Carol Pollard Autumn Ridenour and Jonathan Moser Thanks also to the folks at the New Haven dog park for keeping my dear departed Buttercup and me company during my residency at Yale Many thanks to my wife Vanessa who gave me significant scientific guidance and lots of encouragement as I worked out these issues and drafted the original book and who helped redraft Chapter 3 for this edition Thanks to my 3‐year‐old daughter Amelia whose appearance brought new purpose to my life and my work My parents Eva Hwa and Richard Koepsell provided commentary and feedback on early drafts of chapters and I am as always grateful for their continuing encouragement My dear friend Peter Hare who passed away in 2008 also kept me company bought me lunches and encouraged my work while at Yale hellip I am grateful for his guidance and friendship and will miss him dearly Thanks to Barry Smith who has remained a helpful and encouraging mentor as I pursue the sometimes
Acknowledgments ix
frustrating but often fruitful path of philosophy Thank you also to Denise Riley who helped dig up obscure articles and arranged almost all the research for my initial trip to Yale that hatched the first edition Finally many thanks to anyone I have forgotten including all those who have given me probing questions puzzling scenarios and further guidance in the talks I have given on this fascinating subject over the past 8 years
David KoepsellAugust 14 2014
Mexico City Mexico
Preface to the Second Edition
A lot has happened in nearly every respect since I first decided to try to delve into philosophical issues of gene patenting nearly a decade ago I have learned much the world has changed and I have changed I would very much like to think I have played a role in that change though chances are things would have changed in almost exactly the same way without my small contribution When the first edition came out patenting genes was still a regular part of biotech and only months after the first edition appeared did a surprising and now‐landmark lawsuit alter that significantly Little did I realize the nature of the forces that would be involved in what I had originally assumed was no more than an academic exercise but which became a matter of weighty and heated public debate and finally judicial action
I first became interested in the subject of gene patents when I began reading up on the topic my future wife was researching pharmacogenom-ics To grasp what she did I first needed to study the science and in so doing I also studied the history of that science Along the way I read about the Human Genome Project and learned about the practice of gene patenting that it spawned Having had some experience and interest in general issues of the philosophy of intellectual property (see my 1997 PhD thesis turned 2000 book The Ontology of Cyberspace) my ears perked up when I first read about the notion of patenting genes So I dived into the research and thinking in my ordinary style of philosophical work Although I sometimes teach ethics my primary field is ontology and it is from an ontological approach that I start with everything in philosophy Thus I began to try to get a grip on the nature of the existence of the underlying objects some of which are ldquobrute factsrdquo (molecules exist with or without social institutions or intentionality) and some of which are social objects (like laws rights and other parts of ldquosocial realityrdquo existing only because of
Preface to the Second Edition xi
collective intentionality) The book was an attempt to lay all this out and to connect it together into a theory that is somehow connected to notions of ldquojusticerdquo which I argued bridges the worlds of brute facts and social objects
The conclusions I reached were I thought pretty neat Specifically I worked out an ontology of ldquothe commonsrdquo that I had never heard expressed before and one that connected nicely with the objects involved to show why artifacts and nature ought to be treated differently and how to decide what constitutes an artifact and what constitutes nature and a defense of the viewpoint that unmodified genes were clearly not artifacts It seemed all the more relevant and interesting even perhaps somewhat important in light of the then ongoing practice of gene patenting I was much too focused on the ontological arguments and their seeming relevance to real‐world practices than I was to the scientific and legal terminology with which I was engaging and this was an error When the book was released minor errors I made in using technical terminology from both the science and the law were latched onto by a couple critical reviewers from the Intellectual Property law and teaching worlds and urged as a basis to ignore my substantive arguments They were right to call out the errors and I have attempted to correct them in this edition Regardless the underlying argu-ments I had set forth would become shortly echoed nearly precisely in the lawsuit that the American Civil Liberties Union (ACLU) spearheaded against Myriad Corp over the BRCA1amp2 gene patents
For a brief period of time partly due to lucky timing I was thrust head-long into the public debates about gene patenting with the Myriad case leading the headlines Given numerous opportunities to engage publicly with the issues and ideas I had previously assumed were only academic musings unlikely to alter public policy and given feedback and counterar-guments in those same venues the general arguments could be more finely honed This edition attempts to coalesce them
Perhaps more importantly in the intervening years since I began my musings about the nature of genes artifacts nature and patents I came to learn the very personal impact that gene patents have on peoplersquos lives Because the ACLU chose to sue over the patents on BRCA1amp2 genes there was a ready‐made large and passionate community (mostly women) whose heredity put them at risk of breast and ovarian cancers but who were basically forced into paying monopolistic prices for the only test available for the gene which was patented by Myriad Corp Breast cancer and the threat of inherited tendencies for breast cancer are real They are not legal
xii Preface to the Second Edition
sophistry they are not philosophical musing They kill people or alter their lives irrevocably
I began researching and considering the effects of gene patents believing they were potentially a threat to the conduct of science whose foundational objects I argued were part of a commons‐by‐necessity but I realized after my book came out that real lives were being harmed by patents on genes The Myriad case brought together the theoretical with the actual for me and the dynamics of both the case and the loud and sometimes angry public debate raised my awareness not only about this particular subject but also the power and responsibility of academic research in the sphere of public policy Suddenly ideas seemed more important had relevance outside the academy and could perhaps make a difference in peoplesrsquo lives I began to interact with the activists who were fighting to liberate genes to stop com-panies like Myriad in the courts and engage not just in the philosophical arguments but in those fights I joined with authors of amicus (friend of the court) briefs interviewed and interacted with BRCA1amp2 mutation‐positive women who were actively pursuing an end to a practice that I had only pre-viously considered to be an interesting metaphysical conundrum I also debated Intellectual Property (IP) attorneys and others primarily with backgrounds in biotech industries and learning better the nature of their arguments I came to understand that most of them including Kevin Noonan who once called me a ldquoliarrdquo on his blog but who has now drafted the foreword to this edition that they too generally have the best intentions Many like Dr Noonan truly expect that without gene patents as they existed until recently the sort of innovation we need in biomedical technol-ogies would not occur as it should
Throughout the course of the litigation in Myriad I remained engaged continued to speak to hone my arguments adding to my list of criteria for something to be a creation (artifact) capable of patent ldquodesignrdquo (as well as intention and being man‐made) and finally rejoicing when the decision of the Supreme Court came out as close to what I believed and argued was right as possible I had seen an academic idea mature and bloom into public policy real law enforceable justice While I realistically believe that the first edition of this book had only a very minor role in what finally happened I am proud to have played some part to have foreseen the issues to argue them honestly from what I think is a rational and logical standpoint and see that the world can be changed by ideas
Preface to the Second Edition xiii
There remain issues to discuss and not everything about gene patents has been resolved by Myriad Some still argue that cDNA ought not to be patent‐eligible (in fact I still think it should be under the criteria I have set forth though there are also arguments to be made that it is not somehow ldquodesignedrdquo by man) Moreover we should expect patent attorneys to do their creative best to continue to pursue patents on as much of the genome as they can within the constraints of Myriad Finally Myriad Corp has not given up They are still suing potential competitors under theories of infringement of parts of their patents that might have survived the ACLUrsquos case against them We shall see how they are eventually resolved and what the future holds for companies like theirs who profited mightily from gene patents for decades I describe as much of this recent legal history as possible in this edition
This book is meant to be a definitive version sewing up the past five years since the first edition emerged and so much changed in the world summa-rizing that recent history and refining the arguments I originally made correcting errors and describing where we are where we yet may be and why gene patents as they once were ought never to be again
David KoepsellAugust 14 2014
Mexico City Mexico
Foreword
David and I have had a friendly disagreement about the subject (and even the title) of this book ever since it was first published and I am happy that he asked me to write this Foreword to the Second Edition The issues David raises in the pages to follow continue to be relevant to a discussion of philosophy and patent law with events that have occurred since the first edition justifying (indeed demanding) this update
Without getting into the deep waters of philosophy (Davidrsquos meacutetier not mine) as we have discussed the issues in the book David contends that he takes a deontological approach and has characterized mine as a utilitarian one Accepting that dichotomy I understand the difference to be that David is operating from ldquofirst principlesrdquo about the rules society should impose on human activity and specifically on what the law permits individuals to ldquoownrdquo with regard to genes and more broadly naturally occurring substances I disagree with that approach on several levels perhaps the most germane of which is that if we posit rules we need to impose a rule‐giver and the potential for improvident rules (if not outright abuse of the privilege) makes me wary in some ways I subscribe to Lani Gruinierrsquos suspicions about the effects of the ldquotyranny of the majorityrdquo in this regard
Part of that tyranny is also the tyranny of unintended or intentional ignorance The issue heremdashldquogenerdquo patentingmdashis one at the intersection of molecular biology and modern genetics on the one hand and patent law (an area notorious for its arcane minutiae) I used to joke with my col-leagues about the effect of trying to explain my position to a lay audience of any type and how I distrusted those who advocated that all that was needed was to ldquoeducaterdquo the public the press and policy makers The problem for proponents of gene patenting has been that opponents have gotten the better part of the debate not by making a reasoned philosophical argument such as the one you will find in these pages but instead by making an
Foreword xv
emotional plea to individuals afraid that corporate America was trying to ldquostealrdquo their genes which has proven very effective This process began with an Op‐Ed piece in The New York Times by Michael Crichton wherein he posited a scenario where a patent holder knocks on your door one day and demands payment for the use of ldquoherrdquo patented gene that resides in your liver (Not coincidentally Dr Crichton had just published a novel on the perils of genetic engineering and corporate ownership of human genes complete with an essay as an addendum containing his arguments against the practice And it should be noted that a constant theme in his novels was a mistrust of technology and particularly the ability of humans to use it without dire consequences) Academics like my friend Lori Andrews at Illinois Institute of Technology (IIT)‐Kent School of Law joined in this theme which was picked up eventually by most popular press outlets and became regrettably the canonical narrative on gene patenting culminating in the American Civil Liberties Unionrsquos (ACLUrsquos) ldquoKeep Your Hands Off My Genesrdquo slogan and logo I hope that this essay provides some antidote to this argument which is founded on the literal fear that someone can ldquoownrdquo you (David assures me that his title is allegorical and that he acknowledges that in all countries that have banned slavery no one can ldquoownrdquo another human being or a part of them See the 13th Amendment I assure you that the ACLU has no such illusions about the intended consequences of their ownership rhetoric)
My philosophy is that the principle we should follow is the greatest good to the greatest number while not infringing on individual rights without (at least) compensation As regards patent law this principle is translated into rules that foster the broadest disclosure of technology possible in return for exclusive patent rights and robust‐enough enforcement rights for patents that they provide sufficient certainty to promote investment so his technology is commercialized to benefit the greatest number In my role as a biotechnology patent attorney I have seen how risky investment in biotechnology can be (indeed the evidence is overwhelming that for all its successes biotechrsquos history is littered with the remains of companies that have failed) and how important it is to have a sound patent system of predictable rights go support that investment
The evidence in support of ldquogene patentingrdquo and more broadly natural products patenting is strong the biotechnology industry has promoted innovation in the form of new drugs and diagnostics assays for a genera-tion This may continue despite the recent restrictions on patent protection
xvi Foreword
for genes and natural products (including patent‐restricting decisions in Mayo Collaborative Labs v Prometheus Labs and Assoc of Molecular Pathologists v Myriad Genetics and recently promulgated US Patent and Trademark Office Guidances on Subject Matter Eligibility) In fact these very restrictions suggest that we would benefit from an appreciation of the facts surrounding the past thirty years of gene patenting to understand why these restrictions are not only wrongheaded but dangerous for future innovation
These include debunking several myths First the concern that patents on specific human genes in some way inhibit innovation in basic genetic research is entirely unfounded One reason is that the genetic information itself is not patented while isolated DNA is encompassed by gene patent claims and described in those claims by its sequence the sequence itself is unpatented information that can be used freely for any purpose (eg inter-rogating genetic databases from other species or even human DNA inter alia to find related genes in those databases) Indeed the innovative benefits to gene patenting are evident in at least two ways First scientific publication databases reveal that there have been more than 11 000 scientific papers published on the BRCA1 and BRCA2 genes since the patents claiming them were granted This outcome refutes the prediction that gene patenting would create a ldquotragedy of the anticommonsrdquo where scientific research would be stifled by patenting (see Heller amp Eisenberg 1998 ldquoCan Patents Deter Innovation The Anticommons in Biomedical Researchrdquo Science 280 698ndash701)) a conclusion supported by the overwhelming majority of studies done on this subject (see for example Walsh et al 2003 ldquoScience and the Law Working Through the Patent Problemrdquo Science 299 1020 Walsh et al 2005 ldquoScience and Law View from the Bench Patents and Material Transfersrdquo Science 309 2002ndash03)
In addition policies that the US Patent and Trademark Office adopted in 2001 required applicants to disclose a practical utility for the product of a gene claimed in a patent These requirements were imposed at a time when the standards for scientific journal publication were much less stringent so that identifying a gene by the extent of genetic similarity between the ldquonewrdquo gene and previously discovered genes was enough for publication But it was not enough for a patent which has been held to be ldquonot a hunting license It is not a reward for the search but compensation for its successful conclusionrdquo Thus genes encoding proteins having no known use or biological activity cannot be patented because to do so would allow the
Foreword xvii
gene to be within the exclusive patent right undeservedly the public would not have received its quid pro quo of a useful invention in return for patent exclusivity All such genes not having patent protection are in the public domain (from which they cannot be retrieved for future patenting) and for humans these constitute the vast majority of genes identified inter alia by the Human Genome Project
The role for patenting genes and the related genetic diagnostic methods using this genetic information in the successes of the biotechnology era are evident The industry has produced hundreds of biologic drugs (at an ever‐increasing rate) that have provided effective treatment for a variety of illnesses and decoding the human genome has enabled researchers to iden-tify genes like the BRCA1 and BRCA2 genes that can be used in predictive genetic diagnostic tests Even the much‐maligned Myriad Genetics has played a positive role in the development and prevalence of genetic diagnostic testing It must be remembered that in 1997 (when Myriadrsquos BRCA gene patents were granted) genetic testing was in its infancy and companies like Myriad were under the burden of convincing payers that the tests did the one thing that all insurers public or private require of such tests save them money in the long run by identifying patients with a high probability of becoming ill and costing the insurers much more for treatment than the costs of prophylaxis Moreover Myriad and like com-panies needed to convince doctors that the testing was worthwhile and to establish a network of genetic counselors who could explain to healthy women that they were at much greater risk of developing breast or ovarian cancer than normal under circumstances that resulted in empowerment from the information and not abject fear And in 1997 genetic sequencing technology was not as developed as it is now and the mechanisms and tech-niques needed to minimize or eliminate the occurrence of false positives or negatives had not been conclusively established All these burdens were ones borne by Myriad and these activities produced the world we have today
It is possible as some have argued that BRCA tests may have been devel-oped independently by individual researchers in the absence of patent pro-tection However it is almost certain that such researchers would have been located in medical centers in urban environments Under these circum-stances women living in or near cities such as New York Boston Philadelphia Cleveland Chicago Houston Denver Los Angeles San Francisco Portland and Seattle might have had access to these tests But what of women in
xviii Foreword
Appalachia or the Four Corners region in the Southwest or more generally in rural or other relatively remote locations Would Yale University for example have had any incentive to provide access to the BRCA tests to these women in these far‐off locations Or to provide genetic counseling where the women lived Or to lobby state Medicare administrators or private insurance commissioners to cover the test I think that unlikely Myriad Genetics did all of this as well as perform outreach to the obstetrics and gynecology doctors throughout the United States so that these primary care doctors were aware of the tests Myriad did not ace from altruism but as part of their business plan in order to expand the number of patients who received the test and thus maximize the companyrsquos revenue While it may be counterintuitive to some these circumstances may have been the most effective way not only to pro-mulgate the BRCA tests but also to facilitate acceptance of genetic diagnostic testing for other diseases showing that in this instance Adam Smith rather than Karl Marx provided the most practical solution to the problem of estab-lishing genetic diagnostic testing as a recognized component of a physicianrsquos diagnostic armamentarium
Fortunately the significance and impact of recent US court decisions (spe-cifically the Myriad case) is much less than it would have been ten to thirty years ago Due to patent term rules most patents (and applications) on iso-lated DNA filed in the heyday of the Human Genome Project (approxi-mately 1998ndash2001) are near the end of their actual or potential term indeed a recent study shows that the number of granted patents having at least one claim reciting an isolate DNA comprising a gene peaked in 1999 and has been dropping since 2005 (Graff et al 2013 ldquoNot quite a myriad of gene pat-entsrdquo Nature Biotechnology 31 404ndash410)) These recent decisions in the United States have not harmed the biotechnology industry because they retained patent eligibility for species of DNA that show evidence of the ldquohand of manrdquo and do not occur in nature These include enzymatically pro-duced copies (cDNA) of cellular messenger RNA and should also encom-pass the tools of the recombinant geneticist (eg including recombinant vectors for cloning and expressing genes in heterologous cells) Most impor-tantly the US Supreme Court did not overturn its Diamond v Chakrabarty decision wherein recombinant cells were determined to be patent eligible
Thus in many ways the question of patent eligibility for human genes is a philosophical one However that does not mean that how we think about patent eligibility for isolated DNA is irrelevant to important questions regarding the usefulness of patents for promoting progress and innovation
Foreword xix
Indeed the most pernicious effects of the current trend in the zeitgeist against patenting has been not that genes have become harder to patent but rather that the ability to patent other natural products has been called into question It is the extension of these recent decisions on isolated DNA to all natural products that poses the greatest threat to innovation This threat can be illustrated by a thought experiment for which of these substances should patent protection be withheld
bull A petrochemical with excellent lubrication qualities isolated in pure form and used as improved motor oil
bull Vitamin B12 isolated from beef muscle formulated into a medicament used to cure anemia in children
bull The drug penicillin isolated from a mixture of naturally produced chemicals made by a mold and formulated as a drug to cure syphilis (which is otherwise eventually fatal)
bull Human urinary erythropoietin formulated to treat anemia in kidney dialysis patients
bull The gene responsible for Gaucherrsquos disease a lipid storage disease wherein the gene is used to make the missing protein that is administered to children and that cures an otherwise incurable and fatal disease
The current answer is that none of them are patent‐eligible per se (although there may be ways to claim them that could pass eligibility muster that remains to be seen) Judge Sweet the US District Court judge who first ruled that isolated DNA was not patent‐eligible did so using language carefully crafted to avoid encompassing all natural products into his decision Specifically Judge Sweet distinguished isolated DNA as the ldquophysical embodiments of genetic informationrdquo a property limited to DNA and not shared by other natural products (While an enzymatic protein could be characterized as the physical embodiment of catalysis of a particular chemical reaction that formulation has much less appeal and inherent rationale than Judge Sweetrsquos regarding DNA) Instead of this careful formu-lation the broader language employed by the Supreme Court as well as the broader rationale the Court used in finding genomic DNA unpatentable has made it easier to employ that fractured logic to render patent‐ineligible naturally occurring molecules other than DNA
I would be remiss not to mention the rather comical (but persistent) efforts of former Acting Solicitor General Neal Katyal who included in the
xx Foreword
US Governmentrsquos amicus brief to the Federal Circuit the distinction engine he called a ldquomagic microscoperdquo embodying the concept that if you are able to visualize a natural product (like a genomic DNA molecule) using this mythical microscope then the natural product would not be patent‐eligible whereas if you could not (eg a cDNA molecule) then the natural product could be eligible for patenting Fortunately the disdain with which the Federal Circuit greeted this fantasy (particularly from Judge Moore) prompted its quick abandonment as are argumentative distinction as the case moved forward Nonetheless both the courts and the US Patent and Trademark Office have adopted this standard de facto even as it becomes the theory that dare not speak its name in legal circles
The philosophical point here is that these substances and natural products generally have been deemed patent‐ineligible categorically which while consistent with (and perhaps even mandated by) the deon-tological approach imposes a distinction that cannot be flexibly applied to the individual circumstances Without such flexibility the law is con-strained to use one criterion that the substance can be found in some form in nature to decide patent eligibility instead of making the deter-mination of whether permitting patenting exclusivity satisfies the cri-teria that the invention ldquopromotes progressrdquo as the US Constitution requires and has a benefit to the public that outweighs any categorical disabilities
The potential that using this standard for determining patent eligibility will result in negative practical outcomes that no one in this debate desires is illustrated by a 2012 Report from the National Institutes of Health Natural Product Branch regarding statistics relating to the number of FDA approvals (a total of 1355) for new drugs falling into the following categories
Drug typesource Number
Biological (B) 203Natural product (N) 55Natural product (botanical) (NB) 149Derived from a natural product (ND) 298Totally synthetic (S) 393Total synthesisnatural product (S) 176Vaccine (S) 81
Foreword xxi
These statistics illustrate the consequences of a general ban on patenting naturally derived products of the 1355 drugs approved between 1981 and 2010
bull Fifty percent of all small‐molecule drugs approved between 2000 and 2010 are natural products
bull About 75 of antibacterial drugs are natural products or derived from natural products
bull Almost 80 of small‐molecule anticancer drugs were natural products or derivatives
In addition only 15 of drugs approved during this time frame were so‐called biologic drugs which are also putatively patent‐ineligible This the problems caused by the current interpretation of the law excluding natural product drugs from patent eligibility will be exacerbated in view of reports from every study showing that the percentage of drugs that are biologic drugs has been growing and will be the predominant type of drug devel-oped in the 2011ndash2030 time period
Another ldquothought experimentrdquo illustrating the practical illogic (David can provide his philosophical justifications in the body of the text) of broad natural products patent ineligibility is as follows Suppose a researcher finds a molecule produced by the human body that causes blood pressure homeo-stasis that is lack of this molecule causes or contributes to the disease of high blood pressure The logical consequence of the current natural prod-uct patent ineligibility standards would be that the closer a drug molecule is to the structure of the molecule as it occurs in the body the less patent‐eli-gible it would be Practically speaking there would be no incentive to modify the molecule to confer patent eligibility on the altered molecule because of the unpredictability of such changes on the molecule such as its biological activity half‐life stability antigenicity or other biological prop-erties And there would be even less incentive to develop the molecule as a drug because without patent protection the available regulatory exclusiv-ities would not pass economic muster to sufficiently defray the large development costs (some of which prevent drugs neither safe nor effica-cious from being sold and thus provide their own justification)
There is one further pernicious outcome that can be predicted to arise from a ban on natural products patents (including patents on isolated DNA and genetic diagnostic methods based on such isolated DNA) Natural
xxii Foreword
products are almost by nature complex and an ldquoactive principlerdquo isolated from nature is beneficial because it is isolated Kodak ran an advertisement in the journal Nature in the 1970s showing a scientist in a lab coat holding a 250‐ml flask and standing next to several bushels of green peppers wherein the content of the flask was the purified ldquoessence of green pepperrdquo equivalent to that substance contained in all the peppers in all the bushels and bushels that the scientist was standing beside But this very complexity makes it possible for the ldquoactive principlerdquo (either as a chemical compound or as a diagnostic genetic sequence) to be ldquohidden in plain sightrdquo in ways that may be particularly refractory to reverse engineering
For example even using somewhat dated ldquogene chiprdquo technology genetically diagnostic markers could be encrypted onto a microchip comprising 10 000 unique sequences wherein a computer‐readable bar code would be used to identify the positions of diagnostically relevant sequences on the chip This form of encryption which can be random and confounded by the presence of positive and negative control sequences as well as variable numbers and lengths of sequences specific for the gene (or more likely genes) of interest would be very difficult if not impossible to reverse‐engineer Even if reverse engineering could be done it would be difficult and expensive to undertake and thus make it more likely that the innovator would be able to avoid com-petition (ie it would provide unlimited exclusivity to its purveyor not con-strained by patent term or burdened by the requirement that the invention be disclosed with the specificity required by the Patent Act) While the possi-bility that this type of chip could be made exists with or without patents the absence of patent protection could tip the scales in favor of the extra effort needed and risk entailed in nondisclosure if the reward of extended ldquomonopolyrdquo is great enough But particularly for genetic diagnostic inven-tions the benefits of developing a proprietary database for which a corpora-tion could provide the economic and marketing wherewithal to expeditiously produce would result in a ldquoworst of both worldsrdquo outcome unlimited exclu-sivity based on undisclosed proprietary information that not only is difficult to replicate but whose existence would inhibit competition After all if a company had such a database its outcome for any particular patientrsquos test would be more accurate (and might identify disease riskndashassociated genetic variants not available elsewhere) and this would provide little incentive for a physician to choose an alternative provider to perform the test (and even more malevolently could create a system where the wealthy could afford the best diagnostic testing while the less affluent would be restricted to the more
Foreword xxiii
limited assays offered by companies without access to the ldquoinnovatorrsquosrdquo proprietary database information)
The other aspect of foreclosing patents for certain substances or technology areas categorically is that it upsets a carefully crafted dynamic that has worked extremely well during the biotech era between ldquotruerdquo innovators (typically university professors or small start‐up biotechnology companies) and more established companies capable of commercializing innovation Pundits who worry that permitting patenting will harm innovation miss an important point innovation will happen particularly in universities research institutes and like places because human nature demands it and regardless of whether patent protection is available The intelligent ape in us wants to know and the disparity between how univer-sity professors and patent lawyers are paid should establish how powerful the need to know can be Patenting and the impetus for patenting provided for example by the BayhndashDole Act in the United States prevents the fruits of these inventive efforts from mere predation by commercial concerns The benefits that can be had from a system where private commercializa-tion is encouraged are tempered by the types of corporate shenanigans that raise cogent criticisms of the system But perhaps it is mere human nature that people (in the corporate as well as individual sense) will want to expro-priate technology rather than pay for it and patenting prohibits (or at least retards) this outcome (if not these tendencies) Thus paradoxically limiting patent rights does not free innovation but rather makes it more likely to be kept captive by the entities capable of using such innovation to make a commercial product that is not from the power of building a better mouse-trap but by being able to outcompete smaller innovators merely by their greater economic prowess and resources Conversely patents provide a way for the innovators to protect their innovations and compel corporations to license their inventions producing revenue that can be used to fund future research endeavors This useful cycle has resulted in the successes of the biotechnology era and is something that we abandon at our peril
Thus in my view patents are a useful tool for achieving these societally ben-eficial goals promoting innovation and commercialization and protecting and supporting individuals who use the patent system to protect the products of their labors from being expropriated by others David provides a cogent and honest counterpoint to these thoughts Enjoy reading them
Kevin E NoonanChicago Illinois 2014
Blackwell Public PhilosophyEdited by Michael Boylan Marymount University
In a world of 24‐hour news cycles and increasingly specialized knowledge the Blackwell Public Philosophy series takes seriously the idea that there is a need and demand for engaging and thoughtful discussion of topics of broad public impor-tance Philosophy itself is historically grounded in the public square bringing people together to try to understand the various issues that shape their lives and give them meaning This ldquolove of wisdomrdquomdashthe essence of philosophymdashlies at the heart of the series Written in an accessible jargon‐free manner by internationally renowned authors each book is an invitation to the world beyond newsflashes and sound bites and into public wisdom
1 Permission to Steal Revealing the Roots of Corporate Scandal by Lisa H Newton
2 Doubting Darwin Creationist Designs on Evolution by Sahotra Sarkar
3 The Extinction of Desire A Tale of Enlightenment by Michael Boylan
4 Torture and the Ticking Bomb by Bob Brecher
5 In Defense of Dolphins The New Moral Frontier by Thomas I White
6 Terrorism and Counter‐Terrorism Ethics and Liberal Democracy by Seumas Miller
7 Who Owns You The Corporate Gold Rush to Patent Your Genes by David Koepsell
8 Animalkind What We Owe to Animals by Jean Kazez
9 In the Name of God The Evolutionary Origins of Religious Ethics and Violence by John Teehan
10 The Secular Outlook In Defense of Moral and Political Secularism by Paul Cliteur
11 Freedom of Religion and the Secular State by Russell Blackford
12 As Free and as Just as Possible The Theory of Marxian Liberalism by Jeffrey Reiman
13 Happy‐People‐Pills For All by Mark Walker
14 Life Liberty and the Pursuit of Dao by Sam Crane
15 The Justification of Religious Violence by Steve Clarke
16 Who Owns You Science Innovation and the Gene Patent Wars by David Koepsell
Who Owns You
Science Innovation and the Gene Patent Wars
SECoND EDITIoN
David Koepsell
This second edition first published 2015copy 2015 John Wiley amp Sons Ltd
Edition history John Wiley amp Sons Ltd (1e 2009)
Registered OfficeJohn Wiley amp Sons Ltd The Atrium Southern Gate Chichester West Sussex Po19 8SQ UK
Editorial Offices350 Main Street Malden MA 02148‐5020 USA9600 Garsington Road oxford oX4 2DQ UKThe Atrium Southern Gate Chichester West Sussex Po19 8SQ UK
For details of our global editorial offices for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at wwwwileycomwiley‐blackwell
The right of David Koepsell to be identified as the author of this work has been asserted in accordance with the UK Copyright Designs and Patents Act 1988
All rights reserved No part of this publication may be reproduced stored in a retrieval system or transmitted in any form or by any means electronic mechanical photocopying recording or otherwise except as permitted by the UK Copyright Designs and Patents Act 1988 without the prior permission of the publisher
Wiley also publishes its books in a variety of electronic formats Some content that appears in print may not be available in electronic books
Designations used by companies to distinguish their products are often claimed as trademarks All brand names and product names used in this book are trade names service marks trademarks or registered trademarks of their respective owners The publisher is not associated with any product or vendor mentioned in this book
Limit of LiabilityDisclaimer of Warranty While the publisher and author have used their best efforts in preparing this book they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose It is sold on the understanding that the publisher is not engaged in rendering professional services and neither the publisher nor the author shall be liable for damages arising herefrom If professional advice or other expert assistance is required the services of a competent professional should be sought
Library of Congress Cataloging‐in‐Publication DataKoepsell David R (David Richard) authorWho owns you science innovation and the gene patent wars David Koepsell ndash Second edition p cm Previous edition has subtitle the corporate gold-rush to patent your genes Includes bibliographical references and index ISBN 978-1-118-94850-7 (pbk)I Title [DNLM 1 Genetics Medicalndashlegislation amp jurisprudence 2 Patents as Topicndashlegislation amp jurisprudence 3 ownershipndashethics QZ 324] K1519B54 34604prime86ndashdc23 2014048341A catalogue record for this book is available from the British Library
Cover image copy esenkartal
Set in 10513pt Minion by SPi Publisher Services Pondicherry India
2 2015
To Alexandro
Contents
Acknowledgments viii
Preface to the Second Edition x
Foreword xiv
Introduction xxiv
1 Individual and Collective Rights in Genomic Data Preliminary Issues 1
2 Ethics and Ontology A Brief Discourse on Method 21
3 The Science of Genes 30
4 DNA Species Individuals and Persons 52
5 Legal Dimensions in Gene Ownership 69
6 BRCA1 and 2 The Myriad Case and Beyond 88
7 Are Genes Intellectual Property 101
8 DNA and The Commons 119
9 Pragmatic Considerations of Gene Ownership 137
10 Nature Genes and the Scientific Commons A Social Ontology of Invention 155
11 So Who Owns You Some Conclusions About Genes Property and Personhood 165
Notes 182
Index 194
Acknowledgments
Many thanks must be given to those whom I have spoken to about the issues discussed herein since the first edition and who helped inform the updates including Tania Simoncelli Luigi Palombi Joanna Rudnick Dan Ravicher Kevin Noonan James Watson and numerous online commenters who helped point out errors and hone my arguments Thank you also to my colleagues at Delft University of Technology where I have worked the past 6 years and continued discussing and sharpening my approach to the ideas in this book and others
I remain grateful to the Yale Interdisciplinary Bioethics Center for appointing me as their Donaghue Initiative Fellow in Research Ethics 2006ndash2007 I drafted a significant portion of this book during that appoint-ment and had the chance to hash out many of these issues with the staff affiliated faculty and others who participated in events that year Special thanks to all the good people at Yale including especially Robert Levine Julius Landwirth Carol Pollard Autumn Ridenour and Jonathan Moser Thanks also to the folks at the New Haven dog park for keeping my dear departed Buttercup and me company during my residency at Yale Many thanks to my wife Vanessa who gave me significant scientific guidance and lots of encouragement as I worked out these issues and drafted the original book and who helped redraft Chapter 3 for this edition Thanks to my 3‐year‐old daughter Amelia whose appearance brought new purpose to my life and my work My parents Eva Hwa and Richard Koepsell provided commentary and feedback on early drafts of chapters and I am as always grateful for their continuing encouragement My dear friend Peter Hare who passed away in 2008 also kept me company bought me lunches and encouraged my work while at Yale hellip I am grateful for his guidance and friendship and will miss him dearly Thanks to Barry Smith who has remained a helpful and encouraging mentor as I pursue the sometimes
Acknowledgments ix
frustrating but often fruitful path of philosophy Thank you also to Denise Riley who helped dig up obscure articles and arranged almost all the research for my initial trip to Yale that hatched the first edition Finally many thanks to anyone I have forgotten including all those who have given me probing questions puzzling scenarios and further guidance in the talks I have given on this fascinating subject over the past 8 years
David KoepsellAugust 14 2014
Mexico City Mexico
Preface to the Second Edition
A lot has happened in nearly every respect since I first decided to try to delve into philosophical issues of gene patenting nearly a decade ago I have learned much the world has changed and I have changed I would very much like to think I have played a role in that change though chances are things would have changed in almost exactly the same way without my small contribution When the first edition came out patenting genes was still a regular part of biotech and only months after the first edition appeared did a surprising and now‐landmark lawsuit alter that significantly Little did I realize the nature of the forces that would be involved in what I had originally assumed was no more than an academic exercise but which became a matter of weighty and heated public debate and finally judicial action
I first became interested in the subject of gene patents when I began reading up on the topic my future wife was researching pharmacogenom-ics To grasp what she did I first needed to study the science and in so doing I also studied the history of that science Along the way I read about the Human Genome Project and learned about the practice of gene patenting that it spawned Having had some experience and interest in general issues of the philosophy of intellectual property (see my 1997 PhD thesis turned 2000 book The Ontology of Cyberspace) my ears perked up when I first read about the notion of patenting genes So I dived into the research and thinking in my ordinary style of philosophical work Although I sometimes teach ethics my primary field is ontology and it is from an ontological approach that I start with everything in philosophy Thus I began to try to get a grip on the nature of the existence of the underlying objects some of which are ldquobrute factsrdquo (molecules exist with or without social institutions or intentionality) and some of which are social objects (like laws rights and other parts of ldquosocial realityrdquo existing only because of
Preface to the Second Edition xi
collective intentionality) The book was an attempt to lay all this out and to connect it together into a theory that is somehow connected to notions of ldquojusticerdquo which I argued bridges the worlds of brute facts and social objects
The conclusions I reached were I thought pretty neat Specifically I worked out an ontology of ldquothe commonsrdquo that I had never heard expressed before and one that connected nicely with the objects involved to show why artifacts and nature ought to be treated differently and how to decide what constitutes an artifact and what constitutes nature and a defense of the viewpoint that unmodified genes were clearly not artifacts It seemed all the more relevant and interesting even perhaps somewhat important in light of the then ongoing practice of gene patenting I was much too focused on the ontological arguments and their seeming relevance to real‐world practices than I was to the scientific and legal terminology with which I was engaging and this was an error When the book was released minor errors I made in using technical terminology from both the science and the law were latched onto by a couple critical reviewers from the Intellectual Property law and teaching worlds and urged as a basis to ignore my substantive arguments They were right to call out the errors and I have attempted to correct them in this edition Regardless the underlying argu-ments I had set forth would become shortly echoed nearly precisely in the lawsuit that the American Civil Liberties Union (ACLU) spearheaded against Myriad Corp over the BRCA1amp2 gene patents
For a brief period of time partly due to lucky timing I was thrust head-long into the public debates about gene patenting with the Myriad case leading the headlines Given numerous opportunities to engage publicly with the issues and ideas I had previously assumed were only academic musings unlikely to alter public policy and given feedback and counterar-guments in those same venues the general arguments could be more finely honed This edition attempts to coalesce them
Perhaps more importantly in the intervening years since I began my musings about the nature of genes artifacts nature and patents I came to learn the very personal impact that gene patents have on peoplersquos lives Because the ACLU chose to sue over the patents on BRCA1amp2 genes there was a ready‐made large and passionate community (mostly women) whose heredity put them at risk of breast and ovarian cancers but who were basically forced into paying monopolistic prices for the only test available for the gene which was patented by Myriad Corp Breast cancer and the threat of inherited tendencies for breast cancer are real They are not legal
xii Preface to the Second Edition
sophistry they are not philosophical musing They kill people or alter their lives irrevocably
I began researching and considering the effects of gene patents believing they were potentially a threat to the conduct of science whose foundational objects I argued were part of a commons‐by‐necessity but I realized after my book came out that real lives were being harmed by patents on genes The Myriad case brought together the theoretical with the actual for me and the dynamics of both the case and the loud and sometimes angry public debate raised my awareness not only about this particular subject but also the power and responsibility of academic research in the sphere of public policy Suddenly ideas seemed more important had relevance outside the academy and could perhaps make a difference in peoplesrsquo lives I began to interact with the activists who were fighting to liberate genes to stop com-panies like Myriad in the courts and engage not just in the philosophical arguments but in those fights I joined with authors of amicus (friend of the court) briefs interviewed and interacted with BRCA1amp2 mutation‐positive women who were actively pursuing an end to a practice that I had only pre-viously considered to be an interesting metaphysical conundrum I also debated Intellectual Property (IP) attorneys and others primarily with backgrounds in biotech industries and learning better the nature of their arguments I came to understand that most of them including Kevin Noonan who once called me a ldquoliarrdquo on his blog but who has now drafted the foreword to this edition that they too generally have the best intentions Many like Dr Noonan truly expect that without gene patents as they existed until recently the sort of innovation we need in biomedical technol-ogies would not occur as it should
Throughout the course of the litigation in Myriad I remained engaged continued to speak to hone my arguments adding to my list of criteria for something to be a creation (artifact) capable of patent ldquodesignrdquo (as well as intention and being man‐made) and finally rejoicing when the decision of the Supreme Court came out as close to what I believed and argued was right as possible I had seen an academic idea mature and bloom into public policy real law enforceable justice While I realistically believe that the first edition of this book had only a very minor role in what finally happened I am proud to have played some part to have foreseen the issues to argue them honestly from what I think is a rational and logical standpoint and see that the world can be changed by ideas
Preface to the Second Edition xiii
There remain issues to discuss and not everything about gene patents has been resolved by Myriad Some still argue that cDNA ought not to be patent‐eligible (in fact I still think it should be under the criteria I have set forth though there are also arguments to be made that it is not somehow ldquodesignedrdquo by man) Moreover we should expect patent attorneys to do their creative best to continue to pursue patents on as much of the genome as they can within the constraints of Myriad Finally Myriad Corp has not given up They are still suing potential competitors under theories of infringement of parts of their patents that might have survived the ACLUrsquos case against them We shall see how they are eventually resolved and what the future holds for companies like theirs who profited mightily from gene patents for decades I describe as much of this recent legal history as possible in this edition
This book is meant to be a definitive version sewing up the past five years since the first edition emerged and so much changed in the world summa-rizing that recent history and refining the arguments I originally made correcting errors and describing where we are where we yet may be and why gene patents as they once were ought never to be again
David KoepsellAugust 14 2014
Mexico City Mexico
Foreword
David and I have had a friendly disagreement about the subject (and even the title) of this book ever since it was first published and I am happy that he asked me to write this Foreword to the Second Edition The issues David raises in the pages to follow continue to be relevant to a discussion of philosophy and patent law with events that have occurred since the first edition justifying (indeed demanding) this update
Without getting into the deep waters of philosophy (Davidrsquos meacutetier not mine) as we have discussed the issues in the book David contends that he takes a deontological approach and has characterized mine as a utilitarian one Accepting that dichotomy I understand the difference to be that David is operating from ldquofirst principlesrdquo about the rules society should impose on human activity and specifically on what the law permits individuals to ldquoownrdquo with regard to genes and more broadly naturally occurring substances I disagree with that approach on several levels perhaps the most germane of which is that if we posit rules we need to impose a rule‐giver and the potential for improvident rules (if not outright abuse of the privilege) makes me wary in some ways I subscribe to Lani Gruinierrsquos suspicions about the effects of the ldquotyranny of the majorityrdquo in this regard
Part of that tyranny is also the tyranny of unintended or intentional ignorance The issue heremdashldquogenerdquo patentingmdashis one at the intersection of molecular biology and modern genetics on the one hand and patent law (an area notorious for its arcane minutiae) I used to joke with my col-leagues about the effect of trying to explain my position to a lay audience of any type and how I distrusted those who advocated that all that was needed was to ldquoeducaterdquo the public the press and policy makers The problem for proponents of gene patenting has been that opponents have gotten the better part of the debate not by making a reasoned philosophical argument such as the one you will find in these pages but instead by making an
Foreword xv
emotional plea to individuals afraid that corporate America was trying to ldquostealrdquo their genes which has proven very effective This process began with an Op‐Ed piece in The New York Times by Michael Crichton wherein he posited a scenario where a patent holder knocks on your door one day and demands payment for the use of ldquoherrdquo patented gene that resides in your liver (Not coincidentally Dr Crichton had just published a novel on the perils of genetic engineering and corporate ownership of human genes complete with an essay as an addendum containing his arguments against the practice And it should be noted that a constant theme in his novels was a mistrust of technology and particularly the ability of humans to use it without dire consequences) Academics like my friend Lori Andrews at Illinois Institute of Technology (IIT)‐Kent School of Law joined in this theme which was picked up eventually by most popular press outlets and became regrettably the canonical narrative on gene patenting culminating in the American Civil Liberties Unionrsquos (ACLUrsquos) ldquoKeep Your Hands Off My Genesrdquo slogan and logo I hope that this essay provides some antidote to this argument which is founded on the literal fear that someone can ldquoownrdquo you (David assures me that his title is allegorical and that he acknowledges that in all countries that have banned slavery no one can ldquoownrdquo another human being or a part of them See the 13th Amendment I assure you that the ACLU has no such illusions about the intended consequences of their ownership rhetoric)
My philosophy is that the principle we should follow is the greatest good to the greatest number while not infringing on individual rights without (at least) compensation As regards patent law this principle is translated into rules that foster the broadest disclosure of technology possible in return for exclusive patent rights and robust‐enough enforcement rights for patents that they provide sufficient certainty to promote investment so his technology is commercialized to benefit the greatest number In my role as a biotechnology patent attorney I have seen how risky investment in biotechnology can be (indeed the evidence is overwhelming that for all its successes biotechrsquos history is littered with the remains of companies that have failed) and how important it is to have a sound patent system of predictable rights go support that investment
The evidence in support of ldquogene patentingrdquo and more broadly natural products patenting is strong the biotechnology industry has promoted innovation in the form of new drugs and diagnostics assays for a genera-tion This may continue despite the recent restrictions on patent protection
xvi Foreword
for genes and natural products (including patent‐restricting decisions in Mayo Collaborative Labs v Prometheus Labs and Assoc of Molecular Pathologists v Myriad Genetics and recently promulgated US Patent and Trademark Office Guidances on Subject Matter Eligibility) In fact these very restrictions suggest that we would benefit from an appreciation of the facts surrounding the past thirty years of gene patenting to understand why these restrictions are not only wrongheaded but dangerous for future innovation
These include debunking several myths First the concern that patents on specific human genes in some way inhibit innovation in basic genetic research is entirely unfounded One reason is that the genetic information itself is not patented while isolated DNA is encompassed by gene patent claims and described in those claims by its sequence the sequence itself is unpatented information that can be used freely for any purpose (eg inter-rogating genetic databases from other species or even human DNA inter alia to find related genes in those databases) Indeed the innovative benefits to gene patenting are evident in at least two ways First scientific publication databases reveal that there have been more than 11 000 scientific papers published on the BRCA1 and BRCA2 genes since the patents claiming them were granted This outcome refutes the prediction that gene patenting would create a ldquotragedy of the anticommonsrdquo where scientific research would be stifled by patenting (see Heller amp Eisenberg 1998 ldquoCan Patents Deter Innovation The Anticommons in Biomedical Researchrdquo Science 280 698ndash701)) a conclusion supported by the overwhelming majority of studies done on this subject (see for example Walsh et al 2003 ldquoScience and the Law Working Through the Patent Problemrdquo Science 299 1020 Walsh et al 2005 ldquoScience and Law View from the Bench Patents and Material Transfersrdquo Science 309 2002ndash03)
In addition policies that the US Patent and Trademark Office adopted in 2001 required applicants to disclose a practical utility for the product of a gene claimed in a patent These requirements were imposed at a time when the standards for scientific journal publication were much less stringent so that identifying a gene by the extent of genetic similarity between the ldquonewrdquo gene and previously discovered genes was enough for publication But it was not enough for a patent which has been held to be ldquonot a hunting license It is not a reward for the search but compensation for its successful conclusionrdquo Thus genes encoding proteins having no known use or biological activity cannot be patented because to do so would allow the
Foreword xvii
gene to be within the exclusive patent right undeservedly the public would not have received its quid pro quo of a useful invention in return for patent exclusivity All such genes not having patent protection are in the public domain (from which they cannot be retrieved for future patenting) and for humans these constitute the vast majority of genes identified inter alia by the Human Genome Project
The role for patenting genes and the related genetic diagnostic methods using this genetic information in the successes of the biotechnology era are evident The industry has produced hundreds of biologic drugs (at an ever‐increasing rate) that have provided effective treatment for a variety of illnesses and decoding the human genome has enabled researchers to iden-tify genes like the BRCA1 and BRCA2 genes that can be used in predictive genetic diagnostic tests Even the much‐maligned Myriad Genetics has played a positive role in the development and prevalence of genetic diagnostic testing It must be remembered that in 1997 (when Myriadrsquos BRCA gene patents were granted) genetic testing was in its infancy and companies like Myriad were under the burden of convincing payers that the tests did the one thing that all insurers public or private require of such tests save them money in the long run by identifying patients with a high probability of becoming ill and costing the insurers much more for treatment than the costs of prophylaxis Moreover Myriad and like com-panies needed to convince doctors that the testing was worthwhile and to establish a network of genetic counselors who could explain to healthy women that they were at much greater risk of developing breast or ovarian cancer than normal under circumstances that resulted in empowerment from the information and not abject fear And in 1997 genetic sequencing technology was not as developed as it is now and the mechanisms and tech-niques needed to minimize or eliminate the occurrence of false positives or negatives had not been conclusively established All these burdens were ones borne by Myriad and these activities produced the world we have today
It is possible as some have argued that BRCA tests may have been devel-oped independently by individual researchers in the absence of patent pro-tection However it is almost certain that such researchers would have been located in medical centers in urban environments Under these circum-stances women living in or near cities such as New York Boston Philadelphia Cleveland Chicago Houston Denver Los Angeles San Francisco Portland and Seattle might have had access to these tests But what of women in
xviii Foreword
Appalachia or the Four Corners region in the Southwest or more generally in rural or other relatively remote locations Would Yale University for example have had any incentive to provide access to the BRCA tests to these women in these far‐off locations Or to provide genetic counseling where the women lived Or to lobby state Medicare administrators or private insurance commissioners to cover the test I think that unlikely Myriad Genetics did all of this as well as perform outreach to the obstetrics and gynecology doctors throughout the United States so that these primary care doctors were aware of the tests Myriad did not ace from altruism but as part of their business plan in order to expand the number of patients who received the test and thus maximize the companyrsquos revenue While it may be counterintuitive to some these circumstances may have been the most effective way not only to pro-mulgate the BRCA tests but also to facilitate acceptance of genetic diagnostic testing for other diseases showing that in this instance Adam Smith rather than Karl Marx provided the most practical solution to the problem of estab-lishing genetic diagnostic testing as a recognized component of a physicianrsquos diagnostic armamentarium
Fortunately the significance and impact of recent US court decisions (spe-cifically the Myriad case) is much less than it would have been ten to thirty years ago Due to patent term rules most patents (and applications) on iso-lated DNA filed in the heyday of the Human Genome Project (approxi-mately 1998ndash2001) are near the end of their actual or potential term indeed a recent study shows that the number of granted patents having at least one claim reciting an isolate DNA comprising a gene peaked in 1999 and has been dropping since 2005 (Graff et al 2013 ldquoNot quite a myriad of gene pat-entsrdquo Nature Biotechnology 31 404ndash410)) These recent decisions in the United States have not harmed the biotechnology industry because they retained patent eligibility for species of DNA that show evidence of the ldquohand of manrdquo and do not occur in nature These include enzymatically pro-duced copies (cDNA) of cellular messenger RNA and should also encom-pass the tools of the recombinant geneticist (eg including recombinant vectors for cloning and expressing genes in heterologous cells) Most impor-tantly the US Supreme Court did not overturn its Diamond v Chakrabarty decision wherein recombinant cells were determined to be patent eligible
Thus in many ways the question of patent eligibility for human genes is a philosophical one However that does not mean that how we think about patent eligibility for isolated DNA is irrelevant to important questions regarding the usefulness of patents for promoting progress and innovation
Foreword xix
Indeed the most pernicious effects of the current trend in the zeitgeist against patenting has been not that genes have become harder to patent but rather that the ability to patent other natural products has been called into question It is the extension of these recent decisions on isolated DNA to all natural products that poses the greatest threat to innovation This threat can be illustrated by a thought experiment for which of these substances should patent protection be withheld
bull A petrochemical with excellent lubrication qualities isolated in pure form and used as improved motor oil
bull Vitamin B12 isolated from beef muscle formulated into a medicament used to cure anemia in children
bull The drug penicillin isolated from a mixture of naturally produced chemicals made by a mold and formulated as a drug to cure syphilis (which is otherwise eventually fatal)
bull Human urinary erythropoietin formulated to treat anemia in kidney dialysis patients
bull The gene responsible for Gaucherrsquos disease a lipid storage disease wherein the gene is used to make the missing protein that is administered to children and that cures an otherwise incurable and fatal disease
The current answer is that none of them are patent‐eligible per se (although there may be ways to claim them that could pass eligibility muster that remains to be seen) Judge Sweet the US District Court judge who first ruled that isolated DNA was not patent‐eligible did so using language carefully crafted to avoid encompassing all natural products into his decision Specifically Judge Sweet distinguished isolated DNA as the ldquophysical embodiments of genetic informationrdquo a property limited to DNA and not shared by other natural products (While an enzymatic protein could be characterized as the physical embodiment of catalysis of a particular chemical reaction that formulation has much less appeal and inherent rationale than Judge Sweetrsquos regarding DNA) Instead of this careful formu-lation the broader language employed by the Supreme Court as well as the broader rationale the Court used in finding genomic DNA unpatentable has made it easier to employ that fractured logic to render patent‐ineligible naturally occurring molecules other than DNA
I would be remiss not to mention the rather comical (but persistent) efforts of former Acting Solicitor General Neal Katyal who included in the
xx Foreword
US Governmentrsquos amicus brief to the Federal Circuit the distinction engine he called a ldquomagic microscoperdquo embodying the concept that if you are able to visualize a natural product (like a genomic DNA molecule) using this mythical microscope then the natural product would not be patent‐eligible whereas if you could not (eg a cDNA molecule) then the natural product could be eligible for patenting Fortunately the disdain with which the Federal Circuit greeted this fantasy (particularly from Judge Moore) prompted its quick abandonment as are argumentative distinction as the case moved forward Nonetheless both the courts and the US Patent and Trademark Office have adopted this standard de facto even as it becomes the theory that dare not speak its name in legal circles
The philosophical point here is that these substances and natural products generally have been deemed patent‐ineligible categorically which while consistent with (and perhaps even mandated by) the deon-tological approach imposes a distinction that cannot be flexibly applied to the individual circumstances Without such flexibility the law is con-strained to use one criterion that the substance can be found in some form in nature to decide patent eligibility instead of making the deter-mination of whether permitting patenting exclusivity satisfies the cri-teria that the invention ldquopromotes progressrdquo as the US Constitution requires and has a benefit to the public that outweighs any categorical disabilities
The potential that using this standard for determining patent eligibility will result in negative practical outcomes that no one in this debate desires is illustrated by a 2012 Report from the National Institutes of Health Natural Product Branch regarding statistics relating to the number of FDA approvals (a total of 1355) for new drugs falling into the following categories
Drug typesource Number
Biological (B) 203Natural product (N) 55Natural product (botanical) (NB) 149Derived from a natural product (ND) 298Totally synthetic (S) 393Total synthesisnatural product (S) 176Vaccine (S) 81
Foreword xxi
These statistics illustrate the consequences of a general ban on patenting naturally derived products of the 1355 drugs approved between 1981 and 2010
bull Fifty percent of all small‐molecule drugs approved between 2000 and 2010 are natural products
bull About 75 of antibacterial drugs are natural products or derived from natural products
bull Almost 80 of small‐molecule anticancer drugs were natural products or derivatives
In addition only 15 of drugs approved during this time frame were so‐called biologic drugs which are also putatively patent‐ineligible This the problems caused by the current interpretation of the law excluding natural product drugs from patent eligibility will be exacerbated in view of reports from every study showing that the percentage of drugs that are biologic drugs has been growing and will be the predominant type of drug devel-oped in the 2011ndash2030 time period
Another ldquothought experimentrdquo illustrating the practical illogic (David can provide his philosophical justifications in the body of the text) of broad natural products patent ineligibility is as follows Suppose a researcher finds a molecule produced by the human body that causes blood pressure homeo-stasis that is lack of this molecule causes or contributes to the disease of high blood pressure The logical consequence of the current natural prod-uct patent ineligibility standards would be that the closer a drug molecule is to the structure of the molecule as it occurs in the body the less patent‐eli-gible it would be Practically speaking there would be no incentive to modify the molecule to confer patent eligibility on the altered molecule because of the unpredictability of such changes on the molecule such as its biological activity half‐life stability antigenicity or other biological prop-erties And there would be even less incentive to develop the molecule as a drug because without patent protection the available regulatory exclusiv-ities would not pass economic muster to sufficiently defray the large development costs (some of which prevent drugs neither safe nor effica-cious from being sold and thus provide their own justification)
There is one further pernicious outcome that can be predicted to arise from a ban on natural products patents (including patents on isolated DNA and genetic diagnostic methods based on such isolated DNA) Natural
xxii Foreword
products are almost by nature complex and an ldquoactive principlerdquo isolated from nature is beneficial because it is isolated Kodak ran an advertisement in the journal Nature in the 1970s showing a scientist in a lab coat holding a 250‐ml flask and standing next to several bushels of green peppers wherein the content of the flask was the purified ldquoessence of green pepperrdquo equivalent to that substance contained in all the peppers in all the bushels and bushels that the scientist was standing beside But this very complexity makes it possible for the ldquoactive principlerdquo (either as a chemical compound or as a diagnostic genetic sequence) to be ldquohidden in plain sightrdquo in ways that may be particularly refractory to reverse engineering
For example even using somewhat dated ldquogene chiprdquo technology genetically diagnostic markers could be encrypted onto a microchip comprising 10 000 unique sequences wherein a computer‐readable bar code would be used to identify the positions of diagnostically relevant sequences on the chip This form of encryption which can be random and confounded by the presence of positive and negative control sequences as well as variable numbers and lengths of sequences specific for the gene (or more likely genes) of interest would be very difficult if not impossible to reverse‐engineer Even if reverse engineering could be done it would be difficult and expensive to undertake and thus make it more likely that the innovator would be able to avoid com-petition (ie it would provide unlimited exclusivity to its purveyor not con-strained by patent term or burdened by the requirement that the invention be disclosed with the specificity required by the Patent Act) While the possi-bility that this type of chip could be made exists with or without patents the absence of patent protection could tip the scales in favor of the extra effort needed and risk entailed in nondisclosure if the reward of extended ldquomonopolyrdquo is great enough But particularly for genetic diagnostic inven-tions the benefits of developing a proprietary database for which a corpora-tion could provide the economic and marketing wherewithal to expeditiously produce would result in a ldquoworst of both worldsrdquo outcome unlimited exclu-sivity based on undisclosed proprietary information that not only is difficult to replicate but whose existence would inhibit competition After all if a company had such a database its outcome for any particular patientrsquos test would be more accurate (and might identify disease riskndashassociated genetic variants not available elsewhere) and this would provide little incentive for a physician to choose an alternative provider to perform the test (and even more malevolently could create a system where the wealthy could afford the best diagnostic testing while the less affluent would be restricted to the more
Foreword xxiii
limited assays offered by companies without access to the ldquoinnovatorrsquosrdquo proprietary database information)
The other aspect of foreclosing patents for certain substances or technology areas categorically is that it upsets a carefully crafted dynamic that has worked extremely well during the biotech era between ldquotruerdquo innovators (typically university professors or small start‐up biotechnology companies) and more established companies capable of commercializing innovation Pundits who worry that permitting patenting will harm innovation miss an important point innovation will happen particularly in universities research institutes and like places because human nature demands it and regardless of whether patent protection is available The intelligent ape in us wants to know and the disparity between how univer-sity professors and patent lawyers are paid should establish how powerful the need to know can be Patenting and the impetus for patenting provided for example by the BayhndashDole Act in the United States prevents the fruits of these inventive efforts from mere predation by commercial concerns The benefits that can be had from a system where private commercializa-tion is encouraged are tempered by the types of corporate shenanigans that raise cogent criticisms of the system But perhaps it is mere human nature that people (in the corporate as well as individual sense) will want to expro-priate technology rather than pay for it and patenting prohibits (or at least retards) this outcome (if not these tendencies) Thus paradoxically limiting patent rights does not free innovation but rather makes it more likely to be kept captive by the entities capable of using such innovation to make a commercial product that is not from the power of building a better mouse-trap but by being able to outcompete smaller innovators merely by their greater economic prowess and resources Conversely patents provide a way for the innovators to protect their innovations and compel corporations to license their inventions producing revenue that can be used to fund future research endeavors This useful cycle has resulted in the successes of the biotechnology era and is something that we abandon at our peril
Thus in my view patents are a useful tool for achieving these societally ben-eficial goals promoting innovation and commercialization and protecting and supporting individuals who use the patent system to protect the products of their labors from being expropriated by others David provides a cogent and honest counterpoint to these thoughts Enjoy reading them
Kevin E NoonanChicago Illinois 2014
Who Owns You
Science Innovation and the Gene Patent Wars
SECoND EDITIoN
David Koepsell
This second edition first published 2015copy 2015 John Wiley amp Sons Ltd
Edition history John Wiley amp Sons Ltd (1e 2009)
Registered OfficeJohn Wiley amp Sons Ltd The Atrium Southern Gate Chichester West Sussex Po19 8SQ UK
Editorial Offices350 Main Street Malden MA 02148‐5020 USA9600 Garsington Road oxford oX4 2DQ UKThe Atrium Southern Gate Chichester West Sussex Po19 8SQ UK
For details of our global editorial offices for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at wwwwileycomwiley‐blackwell
The right of David Koepsell to be identified as the author of this work has been asserted in accordance with the UK Copyright Designs and Patents Act 1988
All rights reserved No part of this publication may be reproduced stored in a retrieval system or transmitted in any form or by any means electronic mechanical photocopying recording or otherwise except as permitted by the UK Copyright Designs and Patents Act 1988 without the prior permission of the publisher
Wiley also publishes its books in a variety of electronic formats Some content that appears in print may not be available in electronic books
Designations used by companies to distinguish their products are often claimed as trademarks All brand names and product names used in this book are trade names service marks trademarks or registered trademarks of their respective owners The publisher is not associated with any product or vendor mentioned in this book
Limit of LiabilityDisclaimer of Warranty While the publisher and author have used their best efforts in preparing this book they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose It is sold on the understanding that the publisher is not engaged in rendering professional services and neither the publisher nor the author shall be liable for damages arising herefrom If professional advice or other expert assistance is required the services of a competent professional should be sought
Library of Congress Cataloging‐in‐Publication DataKoepsell David R (David Richard) authorWho owns you science innovation and the gene patent wars David Koepsell ndash Second edition p cm Previous edition has subtitle the corporate gold-rush to patent your genes Includes bibliographical references and index ISBN 978-1-118-94850-7 (pbk)I Title [DNLM 1 Genetics Medicalndashlegislation amp jurisprudence 2 Patents as Topicndashlegislation amp jurisprudence 3 ownershipndashethics QZ 324] K1519B54 34604prime86ndashdc23 2014048341A catalogue record for this book is available from the British Library
Cover image copy esenkartal
Set in 10513pt Minion by SPi Publisher Services Pondicherry India
2 2015
To Alexandro
Contents
Acknowledgments viii
Preface to the Second Edition x
Foreword xiv
Introduction xxiv
1 Individual and Collective Rights in Genomic Data Preliminary Issues 1
2 Ethics and Ontology A Brief Discourse on Method 21
3 The Science of Genes 30
4 DNA Species Individuals and Persons 52
5 Legal Dimensions in Gene Ownership 69
6 BRCA1 and 2 The Myriad Case and Beyond 88
7 Are Genes Intellectual Property 101
8 DNA and The Commons 119
9 Pragmatic Considerations of Gene Ownership 137
10 Nature Genes and the Scientific Commons A Social Ontology of Invention 155
11 So Who Owns You Some Conclusions About Genes Property and Personhood 165
Notes 182
Index 194
Acknowledgments
Many thanks must be given to those whom I have spoken to about the issues discussed herein since the first edition and who helped inform the updates including Tania Simoncelli Luigi Palombi Joanna Rudnick Dan Ravicher Kevin Noonan James Watson and numerous online commenters who helped point out errors and hone my arguments Thank you also to my colleagues at Delft University of Technology where I have worked the past 6 years and continued discussing and sharpening my approach to the ideas in this book and others
I remain grateful to the Yale Interdisciplinary Bioethics Center for appointing me as their Donaghue Initiative Fellow in Research Ethics 2006ndash2007 I drafted a significant portion of this book during that appoint-ment and had the chance to hash out many of these issues with the staff affiliated faculty and others who participated in events that year Special thanks to all the good people at Yale including especially Robert Levine Julius Landwirth Carol Pollard Autumn Ridenour and Jonathan Moser Thanks also to the folks at the New Haven dog park for keeping my dear departed Buttercup and me company during my residency at Yale Many thanks to my wife Vanessa who gave me significant scientific guidance and lots of encouragement as I worked out these issues and drafted the original book and who helped redraft Chapter 3 for this edition Thanks to my 3‐year‐old daughter Amelia whose appearance brought new purpose to my life and my work My parents Eva Hwa and Richard Koepsell provided commentary and feedback on early drafts of chapters and I am as always grateful for their continuing encouragement My dear friend Peter Hare who passed away in 2008 also kept me company bought me lunches and encouraged my work while at Yale hellip I am grateful for his guidance and friendship and will miss him dearly Thanks to Barry Smith who has remained a helpful and encouraging mentor as I pursue the sometimes
Acknowledgments ix
frustrating but often fruitful path of philosophy Thank you also to Denise Riley who helped dig up obscure articles and arranged almost all the research for my initial trip to Yale that hatched the first edition Finally many thanks to anyone I have forgotten including all those who have given me probing questions puzzling scenarios and further guidance in the talks I have given on this fascinating subject over the past 8 years
David KoepsellAugust 14 2014
Mexico City Mexico
Preface to the Second Edition
A lot has happened in nearly every respect since I first decided to try to delve into philosophical issues of gene patenting nearly a decade ago I have learned much the world has changed and I have changed I would very much like to think I have played a role in that change though chances are things would have changed in almost exactly the same way without my small contribution When the first edition came out patenting genes was still a regular part of biotech and only months after the first edition appeared did a surprising and now‐landmark lawsuit alter that significantly Little did I realize the nature of the forces that would be involved in what I had originally assumed was no more than an academic exercise but which became a matter of weighty and heated public debate and finally judicial action
I first became interested in the subject of gene patents when I began reading up on the topic my future wife was researching pharmacogenom-ics To grasp what she did I first needed to study the science and in so doing I also studied the history of that science Along the way I read about the Human Genome Project and learned about the practice of gene patenting that it spawned Having had some experience and interest in general issues of the philosophy of intellectual property (see my 1997 PhD thesis turned 2000 book The Ontology of Cyberspace) my ears perked up when I first read about the notion of patenting genes So I dived into the research and thinking in my ordinary style of philosophical work Although I sometimes teach ethics my primary field is ontology and it is from an ontological approach that I start with everything in philosophy Thus I began to try to get a grip on the nature of the existence of the underlying objects some of which are ldquobrute factsrdquo (molecules exist with or without social institutions or intentionality) and some of which are social objects (like laws rights and other parts of ldquosocial realityrdquo existing only because of
Preface to the Second Edition xi
collective intentionality) The book was an attempt to lay all this out and to connect it together into a theory that is somehow connected to notions of ldquojusticerdquo which I argued bridges the worlds of brute facts and social objects
The conclusions I reached were I thought pretty neat Specifically I worked out an ontology of ldquothe commonsrdquo that I had never heard expressed before and one that connected nicely with the objects involved to show why artifacts and nature ought to be treated differently and how to decide what constitutes an artifact and what constitutes nature and a defense of the viewpoint that unmodified genes were clearly not artifacts It seemed all the more relevant and interesting even perhaps somewhat important in light of the then ongoing practice of gene patenting I was much too focused on the ontological arguments and their seeming relevance to real‐world practices than I was to the scientific and legal terminology with which I was engaging and this was an error When the book was released minor errors I made in using technical terminology from both the science and the law were latched onto by a couple critical reviewers from the Intellectual Property law and teaching worlds and urged as a basis to ignore my substantive arguments They were right to call out the errors and I have attempted to correct them in this edition Regardless the underlying argu-ments I had set forth would become shortly echoed nearly precisely in the lawsuit that the American Civil Liberties Union (ACLU) spearheaded against Myriad Corp over the BRCA1amp2 gene patents
For a brief period of time partly due to lucky timing I was thrust head-long into the public debates about gene patenting with the Myriad case leading the headlines Given numerous opportunities to engage publicly with the issues and ideas I had previously assumed were only academic musings unlikely to alter public policy and given feedback and counterar-guments in those same venues the general arguments could be more finely honed This edition attempts to coalesce them
Perhaps more importantly in the intervening years since I began my musings about the nature of genes artifacts nature and patents I came to learn the very personal impact that gene patents have on peoplersquos lives Because the ACLU chose to sue over the patents on BRCA1amp2 genes there was a ready‐made large and passionate community (mostly women) whose heredity put them at risk of breast and ovarian cancers but who were basically forced into paying monopolistic prices for the only test available for the gene which was patented by Myriad Corp Breast cancer and the threat of inherited tendencies for breast cancer are real They are not legal
xii Preface to the Second Edition
sophistry they are not philosophical musing They kill people or alter their lives irrevocably
I began researching and considering the effects of gene patents believing they were potentially a threat to the conduct of science whose foundational objects I argued were part of a commons‐by‐necessity but I realized after my book came out that real lives were being harmed by patents on genes The Myriad case brought together the theoretical with the actual for me and the dynamics of both the case and the loud and sometimes angry public debate raised my awareness not only about this particular subject but also the power and responsibility of academic research in the sphere of public policy Suddenly ideas seemed more important had relevance outside the academy and could perhaps make a difference in peoplesrsquo lives I began to interact with the activists who were fighting to liberate genes to stop com-panies like Myriad in the courts and engage not just in the philosophical arguments but in those fights I joined with authors of amicus (friend of the court) briefs interviewed and interacted with BRCA1amp2 mutation‐positive women who were actively pursuing an end to a practice that I had only pre-viously considered to be an interesting metaphysical conundrum I also debated Intellectual Property (IP) attorneys and others primarily with backgrounds in biotech industries and learning better the nature of their arguments I came to understand that most of them including Kevin Noonan who once called me a ldquoliarrdquo on his blog but who has now drafted the foreword to this edition that they too generally have the best intentions Many like Dr Noonan truly expect that without gene patents as they existed until recently the sort of innovation we need in biomedical technol-ogies would not occur as it should
Throughout the course of the litigation in Myriad I remained engaged continued to speak to hone my arguments adding to my list of criteria for something to be a creation (artifact) capable of patent ldquodesignrdquo (as well as intention and being man‐made) and finally rejoicing when the decision of the Supreme Court came out as close to what I believed and argued was right as possible I had seen an academic idea mature and bloom into public policy real law enforceable justice While I realistically believe that the first edition of this book had only a very minor role in what finally happened I am proud to have played some part to have foreseen the issues to argue them honestly from what I think is a rational and logical standpoint and see that the world can be changed by ideas
Preface to the Second Edition xiii
There remain issues to discuss and not everything about gene patents has been resolved by Myriad Some still argue that cDNA ought not to be patent‐eligible (in fact I still think it should be under the criteria I have set forth though there are also arguments to be made that it is not somehow ldquodesignedrdquo by man) Moreover we should expect patent attorneys to do their creative best to continue to pursue patents on as much of the genome as they can within the constraints of Myriad Finally Myriad Corp has not given up They are still suing potential competitors under theories of infringement of parts of their patents that might have survived the ACLUrsquos case against them We shall see how they are eventually resolved and what the future holds for companies like theirs who profited mightily from gene patents for decades I describe as much of this recent legal history as possible in this edition
This book is meant to be a definitive version sewing up the past five years since the first edition emerged and so much changed in the world summa-rizing that recent history and refining the arguments I originally made correcting errors and describing where we are where we yet may be and why gene patents as they once were ought never to be again
David KoepsellAugust 14 2014
Mexico City Mexico
Foreword
David and I have had a friendly disagreement about the subject (and even the title) of this book ever since it was first published and I am happy that he asked me to write this Foreword to the Second Edition The issues David raises in the pages to follow continue to be relevant to a discussion of philosophy and patent law with events that have occurred since the first edition justifying (indeed demanding) this update
Without getting into the deep waters of philosophy (Davidrsquos meacutetier not mine) as we have discussed the issues in the book David contends that he takes a deontological approach and has characterized mine as a utilitarian one Accepting that dichotomy I understand the difference to be that David is operating from ldquofirst principlesrdquo about the rules society should impose on human activity and specifically on what the law permits individuals to ldquoownrdquo with regard to genes and more broadly naturally occurring substances I disagree with that approach on several levels perhaps the most germane of which is that if we posit rules we need to impose a rule‐giver and the potential for improvident rules (if not outright abuse of the privilege) makes me wary in some ways I subscribe to Lani Gruinierrsquos suspicions about the effects of the ldquotyranny of the majorityrdquo in this regard
Part of that tyranny is also the tyranny of unintended or intentional ignorance The issue heremdashldquogenerdquo patentingmdashis one at the intersection of molecular biology and modern genetics on the one hand and patent law (an area notorious for its arcane minutiae) I used to joke with my col-leagues about the effect of trying to explain my position to a lay audience of any type and how I distrusted those who advocated that all that was needed was to ldquoeducaterdquo the public the press and policy makers The problem for proponents of gene patenting has been that opponents have gotten the better part of the debate not by making a reasoned philosophical argument such as the one you will find in these pages but instead by making an
Foreword xv
emotional plea to individuals afraid that corporate America was trying to ldquostealrdquo their genes which has proven very effective This process began with an Op‐Ed piece in The New York Times by Michael Crichton wherein he posited a scenario where a patent holder knocks on your door one day and demands payment for the use of ldquoherrdquo patented gene that resides in your liver (Not coincidentally Dr Crichton had just published a novel on the perils of genetic engineering and corporate ownership of human genes complete with an essay as an addendum containing his arguments against the practice And it should be noted that a constant theme in his novels was a mistrust of technology and particularly the ability of humans to use it without dire consequences) Academics like my friend Lori Andrews at Illinois Institute of Technology (IIT)‐Kent School of Law joined in this theme which was picked up eventually by most popular press outlets and became regrettably the canonical narrative on gene patenting culminating in the American Civil Liberties Unionrsquos (ACLUrsquos) ldquoKeep Your Hands Off My Genesrdquo slogan and logo I hope that this essay provides some antidote to this argument which is founded on the literal fear that someone can ldquoownrdquo you (David assures me that his title is allegorical and that he acknowledges that in all countries that have banned slavery no one can ldquoownrdquo another human being or a part of them See the 13th Amendment I assure you that the ACLU has no such illusions about the intended consequences of their ownership rhetoric)
My philosophy is that the principle we should follow is the greatest good to the greatest number while not infringing on individual rights without (at least) compensation As regards patent law this principle is translated into rules that foster the broadest disclosure of technology possible in return for exclusive patent rights and robust‐enough enforcement rights for patents that they provide sufficient certainty to promote investment so his technology is commercialized to benefit the greatest number In my role as a biotechnology patent attorney I have seen how risky investment in biotechnology can be (indeed the evidence is overwhelming that for all its successes biotechrsquos history is littered with the remains of companies that have failed) and how important it is to have a sound patent system of predictable rights go support that investment
The evidence in support of ldquogene patentingrdquo and more broadly natural products patenting is strong the biotechnology industry has promoted innovation in the form of new drugs and diagnostics assays for a genera-tion This may continue despite the recent restrictions on patent protection
xvi Foreword
for genes and natural products (including patent‐restricting decisions in Mayo Collaborative Labs v Prometheus Labs and Assoc of Molecular Pathologists v Myriad Genetics and recently promulgated US Patent and Trademark Office Guidances on Subject Matter Eligibility) In fact these very restrictions suggest that we would benefit from an appreciation of the facts surrounding the past thirty years of gene patenting to understand why these restrictions are not only wrongheaded but dangerous for future innovation
These include debunking several myths First the concern that patents on specific human genes in some way inhibit innovation in basic genetic research is entirely unfounded One reason is that the genetic information itself is not patented while isolated DNA is encompassed by gene patent claims and described in those claims by its sequence the sequence itself is unpatented information that can be used freely for any purpose (eg inter-rogating genetic databases from other species or even human DNA inter alia to find related genes in those databases) Indeed the innovative benefits to gene patenting are evident in at least two ways First scientific publication databases reveal that there have been more than 11 000 scientific papers published on the BRCA1 and BRCA2 genes since the patents claiming them were granted This outcome refutes the prediction that gene patenting would create a ldquotragedy of the anticommonsrdquo where scientific research would be stifled by patenting (see Heller amp Eisenberg 1998 ldquoCan Patents Deter Innovation The Anticommons in Biomedical Researchrdquo Science 280 698ndash701)) a conclusion supported by the overwhelming majority of studies done on this subject (see for example Walsh et al 2003 ldquoScience and the Law Working Through the Patent Problemrdquo Science 299 1020 Walsh et al 2005 ldquoScience and Law View from the Bench Patents and Material Transfersrdquo Science 309 2002ndash03)
In addition policies that the US Patent and Trademark Office adopted in 2001 required applicants to disclose a practical utility for the product of a gene claimed in a patent These requirements were imposed at a time when the standards for scientific journal publication were much less stringent so that identifying a gene by the extent of genetic similarity between the ldquonewrdquo gene and previously discovered genes was enough for publication But it was not enough for a patent which has been held to be ldquonot a hunting license It is not a reward for the search but compensation for its successful conclusionrdquo Thus genes encoding proteins having no known use or biological activity cannot be patented because to do so would allow the
Foreword xvii
gene to be within the exclusive patent right undeservedly the public would not have received its quid pro quo of a useful invention in return for patent exclusivity All such genes not having patent protection are in the public domain (from which they cannot be retrieved for future patenting) and for humans these constitute the vast majority of genes identified inter alia by the Human Genome Project
The role for patenting genes and the related genetic diagnostic methods using this genetic information in the successes of the biotechnology era are evident The industry has produced hundreds of biologic drugs (at an ever‐increasing rate) that have provided effective treatment for a variety of illnesses and decoding the human genome has enabled researchers to iden-tify genes like the BRCA1 and BRCA2 genes that can be used in predictive genetic diagnostic tests Even the much‐maligned Myriad Genetics has played a positive role in the development and prevalence of genetic diagnostic testing It must be remembered that in 1997 (when Myriadrsquos BRCA gene patents were granted) genetic testing was in its infancy and companies like Myriad were under the burden of convincing payers that the tests did the one thing that all insurers public or private require of such tests save them money in the long run by identifying patients with a high probability of becoming ill and costing the insurers much more for treatment than the costs of prophylaxis Moreover Myriad and like com-panies needed to convince doctors that the testing was worthwhile and to establish a network of genetic counselors who could explain to healthy women that they were at much greater risk of developing breast or ovarian cancer than normal under circumstances that resulted in empowerment from the information and not abject fear And in 1997 genetic sequencing technology was not as developed as it is now and the mechanisms and tech-niques needed to minimize or eliminate the occurrence of false positives or negatives had not been conclusively established All these burdens were ones borne by Myriad and these activities produced the world we have today
It is possible as some have argued that BRCA tests may have been devel-oped independently by individual researchers in the absence of patent pro-tection However it is almost certain that such researchers would have been located in medical centers in urban environments Under these circum-stances women living in or near cities such as New York Boston Philadelphia Cleveland Chicago Houston Denver Los Angeles San Francisco Portland and Seattle might have had access to these tests But what of women in
xviii Foreword
Appalachia or the Four Corners region in the Southwest or more generally in rural or other relatively remote locations Would Yale University for example have had any incentive to provide access to the BRCA tests to these women in these far‐off locations Or to provide genetic counseling where the women lived Or to lobby state Medicare administrators or private insurance commissioners to cover the test I think that unlikely Myriad Genetics did all of this as well as perform outreach to the obstetrics and gynecology doctors throughout the United States so that these primary care doctors were aware of the tests Myriad did not ace from altruism but as part of their business plan in order to expand the number of patients who received the test and thus maximize the companyrsquos revenue While it may be counterintuitive to some these circumstances may have been the most effective way not only to pro-mulgate the BRCA tests but also to facilitate acceptance of genetic diagnostic testing for other diseases showing that in this instance Adam Smith rather than Karl Marx provided the most practical solution to the problem of estab-lishing genetic diagnostic testing as a recognized component of a physicianrsquos diagnostic armamentarium
Fortunately the significance and impact of recent US court decisions (spe-cifically the Myriad case) is much less than it would have been ten to thirty years ago Due to patent term rules most patents (and applications) on iso-lated DNA filed in the heyday of the Human Genome Project (approxi-mately 1998ndash2001) are near the end of their actual or potential term indeed a recent study shows that the number of granted patents having at least one claim reciting an isolate DNA comprising a gene peaked in 1999 and has been dropping since 2005 (Graff et al 2013 ldquoNot quite a myriad of gene pat-entsrdquo Nature Biotechnology 31 404ndash410)) These recent decisions in the United States have not harmed the biotechnology industry because they retained patent eligibility for species of DNA that show evidence of the ldquohand of manrdquo and do not occur in nature These include enzymatically pro-duced copies (cDNA) of cellular messenger RNA and should also encom-pass the tools of the recombinant geneticist (eg including recombinant vectors for cloning and expressing genes in heterologous cells) Most impor-tantly the US Supreme Court did not overturn its Diamond v Chakrabarty decision wherein recombinant cells were determined to be patent eligible
Thus in many ways the question of patent eligibility for human genes is a philosophical one However that does not mean that how we think about patent eligibility for isolated DNA is irrelevant to important questions regarding the usefulness of patents for promoting progress and innovation
Foreword xix
Indeed the most pernicious effects of the current trend in the zeitgeist against patenting has been not that genes have become harder to patent but rather that the ability to patent other natural products has been called into question It is the extension of these recent decisions on isolated DNA to all natural products that poses the greatest threat to innovation This threat can be illustrated by a thought experiment for which of these substances should patent protection be withheld
bull A petrochemical with excellent lubrication qualities isolated in pure form and used as improved motor oil
bull Vitamin B12 isolated from beef muscle formulated into a medicament used to cure anemia in children
bull The drug penicillin isolated from a mixture of naturally produced chemicals made by a mold and formulated as a drug to cure syphilis (which is otherwise eventually fatal)
bull Human urinary erythropoietin formulated to treat anemia in kidney dialysis patients
bull The gene responsible for Gaucherrsquos disease a lipid storage disease wherein the gene is used to make the missing protein that is administered to children and that cures an otherwise incurable and fatal disease
The current answer is that none of them are patent‐eligible per se (although there may be ways to claim them that could pass eligibility muster that remains to be seen) Judge Sweet the US District Court judge who first ruled that isolated DNA was not patent‐eligible did so using language carefully crafted to avoid encompassing all natural products into his decision Specifically Judge Sweet distinguished isolated DNA as the ldquophysical embodiments of genetic informationrdquo a property limited to DNA and not shared by other natural products (While an enzymatic protein could be characterized as the physical embodiment of catalysis of a particular chemical reaction that formulation has much less appeal and inherent rationale than Judge Sweetrsquos regarding DNA) Instead of this careful formu-lation the broader language employed by the Supreme Court as well as the broader rationale the Court used in finding genomic DNA unpatentable has made it easier to employ that fractured logic to render patent‐ineligible naturally occurring molecules other than DNA
I would be remiss not to mention the rather comical (but persistent) efforts of former Acting Solicitor General Neal Katyal who included in the
xx Foreword
US Governmentrsquos amicus brief to the Federal Circuit the distinction engine he called a ldquomagic microscoperdquo embodying the concept that if you are able to visualize a natural product (like a genomic DNA molecule) using this mythical microscope then the natural product would not be patent‐eligible whereas if you could not (eg a cDNA molecule) then the natural product could be eligible for patenting Fortunately the disdain with which the Federal Circuit greeted this fantasy (particularly from Judge Moore) prompted its quick abandonment as are argumentative distinction as the case moved forward Nonetheless both the courts and the US Patent and Trademark Office have adopted this standard de facto even as it becomes the theory that dare not speak its name in legal circles
The philosophical point here is that these substances and natural products generally have been deemed patent‐ineligible categorically which while consistent with (and perhaps even mandated by) the deon-tological approach imposes a distinction that cannot be flexibly applied to the individual circumstances Without such flexibility the law is con-strained to use one criterion that the substance can be found in some form in nature to decide patent eligibility instead of making the deter-mination of whether permitting patenting exclusivity satisfies the cri-teria that the invention ldquopromotes progressrdquo as the US Constitution requires and has a benefit to the public that outweighs any categorical disabilities
The potential that using this standard for determining patent eligibility will result in negative practical outcomes that no one in this debate desires is illustrated by a 2012 Report from the National Institutes of Health Natural Product Branch regarding statistics relating to the number of FDA approvals (a total of 1355) for new drugs falling into the following categories
Drug typesource Number
Biological (B) 203Natural product (N) 55Natural product (botanical) (NB) 149Derived from a natural product (ND) 298Totally synthetic (S) 393Total synthesisnatural product (S) 176Vaccine (S) 81
Foreword xxi
These statistics illustrate the consequences of a general ban on patenting naturally derived products of the 1355 drugs approved between 1981 and 2010
bull Fifty percent of all small‐molecule drugs approved between 2000 and 2010 are natural products
bull About 75 of antibacterial drugs are natural products or derived from natural products
bull Almost 80 of small‐molecule anticancer drugs were natural products or derivatives
In addition only 15 of drugs approved during this time frame were so‐called biologic drugs which are also putatively patent‐ineligible This the problems caused by the current interpretation of the law excluding natural product drugs from patent eligibility will be exacerbated in view of reports from every study showing that the percentage of drugs that are biologic drugs has been growing and will be the predominant type of drug devel-oped in the 2011ndash2030 time period
Another ldquothought experimentrdquo illustrating the practical illogic (David can provide his philosophical justifications in the body of the text) of broad natural products patent ineligibility is as follows Suppose a researcher finds a molecule produced by the human body that causes blood pressure homeo-stasis that is lack of this molecule causes or contributes to the disease of high blood pressure The logical consequence of the current natural prod-uct patent ineligibility standards would be that the closer a drug molecule is to the structure of the molecule as it occurs in the body the less patent‐eli-gible it would be Practically speaking there would be no incentive to modify the molecule to confer patent eligibility on the altered molecule because of the unpredictability of such changes on the molecule such as its biological activity half‐life stability antigenicity or other biological prop-erties And there would be even less incentive to develop the molecule as a drug because without patent protection the available regulatory exclusiv-ities would not pass economic muster to sufficiently defray the large development costs (some of which prevent drugs neither safe nor effica-cious from being sold and thus provide their own justification)
There is one further pernicious outcome that can be predicted to arise from a ban on natural products patents (including patents on isolated DNA and genetic diagnostic methods based on such isolated DNA) Natural
xxii Foreword
products are almost by nature complex and an ldquoactive principlerdquo isolated from nature is beneficial because it is isolated Kodak ran an advertisement in the journal Nature in the 1970s showing a scientist in a lab coat holding a 250‐ml flask and standing next to several bushels of green peppers wherein the content of the flask was the purified ldquoessence of green pepperrdquo equivalent to that substance contained in all the peppers in all the bushels and bushels that the scientist was standing beside But this very complexity makes it possible for the ldquoactive principlerdquo (either as a chemical compound or as a diagnostic genetic sequence) to be ldquohidden in plain sightrdquo in ways that may be particularly refractory to reverse engineering
For example even using somewhat dated ldquogene chiprdquo technology genetically diagnostic markers could be encrypted onto a microchip comprising 10 000 unique sequences wherein a computer‐readable bar code would be used to identify the positions of diagnostically relevant sequences on the chip This form of encryption which can be random and confounded by the presence of positive and negative control sequences as well as variable numbers and lengths of sequences specific for the gene (or more likely genes) of interest would be very difficult if not impossible to reverse‐engineer Even if reverse engineering could be done it would be difficult and expensive to undertake and thus make it more likely that the innovator would be able to avoid com-petition (ie it would provide unlimited exclusivity to its purveyor not con-strained by patent term or burdened by the requirement that the invention be disclosed with the specificity required by the Patent Act) While the possi-bility that this type of chip could be made exists with or without patents the absence of patent protection could tip the scales in favor of the extra effort needed and risk entailed in nondisclosure if the reward of extended ldquomonopolyrdquo is great enough But particularly for genetic diagnostic inven-tions the benefits of developing a proprietary database for which a corpora-tion could provide the economic and marketing wherewithal to expeditiously produce would result in a ldquoworst of both worldsrdquo outcome unlimited exclu-sivity based on undisclosed proprietary information that not only is difficult to replicate but whose existence would inhibit competition After all if a company had such a database its outcome for any particular patientrsquos test would be more accurate (and might identify disease riskndashassociated genetic variants not available elsewhere) and this would provide little incentive for a physician to choose an alternative provider to perform the test (and even more malevolently could create a system where the wealthy could afford the best diagnostic testing while the less affluent would be restricted to the more
Foreword xxiii
limited assays offered by companies without access to the ldquoinnovatorrsquosrdquo proprietary database information)
The other aspect of foreclosing patents for certain substances or technology areas categorically is that it upsets a carefully crafted dynamic that has worked extremely well during the biotech era between ldquotruerdquo innovators (typically university professors or small start‐up biotechnology companies) and more established companies capable of commercializing innovation Pundits who worry that permitting patenting will harm innovation miss an important point innovation will happen particularly in universities research institutes and like places because human nature demands it and regardless of whether patent protection is available The intelligent ape in us wants to know and the disparity between how univer-sity professors and patent lawyers are paid should establish how powerful the need to know can be Patenting and the impetus for patenting provided for example by the BayhndashDole Act in the United States prevents the fruits of these inventive efforts from mere predation by commercial concerns The benefits that can be had from a system where private commercializa-tion is encouraged are tempered by the types of corporate shenanigans that raise cogent criticisms of the system But perhaps it is mere human nature that people (in the corporate as well as individual sense) will want to expro-priate technology rather than pay for it and patenting prohibits (or at least retards) this outcome (if not these tendencies) Thus paradoxically limiting patent rights does not free innovation but rather makes it more likely to be kept captive by the entities capable of using such innovation to make a commercial product that is not from the power of building a better mouse-trap but by being able to outcompete smaller innovators merely by their greater economic prowess and resources Conversely patents provide a way for the innovators to protect their innovations and compel corporations to license their inventions producing revenue that can be used to fund future research endeavors This useful cycle has resulted in the successes of the biotechnology era and is something that we abandon at our peril
Thus in my view patents are a useful tool for achieving these societally ben-eficial goals promoting innovation and commercialization and protecting and supporting individuals who use the patent system to protect the products of their labors from being expropriated by others David provides a cogent and honest counterpoint to these thoughts Enjoy reading them
Kevin E NoonanChicago Illinois 2014
This second edition first published 2015copy 2015 John Wiley amp Sons Ltd
Edition history John Wiley amp Sons Ltd (1e 2009)
Registered OfficeJohn Wiley amp Sons Ltd The Atrium Southern Gate Chichester West Sussex Po19 8SQ UK
Editorial Offices350 Main Street Malden MA 02148‐5020 USA9600 Garsington Road oxford oX4 2DQ UKThe Atrium Southern Gate Chichester West Sussex Po19 8SQ UK
For details of our global editorial offices for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at wwwwileycomwiley‐blackwell
The right of David Koepsell to be identified as the author of this work has been asserted in accordance with the UK Copyright Designs and Patents Act 1988
All rights reserved No part of this publication may be reproduced stored in a retrieval system or transmitted in any form or by any means electronic mechanical photocopying recording or otherwise except as permitted by the UK Copyright Designs and Patents Act 1988 without the prior permission of the publisher
Wiley also publishes its books in a variety of electronic formats Some content that appears in print may not be available in electronic books
Designations used by companies to distinguish their products are often claimed as trademarks All brand names and product names used in this book are trade names service marks trademarks or registered trademarks of their respective owners The publisher is not associated with any product or vendor mentioned in this book
Limit of LiabilityDisclaimer of Warranty While the publisher and author have used their best efforts in preparing this book they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose It is sold on the understanding that the publisher is not engaged in rendering professional services and neither the publisher nor the author shall be liable for damages arising herefrom If professional advice or other expert assistance is required the services of a competent professional should be sought
Library of Congress Cataloging‐in‐Publication DataKoepsell David R (David Richard) authorWho owns you science innovation and the gene patent wars David Koepsell ndash Second edition p cm Previous edition has subtitle the corporate gold-rush to patent your genes Includes bibliographical references and index ISBN 978-1-118-94850-7 (pbk)I Title [DNLM 1 Genetics Medicalndashlegislation amp jurisprudence 2 Patents as Topicndashlegislation amp jurisprudence 3 ownershipndashethics QZ 324] K1519B54 34604prime86ndashdc23 2014048341A catalogue record for this book is available from the British Library
Cover image copy esenkartal
Set in 10513pt Minion by SPi Publisher Services Pondicherry India
2 2015
To Alexandro
Contents
Acknowledgments viii
Preface to the Second Edition x
Foreword xiv
Introduction xxiv
1 Individual and Collective Rights in Genomic Data Preliminary Issues 1
2 Ethics and Ontology A Brief Discourse on Method 21
3 The Science of Genes 30
4 DNA Species Individuals and Persons 52
5 Legal Dimensions in Gene Ownership 69
6 BRCA1 and 2 The Myriad Case and Beyond 88
7 Are Genes Intellectual Property 101
8 DNA and The Commons 119
9 Pragmatic Considerations of Gene Ownership 137
10 Nature Genes and the Scientific Commons A Social Ontology of Invention 155
11 So Who Owns You Some Conclusions About Genes Property and Personhood 165
Notes 182
Index 194
Acknowledgments
Many thanks must be given to those whom I have spoken to about the issues discussed herein since the first edition and who helped inform the updates including Tania Simoncelli Luigi Palombi Joanna Rudnick Dan Ravicher Kevin Noonan James Watson and numerous online commenters who helped point out errors and hone my arguments Thank you also to my colleagues at Delft University of Technology where I have worked the past 6 years and continued discussing and sharpening my approach to the ideas in this book and others
I remain grateful to the Yale Interdisciplinary Bioethics Center for appointing me as their Donaghue Initiative Fellow in Research Ethics 2006ndash2007 I drafted a significant portion of this book during that appoint-ment and had the chance to hash out many of these issues with the staff affiliated faculty and others who participated in events that year Special thanks to all the good people at Yale including especially Robert Levine Julius Landwirth Carol Pollard Autumn Ridenour and Jonathan Moser Thanks also to the folks at the New Haven dog park for keeping my dear departed Buttercup and me company during my residency at Yale Many thanks to my wife Vanessa who gave me significant scientific guidance and lots of encouragement as I worked out these issues and drafted the original book and who helped redraft Chapter 3 for this edition Thanks to my 3‐year‐old daughter Amelia whose appearance brought new purpose to my life and my work My parents Eva Hwa and Richard Koepsell provided commentary and feedback on early drafts of chapters and I am as always grateful for their continuing encouragement My dear friend Peter Hare who passed away in 2008 also kept me company bought me lunches and encouraged my work while at Yale hellip I am grateful for his guidance and friendship and will miss him dearly Thanks to Barry Smith who has remained a helpful and encouraging mentor as I pursue the sometimes
Acknowledgments ix
frustrating but often fruitful path of philosophy Thank you also to Denise Riley who helped dig up obscure articles and arranged almost all the research for my initial trip to Yale that hatched the first edition Finally many thanks to anyone I have forgotten including all those who have given me probing questions puzzling scenarios and further guidance in the talks I have given on this fascinating subject over the past 8 years
David KoepsellAugust 14 2014
Mexico City Mexico
Preface to the Second Edition
A lot has happened in nearly every respect since I first decided to try to delve into philosophical issues of gene patenting nearly a decade ago I have learned much the world has changed and I have changed I would very much like to think I have played a role in that change though chances are things would have changed in almost exactly the same way without my small contribution When the first edition came out patenting genes was still a regular part of biotech and only months after the first edition appeared did a surprising and now‐landmark lawsuit alter that significantly Little did I realize the nature of the forces that would be involved in what I had originally assumed was no more than an academic exercise but which became a matter of weighty and heated public debate and finally judicial action
I first became interested in the subject of gene patents when I began reading up on the topic my future wife was researching pharmacogenom-ics To grasp what she did I first needed to study the science and in so doing I also studied the history of that science Along the way I read about the Human Genome Project and learned about the practice of gene patenting that it spawned Having had some experience and interest in general issues of the philosophy of intellectual property (see my 1997 PhD thesis turned 2000 book The Ontology of Cyberspace) my ears perked up when I first read about the notion of patenting genes So I dived into the research and thinking in my ordinary style of philosophical work Although I sometimes teach ethics my primary field is ontology and it is from an ontological approach that I start with everything in philosophy Thus I began to try to get a grip on the nature of the existence of the underlying objects some of which are ldquobrute factsrdquo (molecules exist with or without social institutions or intentionality) and some of which are social objects (like laws rights and other parts of ldquosocial realityrdquo existing only because of
Preface to the Second Edition xi
collective intentionality) The book was an attempt to lay all this out and to connect it together into a theory that is somehow connected to notions of ldquojusticerdquo which I argued bridges the worlds of brute facts and social objects
The conclusions I reached were I thought pretty neat Specifically I worked out an ontology of ldquothe commonsrdquo that I had never heard expressed before and one that connected nicely with the objects involved to show why artifacts and nature ought to be treated differently and how to decide what constitutes an artifact and what constitutes nature and a defense of the viewpoint that unmodified genes were clearly not artifacts It seemed all the more relevant and interesting even perhaps somewhat important in light of the then ongoing practice of gene patenting I was much too focused on the ontological arguments and their seeming relevance to real‐world practices than I was to the scientific and legal terminology with which I was engaging and this was an error When the book was released minor errors I made in using technical terminology from both the science and the law were latched onto by a couple critical reviewers from the Intellectual Property law and teaching worlds and urged as a basis to ignore my substantive arguments They were right to call out the errors and I have attempted to correct them in this edition Regardless the underlying argu-ments I had set forth would become shortly echoed nearly precisely in the lawsuit that the American Civil Liberties Union (ACLU) spearheaded against Myriad Corp over the BRCA1amp2 gene patents
For a brief period of time partly due to lucky timing I was thrust head-long into the public debates about gene patenting with the Myriad case leading the headlines Given numerous opportunities to engage publicly with the issues and ideas I had previously assumed were only academic musings unlikely to alter public policy and given feedback and counterar-guments in those same venues the general arguments could be more finely honed This edition attempts to coalesce them
Perhaps more importantly in the intervening years since I began my musings about the nature of genes artifacts nature and patents I came to learn the very personal impact that gene patents have on peoplersquos lives Because the ACLU chose to sue over the patents on BRCA1amp2 genes there was a ready‐made large and passionate community (mostly women) whose heredity put them at risk of breast and ovarian cancers but who were basically forced into paying monopolistic prices for the only test available for the gene which was patented by Myriad Corp Breast cancer and the threat of inherited tendencies for breast cancer are real They are not legal
xii Preface to the Second Edition
sophistry they are not philosophical musing They kill people or alter their lives irrevocably
I began researching and considering the effects of gene patents believing they were potentially a threat to the conduct of science whose foundational objects I argued were part of a commons‐by‐necessity but I realized after my book came out that real lives were being harmed by patents on genes The Myriad case brought together the theoretical with the actual for me and the dynamics of both the case and the loud and sometimes angry public debate raised my awareness not only about this particular subject but also the power and responsibility of academic research in the sphere of public policy Suddenly ideas seemed more important had relevance outside the academy and could perhaps make a difference in peoplesrsquo lives I began to interact with the activists who were fighting to liberate genes to stop com-panies like Myriad in the courts and engage not just in the philosophical arguments but in those fights I joined with authors of amicus (friend of the court) briefs interviewed and interacted with BRCA1amp2 mutation‐positive women who were actively pursuing an end to a practice that I had only pre-viously considered to be an interesting metaphysical conundrum I also debated Intellectual Property (IP) attorneys and others primarily with backgrounds in biotech industries and learning better the nature of their arguments I came to understand that most of them including Kevin Noonan who once called me a ldquoliarrdquo on his blog but who has now drafted the foreword to this edition that they too generally have the best intentions Many like Dr Noonan truly expect that without gene patents as they existed until recently the sort of innovation we need in biomedical technol-ogies would not occur as it should
Throughout the course of the litigation in Myriad I remained engaged continued to speak to hone my arguments adding to my list of criteria for something to be a creation (artifact) capable of patent ldquodesignrdquo (as well as intention and being man‐made) and finally rejoicing when the decision of the Supreme Court came out as close to what I believed and argued was right as possible I had seen an academic idea mature and bloom into public policy real law enforceable justice While I realistically believe that the first edition of this book had only a very minor role in what finally happened I am proud to have played some part to have foreseen the issues to argue them honestly from what I think is a rational and logical standpoint and see that the world can be changed by ideas
Preface to the Second Edition xiii
There remain issues to discuss and not everything about gene patents has been resolved by Myriad Some still argue that cDNA ought not to be patent‐eligible (in fact I still think it should be under the criteria I have set forth though there are also arguments to be made that it is not somehow ldquodesignedrdquo by man) Moreover we should expect patent attorneys to do their creative best to continue to pursue patents on as much of the genome as they can within the constraints of Myriad Finally Myriad Corp has not given up They are still suing potential competitors under theories of infringement of parts of their patents that might have survived the ACLUrsquos case against them We shall see how they are eventually resolved and what the future holds for companies like theirs who profited mightily from gene patents for decades I describe as much of this recent legal history as possible in this edition
This book is meant to be a definitive version sewing up the past five years since the first edition emerged and so much changed in the world summa-rizing that recent history and refining the arguments I originally made correcting errors and describing where we are where we yet may be and why gene patents as they once were ought never to be again
David KoepsellAugust 14 2014
Mexico City Mexico
Foreword
David and I have had a friendly disagreement about the subject (and even the title) of this book ever since it was first published and I am happy that he asked me to write this Foreword to the Second Edition The issues David raises in the pages to follow continue to be relevant to a discussion of philosophy and patent law with events that have occurred since the first edition justifying (indeed demanding) this update
Without getting into the deep waters of philosophy (Davidrsquos meacutetier not mine) as we have discussed the issues in the book David contends that he takes a deontological approach and has characterized mine as a utilitarian one Accepting that dichotomy I understand the difference to be that David is operating from ldquofirst principlesrdquo about the rules society should impose on human activity and specifically on what the law permits individuals to ldquoownrdquo with regard to genes and more broadly naturally occurring substances I disagree with that approach on several levels perhaps the most germane of which is that if we posit rules we need to impose a rule‐giver and the potential for improvident rules (if not outright abuse of the privilege) makes me wary in some ways I subscribe to Lani Gruinierrsquos suspicions about the effects of the ldquotyranny of the majorityrdquo in this regard
Part of that tyranny is also the tyranny of unintended or intentional ignorance The issue heremdashldquogenerdquo patentingmdashis one at the intersection of molecular biology and modern genetics on the one hand and patent law (an area notorious for its arcane minutiae) I used to joke with my col-leagues about the effect of trying to explain my position to a lay audience of any type and how I distrusted those who advocated that all that was needed was to ldquoeducaterdquo the public the press and policy makers The problem for proponents of gene patenting has been that opponents have gotten the better part of the debate not by making a reasoned philosophical argument such as the one you will find in these pages but instead by making an
Foreword xv
emotional plea to individuals afraid that corporate America was trying to ldquostealrdquo their genes which has proven very effective This process began with an Op‐Ed piece in The New York Times by Michael Crichton wherein he posited a scenario where a patent holder knocks on your door one day and demands payment for the use of ldquoherrdquo patented gene that resides in your liver (Not coincidentally Dr Crichton had just published a novel on the perils of genetic engineering and corporate ownership of human genes complete with an essay as an addendum containing his arguments against the practice And it should be noted that a constant theme in his novels was a mistrust of technology and particularly the ability of humans to use it without dire consequences) Academics like my friend Lori Andrews at Illinois Institute of Technology (IIT)‐Kent School of Law joined in this theme which was picked up eventually by most popular press outlets and became regrettably the canonical narrative on gene patenting culminating in the American Civil Liberties Unionrsquos (ACLUrsquos) ldquoKeep Your Hands Off My Genesrdquo slogan and logo I hope that this essay provides some antidote to this argument which is founded on the literal fear that someone can ldquoownrdquo you (David assures me that his title is allegorical and that he acknowledges that in all countries that have banned slavery no one can ldquoownrdquo another human being or a part of them See the 13th Amendment I assure you that the ACLU has no such illusions about the intended consequences of their ownership rhetoric)
My philosophy is that the principle we should follow is the greatest good to the greatest number while not infringing on individual rights without (at least) compensation As regards patent law this principle is translated into rules that foster the broadest disclosure of technology possible in return for exclusive patent rights and robust‐enough enforcement rights for patents that they provide sufficient certainty to promote investment so his technology is commercialized to benefit the greatest number In my role as a biotechnology patent attorney I have seen how risky investment in biotechnology can be (indeed the evidence is overwhelming that for all its successes biotechrsquos history is littered with the remains of companies that have failed) and how important it is to have a sound patent system of predictable rights go support that investment
The evidence in support of ldquogene patentingrdquo and more broadly natural products patenting is strong the biotechnology industry has promoted innovation in the form of new drugs and diagnostics assays for a genera-tion This may continue despite the recent restrictions on patent protection
xvi Foreword
for genes and natural products (including patent‐restricting decisions in Mayo Collaborative Labs v Prometheus Labs and Assoc of Molecular Pathologists v Myriad Genetics and recently promulgated US Patent and Trademark Office Guidances on Subject Matter Eligibility) In fact these very restrictions suggest that we would benefit from an appreciation of the facts surrounding the past thirty years of gene patenting to understand why these restrictions are not only wrongheaded but dangerous for future innovation
These include debunking several myths First the concern that patents on specific human genes in some way inhibit innovation in basic genetic research is entirely unfounded One reason is that the genetic information itself is not patented while isolated DNA is encompassed by gene patent claims and described in those claims by its sequence the sequence itself is unpatented information that can be used freely for any purpose (eg inter-rogating genetic databases from other species or even human DNA inter alia to find related genes in those databases) Indeed the innovative benefits to gene patenting are evident in at least two ways First scientific publication databases reveal that there have been more than 11 000 scientific papers published on the BRCA1 and BRCA2 genes since the patents claiming them were granted This outcome refutes the prediction that gene patenting would create a ldquotragedy of the anticommonsrdquo where scientific research would be stifled by patenting (see Heller amp Eisenberg 1998 ldquoCan Patents Deter Innovation The Anticommons in Biomedical Researchrdquo Science 280 698ndash701)) a conclusion supported by the overwhelming majority of studies done on this subject (see for example Walsh et al 2003 ldquoScience and the Law Working Through the Patent Problemrdquo Science 299 1020 Walsh et al 2005 ldquoScience and Law View from the Bench Patents and Material Transfersrdquo Science 309 2002ndash03)
In addition policies that the US Patent and Trademark Office adopted in 2001 required applicants to disclose a practical utility for the product of a gene claimed in a patent These requirements were imposed at a time when the standards for scientific journal publication were much less stringent so that identifying a gene by the extent of genetic similarity between the ldquonewrdquo gene and previously discovered genes was enough for publication But it was not enough for a patent which has been held to be ldquonot a hunting license It is not a reward for the search but compensation for its successful conclusionrdquo Thus genes encoding proteins having no known use or biological activity cannot be patented because to do so would allow the
Foreword xvii
gene to be within the exclusive patent right undeservedly the public would not have received its quid pro quo of a useful invention in return for patent exclusivity All such genes not having patent protection are in the public domain (from which they cannot be retrieved for future patenting) and for humans these constitute the vast majority of genes identified inter alia by the Human Genome Project
The role for patenting genes and the related genetic diagnostic methods using this genetic information in the successes of the biotechnology era are evident The industry has produced hundreds of biologic drugs (at an ever‐increasing rate) that have provided effective treatment for a variety of illnesses and decoding the human genome has enabled researchers to iden-tify genes like the BRCA1 and BRCA2 genes that can be used in predictive genetic diagnostic tests Even the much‐maligned Myriad Genetics has played a positive role in the development and prevalence of genetic diagnostic testing It must be remembered that in 1997 (when Myriadrsquos BRCA gene patents were granted) genetic testing was in its infancy and companies like Myriad were under the burden of convincing payers that the tests did the one thing that all insurers public or private require of such tests save them money in the long run by identifying patients with a high probability of becoming ill and costing the insurers much more for treatment than the costs of prophylaxis Moreover Myriad and like com-panies needed to convince doctors that the testing was worthwhile and to establish a network of genetic counselors who could explain to healthy women that they were at much greater risk of developing breast or ovarian cancer than normal under circumstances that resulted in empowerment from the information and not abject fear And in 1997 genetic sequencing technology was not as developed as it is now and the mechanisms and tech-niques needed to minimize or eliminate the occurrence of false positives or negatives had not been conclusively established All these burdens were ones borne by Myriad and these activities produced the world we have today
It is possible as some have argued that BRCA tests may have been devel-oped independently by individual researchers in the absence of patent pro-tection However it is almost certain that such researchers would have been located in medical centers in urban environments Under these circum-stances women living in or near cities such as New York Boston Philadelphia Cleveland Chicago Houston Denver Los Angeles San Francisco Portland and Seattle might have had access to these tests But what of women in
xviii Foreword
Appalachia or the Four Corners region in the Southwest or more generally in rural or other relatively remote locations Would Yale University for example have had any incentive to provide access to the BRCA tests to these women in these far‐off locations Or to provide genetic counseling where the women lived Or to lobby state Medicare administrators or private insurance commissioners to cover the test I think that unlikely Myriad Genetics did all of this as well as perform outreach to the obstetrics and gynecology doctors throughout the United States so that these primary care doctors were aware of the tests Myriad did not ace from altruism but as part of their business plan in order to expand the number of patients who received the test and thus maximize the companyrsquos revenue While it may be counterintuitive to some these circumstances may have been the most effective way not only to pro-mulgate the BRCA tests but also to facilitate acceptance of genetic diagnostic testing for other diseases showing that in this instance Adam Smith rather than Karl Marx provided the most practical solution to the problem of estab-lishing genetic diagnostic testing as a recognized component of a physicianrsquos diagnostic armamentarium
Fortunately the significance and impact of recent US court decisions (spe-cifically the Myriad case) is much less than it would have been ten to thirty years ago Due to patent term rules most patents (and applications) on iso-lated DNA filed in the heyday of the Human Genome Project (approxi-mately 1998ndash2001) are near the end of their actual or potential term indeed a recent study shows that the number of granted patents having at least one claim reciting an isolate DNA comprising a gene peaked in 1999 and has been dropping since 2005 (Graff et al 2013 ldquoNot quite a myriad of gene pat-entsrdquo Nature Biotechnology 31 404ndash410)) These recent decisions in the United States have not harmed the biotechnology industry because they retained patent eligibility for species of DNA that show evidence of the ldquohand of manrdquo and do not occur in nature These include enzymatically pro-duced copies (cDNA) of cellular messenger RNA and should also encom-pass the tools of the recombinant geneticist (eg including recombinant vectors for cloning and expressing genes in heterologous cells) Most impor-tantly the US Supreme Court did not overturn its Diamond v Chakrabarty decision wherein recombinant cells were determined to be patent eligible
Thus in many ways the question of patent eligibility for human genes is a philosophical one However that does not mean that how we think about patent eligibility for isolated DNA is irrelevant to important questions regarding the usefulness of patents for promoting progress and innovation
Foreword xix
Indeed the most pernicious effects of the current trend in the zeitgeist against patenting has been not that genes have become harder to patent but rather that the ability to patent other natural products has been called into question It is the extension of these recent decisions on isolated DNA to all natural products that poses the greatest threat to innovation This threat can be illustrated by a thought experiment for which of these substances should patent protection be withheld
bull A petrochemical with excellent lubrication qualities isolated in pure form and used as improved motor oil
bull Vitamin B12 isolated from beef muscle formulated into a medicament used to cure anemia in children
bull The drug penicillin isolated from a mixture of naturally produced chemicals made by a mold and formulated as a drug to cure syphilis (which is otherwise eventually fatal)
bull Human urinary erythropoietin formulated to treat anemia in kidney dialysis patients
bull The gene responsible for Gaucherrsquos disease a lipid storage disease wherein the gene is used to make the missing protein that is administered to children and that cures an otherwise incurable and fatal disease
The current answer is that none of them are patent‐eligible per se (although there may be ways to claim them that could pass eligibility muster that remains to be seen) Judge Sweet the US District Court judge who first ruled that isolated DNA was not patent‐eligible did so using language carefully crafted to avoid encompassing all natural products into his decision Specifically Judge Sweet distinguished isolated DNA as the ldquophysical embodiments of genetic informationrdquo a property limited to DNA and not shared by other natural products (While an enzymatic protein could be characterized as the physical embodiment of catalysis of a particular chemical reaction that formulation has much less appeal and inherent rationale than Judge Sweetrsquos regarding DNA) Instead of this careful formu-lation the broader language employed by the Supreme Court as well as the broader rationale the Court used in finding genomic DNA unpatentable has made it easier to employ that fractured logic to render patent‐ineligible naturally occurring molecules other than DNA
I would be remiss not to mention the rather comical (but persistent) efforts of former Acting Solicitor General Neal Katyal who included in the
xx Foreword
US Governmentrsquos amicus brief to the Federal Circuit the distinction engine he called a ldquomagic microscoperdquo embodying the concept that if you are able to visualize a natural product (like a genomic DNA molecule) using this mythical microscope then the natural product would not be patent‐eligible whereas if you could not (eg a cDNA molecule) then the natural product could be eligible for patenting Fortunately the disdain with which the Federal Circuit greeted this fantasy (particularly from Judge Moore) prompted its quick abandonment as are argumentative distinction as the case moved forward Nonetheless both the courts and the US Patent and Trademark Office have adopted this standard de facto even as it becomes the theory that dare not speak its name in legal circles
The philosophical point here is that these substances and natural products generally have been deemed patent‐ineligible categorically which while consistent with (and perhaps even mandated by) the deon-tological approach imposes a distinction that cannot be flexibly applied to the individual circumstances Without such flexibility the law is con-strained to use one criterion that the substance can be found in some form in nature to decide patent eligibility instead of making the deter-mination of whether permitting patenting exclusivity satisfies the cri-teria that the invention ldquopromotes progressrdquo as the US Constitution requires and has a benefit to the public that outweighs any categorical disabilities
The potential that using this standard for determining patent eligibility will result in negative practical outcomes that no one in this debate desires is illustrated by a 2012 Report from the National Institutes of Health Natural Product Branch regarding statistics relating to the number of FDA approvals (a total of 1355) for new drugs falling into the following categories
Drug typesource Number
Biological (B) 203Natural product (N) 55Natural product (botanical) (NB) 149Derived from a natural product (ND) 298Totally synthetic (S) 393Total synthesisnatural product (S) 176Vaccine (S) 81
Foreword xxi
These statistics illustrate the consequences of a general ban on patenting naturally derived products of the 1355 drugs approved between 1981 and 2010
bull Fifty percent of all small‐molecule drugs approved between 2000 and 2010 are natural products
bull About 75 of antibacterial drugs are natural products or derived from natural products
bull Almost 80 of small‐molecule anticancer drugs were natural products or derivatives
In addition only 15 of drugs approved during this time frame were so‐called biologic drugs which are also putatively patent‐ineligible This the problems caused by the current interpretation of the law excluding natural product drugs from patent eligibility will be exacerbated in view of reports from every study showing that the percentage of drugs that are biologic drugs has been growing and will be the predominant type of drug devel-oped in the 2011ndash2030 time period
Another ldquothought experimentrdquo illustrating the practical illogic (David can provide his philosophical justifications in the body of the text) of broad natural products patent ineligibility is as follows Suppose a researcher finds a molecule produced by the human body that causes blood pressure homeo-stasis that is lack of this molecule causes or contributes to the disease of high blood pressure The logical consequence of the current natural prod-uct patent ineligibility standards would be that the closer a drug molecule is to the structure of the molecule as it occurs in the body the less patent‐eli-gible it would be Practically speaking there would be no incentive to modify the molecule to confer patent eligibility on the altered molecule because of the unpredictability of such changes on the molecule such as its biological activity half‐life stability antigenicity or other biological prop-erties And there would be even less incentive to develop the molecule as a drug because without patent protection the available regulatory exclusiv-ities would not pass economic muster to sufficiently defray the large development costs (some of which prevent drugs neither safe nor effica-cious from being sold and thus provide their own justification)
There is one further pernicious outcome that can be predicted to arise from a ban on natural products patents (including patents on isolated DNA and genetic diagnostic methods based on such isolated DNA) Natural
xxii Foreword
products are almost by nature complex and an ldquoactive principlerdquo isolated from nature is beneficial because it is isolated Kodak ran an advertisement in the journal Nature in the 1970s showing a scientist in a lab coat holding a 250‐ml flask and standing next to several bushels of green peppers wherein the content of the flask was the purified ldquoessence of green pepperrdquo equivalent to that substance contained in all the peppers in all the bushels and bushels that the scientist was standing beside But this very complexity makes it possible for the ldquoactive principlerdquo (either as a chemical compound or as a diagnostic genetic sequence) to be ldquohidden in plain sightrdquo in ways that may be particularly refractory to reverse engineering
For example even using somewhat dated ldquogene chiprdquo technology genetically diagnostic markers could be encrypted onto a microchip comprising 10 000 unique sequences wherein a computer‐readable bar code would be used to identify the positions of diagnostically relevant sequences on the chip This form of encryption which can be random and confounded by the presence of positive and negative control sequences as well as variable numbers and lengths of sequences specific for the gene (or more likely genes) of interest would be very difficult if not impossible to reverse‐engineer Even if reverse engineering could be done it would be difficult and expensive to undertake and thus make it more likely that the innovator would be able to avoid com-petition (ie it would provide unlimited exclusivity to its purveyor not con-strained by patent term or burdened by the requirement that the invention be disclosed with the specificity required by the Patent Act) While the possi-bility that this type of chip could be made exists with or without patents the absence of patent protection could tip the scales in favor of the extra effort needed and risk entailed in nondisclosure if the reward of extended ldquomonopolyrdquo is great enough But particularly for genetic diagnostic inven-tions the benefits of developing a proprietary database for which a corpora-tion could provide the economic and marketing wherewithal to expeditiously produce would result in a ldquoworst of both worldsrdquo outcome unlimited exclu-sivity based on undisclosed proprietary information that not only is difficult to replicate but whose existence would inhibit competition After all if a company had such a database its outcome for any particular patientrsquos test would be more accurate (and might identify disease riskndashassociated genetic variants not available elsewhere) and this would provide little incentive for a physician to choose an alternative provider to perform the test (and even more malevolently could create a system where the wealthy could afford the best diagnostic testing while the less affluent would be restricted to the more
Foreword xxiii
limited assays offered by companies without access to the ldquoinnovatorrsquosrdquo proprietary database information)
The other aspect of foreclosing patents for certain substances or technology areas categorically is that it upsets a carefully crafted dynamic that has worked extremely well during the biotech era between ldquotruerdquo innovators (typically university professors or small start‐up biotechnology companies) and more established companies capable of commercializing innovation Pundits who worry that permitting patenting will harm innovation miss an important point innovation will happen particularly in universities research institutes and like places because human nature demands it and regardless of whether patent protection is available The intelligent ape in us wants to know and the disparity between how univer-sity professors and patent lawyers are paid should establish how powerful the need to know can be Patenting and the impetus for patenting provided for example by the BayhndashDole Act in the United States prevents the fruits of these inventive efforts from mere predation by commercial concerns The benefits that can be had from a system where private commercializa-tion is encouraged are tempered by the types of corporate shenanigans that raise cogent criticisms of the system But perhaps it is mere human nature that people (in the corporate as well as individual sense) will want to expro-priate technology rather than pay for it and patenting prohibits (or at least retards) this outcome (if not these tendencies) Thus paradoxically limiting patent rights does not free innovation but rather makes it more likely to be kept captive by the entities capable of using such innovation to make a commercial product that is not from the power of building a better mouse-trap but by being able to outcompete smaller innovators merely by their greater economic prowess and resources Conversely patents provide a way for the innovators to protect their innovations and compel corporations to license their inventions producing revenue that can be used to fund future research endeavors This useful cycle has resulted in the successes of the biotechnology era and is something that we abandon at our peril
Thus in my view patents are a useful tool for achieving these societally ben-eficial goals promoting innovation and commercialization and protecting and supporting individuals who use the patent system to protect the products of their labors from being expropriated by others David provides a cogent and honest counterpoint to these thoughts Enjoy reading them
Kevin E NoonanChicago Illinois 2014
To Alexandro
Contents
Acknowledgments viii
Preface to the Second Edition x
Foreword xiv
Introduction xxiv
1 Individual and Collective Rights in Genomic Data Preliminary Issues 1
2 Ethics and Ontology A Brief Discourse on Method 21
3 The Science of Genes 30
4 DNA Species Individuals and Persons 52
5 Legal Dimensions in Gene Ownership 69
6 BRCA1 and 2 The Myriad Case and Beyond 88
7 Are Genes Intellectual Property 101
8 DNA and The Commons 119
9 Pragmatic Considerations of Gene Ownership 137
10 Nature Genes and the Scientific Commons A Social Ontology of Invention 155
11 So Who Owns You Some Conclusions About Genes Property and Personhood 165
Notes 182
Index 194
Acknowledgments
Many thanks must be given to those whom I have spoken to about the issues discussed herein since the first edition and who helped inform the updates including Tania Simoncelli Luigi Palombi Joanna Rudnick Dan Ravicher Kevin Noonan James Watson and numerous online commenters who helped point out errors and hone my arguments Thank you also to my colleagues at Delft University of Technology where I have worked the past 6 years and continued discussing and sharpening my approach to the ideas in this book and others
I remain grateful to the Yale Interdisciplinary Bioethics Center for appointing me as their Donaghue Initiative Fellow in Research Ethics 2006ndash2007 I drafted a significant portion of this book during that appoint-ment and had the chance to hash out many of these issues with the staff affiliated faculty and others who participated in events that year Special thanks to all the good people at Yale including especially Robert Levine Julius Landwirth Carol Pollard Autumn Ridenour and Jonathan Moser Thanks also to the folks at the New Haven dog park for keeping my dear departed Buttercup and me company during my residency at Yale Many thanks to my wife Vanessa who gave me significant scientific guidance and lots of encouragement as I worked out these issues and drafted the original book and who helped redraft Chapter 3 for this edition Thanks to my 3‐year‐old daughter Amelia whose appearance brought new purpose to my life and my work My parents Eva Hwa and Richard Koepsell provided commentary and feedback on early drafts of chapters and I am as always grateful for their continuing encouragement My dear friend Peter Hare who passed away in 2008 also kept me company bought me lunches and encouraged my work while at Yale hellip I am grateful for his guidance and friendship and will miss him dearly Thanks to Barry Smith who has remained a helpful and encouraging mentor as I pursue the sometimes
Acknowledgments ix
frustrating but often fruitful path of philosophy Thank you also to Denise Riley who helped dig up obscure articles and arranged almost all the research for my initial trip to Yale that hatched the first edition Finally many thanks to anyone I have forgotten including all those who have given me probing questions puzzling scenarios and further guidance in the talks I have given on this fascinating subject over the past 8 years
David KoepsellAugust 14 2014
Mexico City Mexico
Preface to the Second Edition
A lot has happened in nearly every respect since I first decided to try to delve into philosophical issues of gene patenting nearly a decade ago I have learned much the world has changed and I have changed I would very much like to think I have played a role in that change though chances are things would have changed in almost exactly the same way without my small contribution When the first edition came out patenting genes was still a regular part of biotech and only months after the first edition appeared did a surprising and now‐landmark lawsuit alter that significantly Little did I realize the nature of the forces that would be involved in what I had originally assumed was no more than an academic exercise but which became a matter of weighty and heated public debate and finally judicial action
I first became interested in the subject of gene patents when I began reading up on the topic my future wife was researching pharmacogenom-ics To grasp what she did I first needed to study the science and in so doing I also studied the history of that science Along the way I read about the Human Genome Project and learned about the practice of gene patenting that it spawned Having had some experience and interest in general issues of the philosophy of intellectual property (see my 1997 PhD thesis turned 2000 book The Ontology of Cyberspace) my ears perked up when I first read about the notion of patenting genes So I dived into the research and thinking in my ordinary style of philosophical work Although I sometimes teach ethics my primary field is ontology and it is from an ontological approach that I start with everything in philosophy Thus I began to try to get a grip on the nature of the existence of the underlying objects some of which are ldquobrute factsrdquo (molecules exist with or without social institutions or intentionality) and some of which are social objects (like laws rights and other parts of ldquosocial realityrdquo existing only because of
Preface to the Second Edition xi
collective intentionality) The book was an attempt to lay all this out and to connect it together into a theory that is somehow connected to notions of ldquojusticerdquo which I argued bridges the worlds of brute facts and social objects
The conclusions I reached were I thought pretty neat Specifically I worked out an ontology of ldquothe commonsrdquo that I had never heard expressed before and one that connected nicely with the objects involved to show why artifacts and nature ought to be treated differently and how to decide what constitutes an artifact and what constitutes nature and a defense of the viewpoint that unmodified genes were clearly not artifacts It seemed all the more relevant and interesting even perhaps somewhat important in light of the then ongoing practice of gene patenting I was much too focused on the ontological arguments and their seeming relevance to real‐world practices than I was to the scientific and legal terminology with which I was engaging and this was an error When the book was released minor errors I made in using technical terminology from both the science and the law were latched onto by a couple critical reviewers from the Intellectual Property law and teaching worlds and urged as a basis to ignore my substantive arguments They were right to call out the errors and I have attempted to correct them in this edition Regardless the underlying argu-ments I had set forth would become shortly echoed nearly precisely in the lawsuit that the American Civil Liberties Union (ACLU) spearheaded against Myriad Corp over the BRCA1amp2 gene patents
For a brief period of time partly due to lucky timing I was thrust head-long into the public debates about gene patenting with the Myriad case leading the headlines Given numerous opportunities to engage publicly with the issues and ideas I had previously assumed were only academic musings unlikely to alter public policy and given feedback and counterar-guments in those same venues the general arguments could be more finely honed This edition attempts to coalesce them
Perhaps more importantly in the intervening years since I began my musings about the nature of genes artifacts nature and patents I came to learn the very personal impact that gene patents have on peoplersquos lives Because the ACLU chose to sue over the patents on BRCA1amp2 genes there was a ready‐made large and passionate community (mostly women) whose heredity put them at risk of breast and ovarian cancers but who were basically forced into paying monopolistic prices for the only test available for the gene which was patented by Myriad Corp Breast cancer and the threat of inherited tendencies for breast cancer are real They are not legal
xii Preface to the Second Edition
sophistry they are not philosophical musing They kill people or alter their lives irrevocably
I began researching and considering the effects of gene patents believing they were potentially a threat to the conduct of science whose foundational objects I argued were part of a commons‐by‐necessity but I realized after my book came out that real lives were being harmed by patents on genes The Myriad case brought together the theoretical with the actual for me and the dynamics of both the case and the loud and sometimes angry public debate raised my awareness not only about this particular subject but also the power and responsibility of academic research in the sphere of public policy Suddenly ideas seemed more important had relevance outside the academy and could perhaps make a difference in peoplesrsquo lives I began to interact with the activists who were fighting to liberate genes to stop com-panies like Myriad in the courts and engage not just in the philosophical arguments but in those fights I joined with authors of amicus (friend of the court) briefs interviewed and interacted with BRCA1amp2 mutation‐positive women who were actively pursuing an end to a practice that I had only pre-viously considered to be an interesting metaphysical conundrum I also debated Intellectual Property (IP) attorneys and others primarily with backgrounds in biotech industries and learning better the nature of their arguments I came to understand that most of them including Kevin Noonan who once called me a ldquoliarrdquo on his blog but who has now drafted the foreword to this edition that they too generally have the best intentions Many like Dr Noonan truly expect that without gene patents as they existed until recently the sort of innovation we need in biomedical technol-ogies would not occur as it should
Throughout the course of the litigation in Myriad I remained engaged continued to speak to hone my arguments adding to my list of criteria for something to be a creation (artifact) capable of patent ldquodesignrdquo (as well as intention and being man‐made) and finally rejoicing when the decision of the Supreme Court came out as close to what I believed and argued was right as possible I had seen an academic idea mature and bloom into public policy real law enforceable justice While I realistically believe that the first edition of this book had only a very minor role in what finally happened I am proud to have played some part to have foreseen the issues to argue them honestly from what I think is a rational and logical standpoint and see that the world can be changed by ideas
Preface to the Second Edition xiii
There remain issues to discuss and not everything about gene patents has been resolved by Myriad Some still argue that cDNA ought not to be patent‐eligible (in fact I still think it should be under the criteria I have set forth though there are also arguments to be made that it is not somehow ldquodesignedrdquo by man) Moreover we should expect patent attorneys to do their creative best to continue to pursue patents on as much of the genome as they can within the constraints of Myriad Finally Myriad Corp has not given up They are still suing potential competitors under theories of infringement of parts of their patents that might have survived the ACLUrsquos case against them We shall see how they are eventually resolved and what the future holds for companies like theirs who profited mightily from gene patents for decades I describe as much of this recent legal history as possible in this edition
This book is meant to be a definitive version sewing up the past five years since the first edition emerged and so much changed in the world summa-rizing that recent history and refining the arguments I originally made correcting errors and describing where we are where we yet may be and why gene patents as they once were ought never to be again
David KoepsellAugust 14 2014
Mexico City Mexico
Foreword
David and I have had a friendly disagreement about the subject (and even the title) of this book ever since it was first published and I am happy that he asked me to write this Foreword to the Second Edition The issues David raises in the pages to follow continue to be relevant to a discussion of philosophy and patent law with events that have occurred since the first edition justifying (indeed demanding) this update
Without getting into the deep waters of philosophy (Davidrsquos meacutetier not mine) as we have discussed the issues in the book David contends that he takes a deontological approach and has characterized mine as a utilitarian one Accepting that dichotomy I understand the difference to be that David is operating from ldquofirst principlesrdquo about the rules society should impose on human activity and specifically on what the law permits individuals to ldquoownrdquo with regard to genes and more broadly naturally occurring substances I disagree with that approach on several levels perhaps the most germane of which is that if we posit rules we need to impose a rule‐giver and the potential for improvident rules (if not outright abuse of the privilege) makes me wary in some ways I subscribe to Lani Gruinierrsquos suspicions about the effects of the ldquotyranny of the majorityrdquo in this regard
Part of that tyranny is also the tyranny of unintended or intentional ignorance The issue heremdashldquogenerdquo patentingmdashis one at the intersection of molecular biology and modern genetics on the one hand and patent law (an area notorious for its arcane minutiae) I used to joke with my col-leagues about the effect of trying to explain my position to a lay audience of any type and how I distrusted those who advocated that all that was needed was to ldquoeducaterdquo the public the press and policy makers The problem for proponents of gene patenting has been that opponents have gotten the better part of the debate not by making a reasoned philosophical argument such as the one you will find in these pages but instead by making an
Foreword xv
emotional plea to individuals afraid that corporate America was trying to ldquostealrdquo their genes which has proven very effective This process began with an Op‐Ed piece in The New York Times by Michael Crichton wherein he posited a scenario where a patent holder knocks on your door one day and demands payment for the use of ldquoherrdquo patented gene that resides in your liver (Not coincidentally Dr Crichton had just published a novel on the perils of genetic engineering and corporate ownership of human genes complete with an essay as an addendum containing his arguments against the practice And it should be noted that a constant theme in his novels was a mistrust of technology and particularly the ability of humans to use it without dire consequences) Academics like my friend Lori Andrews at Illinois Institute of Technology (IIT)‐Kent School of Law joined in this theme which was picked up eventually by most popular press outlets and became regrettably the canonical narrative on gene patenting culminating in the American Civil Liberties Unionrsquos (ACLUrsquos) ldquoKeep Your Hands Off My Genesrdquo slogan and logo I hope that this essay provides some antidote to this argument which is founded on the literal fear that someone can ldquoownrdquo you (David assures me that his title is allegorical and that he acknowledges that in all countries that have banned slavery no one can ldquoownrdquo another human being or a part of them See the 13th Amendment I assure you that the ACLU has no such illusions about the intended consequences of their ownership rhetoric)
My philosophy is that the principle we should follow is the greatest good to the greatest number while not infringing on individual rights without (at least) compensation As regards patent law this principle is translated into rules that foster the broadest disclosure of technology possible in return for exclusive patent rights and robust‐enough enforcement rights for patents that they provide sufficient certainty to promote investment so his technology is commercialized to benefit the greatest number In my role as a biotechnology patent attorney I have seen how risky investment in biotechnology can be (indeed the evidence is overwhelming that for all its successes biotechrsquos history is littered with the remains of companies that have failed) and how important it is to have a sound patent system of predictable rights go support that investment
The evidence in support of ldquogene patentingrdquo and more broadly natural products patenting is strong the biotechnology industry has promoted innovation in the form of new drugs and diagnostics assays for a genera-tion This may continue despite the recent restrictions on patent protection
xvi Foreword
for genes and natural products (including patent‐restricting decisions in Mayo Collaborative Labs v Prometheus Labs and Assoc of Molecular Pathologists v Myriad Genetics and recently promulgated US Patent and Trademark Office Guidances on Subject Matter Eligibility) In fact these very restrictions suggest that we would benefit from an appreciation of the facts surrounding the past thirty years of gene patenting to understand why these restrictions are not only wrongheaded but dangerous for future innovation
These include debunking several myths First the concern that patents on specific human genes in some way inhibit innovation in basic genetic research is entirely unfounded One reason is that the genetic information itself is not patented while isolated DNA is encompassed by gene patent claims and described in those claims by its sequence the sequence itself is unpatented information that can be used freely for any purpose (eg inter-rogating genetic databases from other species or even human DNA inter alia to find related genes in those databases) Indeed the innovative benefits to gene patenting are evident in at least two ways First scientific publication databases reveal that there have been more than 11 000 scientific papers published on the BRCA1 and BRCA2 genes since the patents claiming them were granted This outcome refutes the prediction that gene patenting would create a ldquotragedy of the anticommonsrdquo where scientific research would be stifled by patenting (see Heller amp Eisenberg 1998 ldquoCan Patents Deter Innovation The Anticommons in Biomedical Researchrdquo Science 280 698ndash701)) a conclusion supported by the overwhelming majority of studies done on this subject (see for example Walsh et al 2003 ldquoScience and the Law Working Through the Patent Problemrdquo Science 299 1020 Walsh et al 2005 ldquoScience and Law View from the Bench Patents and Material Transfersrdquo Science 309 2002ndash03)
In addition policies that the US Patent and Trademark Office adopted in 2001 required applicants to disclose a practical utility for the product of a gene claimed in a patent These requirements were imposed at a time when the standards for scientific journal publication were much less stringent so that identifying a gene by the extent of genetic similarity between the ldquonewrdquo gene and previously discovered genes was enough for publication But it was not enough for a patent which has been held to be ldquonot a hunting license It is not a reward for the search but compensation for its successful conclusionrdquo Thus genes encoding proteins having no known use or biological activity cannot be patented because to do so would allow the
Foreword xvii
gene to be within the exclusive patent right undeservedly the public would not have received its quid pro quo of a useful invention in return for patent exclusivity All such genes not having patent protection are in the public domain (from which they cannot be retrieved for future patenting) and for humans these constitute the vast majority of genes identified inter alia by the Human Genome Project
The role for patenting genes and the related genetic diagnostic methods using this genetic information in the successes of the biotechnology era are evident The industry has produced hundreds of biologic drugs (at an ever‐increasing rate) that have provided effective treatment for a variety of illnesses and decoding the human genome has enabled researchers to iden-tify genes like the BRCA1 and BRCA2 genes that can be used in predictive genetic diagnostic tests Even the much‐maligned Myriad Genetics has played a positive role in the development and prevalence of genetic diagnostic testing It must be remembered that in 1997 (when Myriadrsquos BRCA gene patents were granted) genetic testing was in its infancy and companies like Myriad were under the burden of convincing payers that the tests did the one thing that all insurers public or private require of such tests save them money in the long run by identifying patients with a high probability of becoming ill and costing the insurers much more for treatment than the costs of prophylaxis Moreover Myriad and like com-panies needed to convince doctors that the testing was worthwhile and to establish a network of genetic counselors who could explain to healthy women that they were at much greater risk of developing breast or ovarian cancer than normal under circumstances that resulted in empowerment from the information and not abject fear And in 1997 genetic sequencing technology was not as developed as it is now and the mechanisms and tech-niques needed to minimize or eliminate the occurrence of false positives or negatives had not been conclusively established All these burdens were ones borne by Myriad and these activities produced the world we have today
It is possible as some have argued that BRCA tests may have been devel-oped independently by individual researchers in the absence of patent pro-tection However it is almost certain that such researchers would have been located in medical centers in urban environments Under these circum-stances women living in or near cities such as New York Boston Philadelphia Cleveland Chicago Houston Denver Los Angeles San Francisco Portland and Seattle might have had access to these tests But what of women in
xviii Foreword
Appalachia or the Four Corners region in the Southwest or more generally in rural or other relatively remote locations Would Yale University for example have had any incentive to provide access to the BRCA tests to these women in these far‐off locations Or to provide genetic counseling where the women lived Or to lobby state Medicare administrators or private insurance commissioners to cover the test I think that unlikely Myriad Genetics did all of this as well as perform outreach to the obstetrics and gynecology doctors throughout the United States so that these primary care doctors were aware of the tests Myriad did not ace from altruism but as part of their business plan in order to expand the number of patients who received the test and thus maximize the companyrsquos revenue While it may be counterintuitive to some these circumstances may have been the most effective way not only to pro-mulgate the BRCA tests but also to facilitate acceptance of genetic diagnostic testing for other diseases showing that in this instance Adam Smith rather than Karl Marx provided the most practical solution to the problem of estab-lishing genetic diagnostic testing as a recognized component of a physicianrsquos diagnostic armamentarium
Fortunately the significance and impact of recent US court decisions (spe-cifically the Myriad case) is much less than it would have been ten to thirty years ago Due to patent term rules most patents (and applications) on iso-lated DNA filed in the heyday of the Human Genome Project (approxi-mately 1998ndash2001) are near the end of their actual or potential term indeed a recent study shows that the number of granted patents having at least one claim reciting an isolate DNA comprising a gene peaked in 1999 and has been dropping since 2005 (Graff et al 2013 ldquoNot quite a myriad of gene pat-entsrdquo Nature Biotechnology 31 404ndash410)) These recent decisions in the United States have not harmed the biotechnology industry because they retained patent eligibility for species of DNA that show evidence of the ldquohand of manrdquo and do not occur in nature These include enzymatically pro-duced copies (cDNA) of cellular messenger RNA and should also encom-pass the tools of the recombinant geneticist (eg including recombinant vectors for cloning and expressing genes in heterologous cells) Most impor-tantly the US Supreme Court did not overturn its Diamond v Chakrabarty decision wherein recombinant cells were determined to be patent eligible
Thus in many ways the question of patent eligibility for human genes is a philosophical one However that does not mean that how we think about patent eligibility for isolated DNA is irrelevant to important questions regarding the usefulness of patents for promoting progress and innovation
Foreword xix
Indeed the most pernicious effects of the current trend in the zeitgeist against patenting has been not that genes have become harder to patent but rather that the ability to patent other natural products has been called into question It is the extension of these recent decisions on isolated DNA to all natural products that poses the greatest threat to innovation This threat can be illustrated by a thought experiment for which of these substances should patent protection be withheld
bull A petrochemical with excellent lubrication qualities isolated in pure form and used as improved motor oil
bull Vitamin B12 isolated from beef muscle formulated into a medicament used to cure anemia in children
bull The drug penicillin isolated from a mixture of naturally produced chemicals made by a mold and formulated as a drug to cure syphilis (which is otherwise eventually fatal)
bull Human urinary erythropoietin formulated to treat anemia in kidney dialysis patients
bull The gene responsible for Gaucherrsquos disease a lipid storage disease wherein the gene is used to make the missing protein that is administered to children and that cures an otherwise incurable and fatal disease
The current answer is that none of them are patent‐eligible per se (although there may be ways to claim them that could pass eligibility muster that remains to be seen) Judge Sweet the US District Court judge who first ruled that isolated DNA was not patent‐eligible did so using language carefully crafted to avoid encompassing all natural products into his decision Specifically Judge Sweet distinguished isolated DNA as the ldquophysical embodiments of genetic informationrdquo a property limited to DNA and not shared by other natural products (While an enzymatic protein could be characterized as the physical embodiment of catalysis of a particular chemical reaction that formulation has much less appeal and inherent rationale than Judge Sweetrsquos regarding DNA) Instead of this careful formu-lation the broader language employed by the Supreme Court as well as the broader rationale the Court used in finding genomic DNA unpatentable has made it easier to employ that fractured logic to render patent‐ineligible naturally occurring molecules other than DNA
I would be remiss not to mention the rather comical (but persistent) efforts of former Acting Solicitor General Neal Katyal who included in the
xx Foreword
US Governmentrsquos amicus brief to the Federal Circuit the distinction engine he called a ldquomagic microscoperdquo embodying the concept that if you are able to visualize a natural product (like a genomic DNA molecule) using this mythical microscope then the natural product would not be patent‐eligible whereas if you could not (eg a cDNA molecule) then the natural product could be eligible for patenting Fortunately the disdain with which the Federal Circuit greeted this fantasy (particularly from Judge Moore) prompted its quick abandonment as are argumentative distinction as the case moved forward Nonetheless both the courts and the US Patent and Trademark Office have adopted this standard de facto even as it becomes the theory that dare not speak its name in legal circles
The philosophical point here is that these substances and natural products generally have been deemed patent‐ineligible categorically which while consistent with (and perhaps even mandated by) the deon-tological approach imposes a distinction that cannot be flexibly applied to the individual circumstances Without such flexibility the law is con-strained to use one criterion that the substance can be found in some form in nature to decide patent eligibility instead of making the deter-mination of whether permitting patenting exclusivity satisfies the cri-teria that the invention ldquopromotes progressrdquo as the US Constitution requires and has a benefit to the public that outweighs any categorical disabilities
The potential that using this standard for determining patent eligibility will result in negative practical outcomes that no one in this debate desires is illustrated by a 2012 Report from the National Institutes of Health Natural Product Branch regarding statistics relating to the number of FDA approvals (a total of 1355) for new drugs falling into the following categories
Drug typesource Number
Biological (B) 203Natural product (N) 55Natural product (botanical) (NB) 149Derived from a natural product (ND) 298Totally synthetic (S) 393Total synthesisnatural product (S) 176Vaccine (S) 81
Foreword xxi
These statistics illustrate the consequences of a general ban on patenting naturally derived products of the 1355 drugs approved between 1981 and 2010
bull Fifty percent of all small‐molecule drugs approved between 2000 and 2010 are natural products
bull About 75 of antibacterial drugs are natural products or derived from natural products
bull Almost 80 of small‐molecule anticancer drugs were natural products or derivatives
In addition only 15 of drugs approved during this time frame were so‐called biologic drugs which are also putatively patent‐ineligible This the problems caused by the current interpretation of the law excluding natural product drugs from patent eligibility will be exacerbated in view of reports from every study showing that the percentage of drugs that are biologic drugs has been growing and will be the predominant type of drug devel-oped in the 2011ndash2030 time period
Another ldquothought experimentrdquo illustrating the practical illogic (David can provide his philosophical justifications in the body of the text) of broad natural products patent ineligibility is as follows Suppose a researcher finds a molecule produced by the human body that causes blood pressure homeo-stasis that is lack of this molecule causes or contributes to the disease of high blood pressure The logical consequence of the current natural prod-uct patent ineligibility standards would be that the closer a drug molecule is to the structure of the molecule as it occurs in the body the less patent‐eli-gible it would be Practically speaking there would be no incentive to modify the molecule to confer patent eligibility on the altered molecule because of the unpredictability of such changes on the molecule such as its biological activity half‐life stability antigenicity or other biological prop-erties And there would be even less incentive to develop the molecule as a drug because without patent protection the available regulatory exclusiv-ities would not pass economic muster to sufficiently defray the large development costs (some of which prevent drugs neither safe nor effica-cious from being sold and thus provide their own justification)
There is one further pernicious outcome that can be predicted to arise from a ban on natural products patents (including patents on isolated DNA and genetic diagnostic methods based on such isolated DNA) Natural
xxii Foreword
products are almost by nature complex and an ldquoactive principlerdquo isolated from nature is beneficial because it is isolated Kodak ran an advertisement in the journal Nature in the 1970s showing a scientist in a lab coat holding a 250‐ml flask and standing next to several bushels of green peppers wherein the content of the flask was the purified ldquoessence of green pepperrdquo equivalent to that substance contained in all the peppers in all the bushels and bushels that the scientist was standing beside But this very complexity makes it possible for the ldquoactive principlerdquo (either as a chemical compound or as a diagnostic genetic sequence) to be ldquohidden in plain sightrdquo in ways that may be particularly refractory to reverse engineering
For example even using somewhat dated ldquogene chiprdquo technology genetically diagnostic markers could be encrypted onto a microchip comprising 10 000 unique sequences wherein a computer‐readable bar code would be used to identify the positions of diagnostically relevant sequences on the chip This form of encryption which can be random and confounded by the presence of positive and negative control sequences as well as variable numbers and lengths of sequences specific for the gene (or more likely genes) of interest would be very difficult if not impossible to reverse‐engineer Even if reverse engineering could be done it would be difficult and expensive to undertake and thus make it more likely that the innovator would be able to avoid com-petition (ie it would provide unlimited exclusivity to its purveyor not con-strained by patent term or burdened by the requirement that the invention be disclosed with the specificity required by the Patent Act) While the possi-bility that this type of chip could be made exists with or without patents the absence of patent protection could tip the scales in favor of the extra effort needed and risk entailed in nondisclosure if the reward of extended ldquomonopolyrdquo is great enough But particularly for genetic diagnostic inven-tions the benefits of developing a proprietary database for which a corpora-tion could provide the economic and marketing wherewithal to expeditiously produce would result in a ldquoworst of both worldsrdquo outcome unlimited exclu-sivity based on undisclosed proprietary information that not only is difficult to replicate but whose existence would inhibit competition After all if a company had such a database its outcome for any particular patientrsquos test would be more accurate (and might identify disease riskndashassociated genetic variants not available elsewhere) and this would provide little incentive for a physician to choose an alternative provider to perform the test (and even more malevolently could create a system where the wealthy could afford the best diagnostic testing while the less affluent would be restricted to the more
Foreword xxiii
limited assays offered by companies without access to the ldquoinnovatorrsquosrdquo proprietary database information)
The other aspect of foreclosing patents for certain substances or technology areas categorically is that it upsets a carefully crafted dynamic that has worked extremely well during the biotech era between ldquotruerdquo innovators (typically university professors or small start‐up biotechnology companies) and more established companies capable of commercializing innovation Pundits who worry that permitting patenting will harm innovation miss an important point innovation will happen particularly in universities research institutes and like places because human nature demands it and regardless of whether patent protection is available The intelligent ape in us wants to know and the disparity between how univer-sity professors and patent lawyers are paid should establish how powerful the need to know can be Patenting and the impetus for patenting provided for example by the BayhndashDole Act in the United States prevents the fruits of these inventive efforts from mere predation by commercial concerns The benefits that can be had from a system where private commercializa-tion is encouraged are tempered by the types of corporate shenanigans that raise cogent criticisms of the system But perhaps it is mere human nature that people (in the corporate as well as individual sense) will want to expro-priate technology rather than pay for it and patenting prohibits (or at least retards) this outcome (if not these tendencies) Thus paradoxically limiting patent rights does not free innovation but rather makes it more likely to be kept captive by the entities capable of using such innovation to make a commercial product that is not from the power of building a better mouse-trap but by being able to outcompete smaller innovators merely by their greater economic prowess and resources Conversely patents provide a way for the innovators to protect their innovations and compel corporations to license their inventions producing revenue that can be used to fund future research endeavors This useful cycle has resulted in the successes of the biotechnology era and is something that we abandon at our peril
Thus in my view patents are a useful tool for achieving these societally ben-eficial goals promoting innovation and commercialization and protecting and supporting individuals who use the patent system to protect the products of their labors from being expropriated by others David provides a cogent and honest counterpoint to these thoughts Enjoy reading them
Kevin E NoonanChicago Illinois 2014
Contents
Acknowledgments viii
Preface to the Second Edition x
Foreword xiv
Introduction xxiv
1 Individual and Collective Rights in Genomic Data Preliminary Issues 1
2 Ethics and Ontology A Brief Discourse on Method 21
3 The Science of Genes 30
4 DNA Species Individuals and Persons 52
5 Legal Dimensions in Gene Ownership 69
6 BRCA1 and 2 The Myriad Case and Beyond 88
7 Are Genes Intellectual Property 101
8 DNA and The Commons 119
9 Pragmatic Considerations of Gene Ownership 137
10 Nature Genes and the Scientific Commons A Social Ontology of Invention 155
11 So Who Owns You Some Conclusions About Genes Property and Personhood 165
Notes 182
Index 194
Acknowledgments
Many thanks must be given to those whom I have spoken to about the issues discussed herein since the first edition and who helped inform the updates including Tania Simoncelli Luigi Palombi Joanna Rudnick Dan Ravicher Kevin Noonan James Watson and numerous online commenters who helped point out errors and hone my arguments Thank you also to my colleagues at Delft University of Technology where I have worked the past 6 years and continued discussing and sharpening my approach to the ideas in this book and others
I remain grateful to the Yale Interdisciplinary Bioethics Center for appointing me as their Donaghue Initiative Fellow in Research Ethics 2006ndash2007 I drafted a significant portion of this book during that appoint-ment and had the chance to hash out many of these issues with the staff affiliated faculty and others who participated in events that year Special thanks to all the good people at Yale including especially Robert Levine Julius Landwirth Carol Pollard Autumn Ridenour and Jonathan Moser Thanks also to the folks at the New Haven dog park for keeping my dear departed Buttercup and me company during my residency at Yale Many thanks to my wife Vanessa who gave me significant scientific guidance and lots of encouragement as I worked out these issues and drafted the original book and who helped redraft Chapter 3 for this edition Thanks to my 3‐year‐old daughter Amelia whose appearance brought new purpose to my life and my work My parents Eva Hwa and Richard Koepsell provided commentary and feedback on early drafts of chapters and I am as always grateful for their continuing encouragement My dear friend Peter Hare who passed away in 2008 also kept me company bought me lunches and encouraged my work while at Yale hellip I am grateful for his guidance and friendship and will miss him dearly Thanks to Barry Smith who has remained a helpful and encouraging mentor as I pursue the sometimes
Acknowledgments ix
frustrating but often fruitful path of philosophy Thank you also to Denise Riley who helped dig up obscure articles and arranged almost all the research for my initial trip to Yale that hatched the first edition Finally many thanks to anyone I have forgotten including all those who have given me probing questions puzzling scenarios and further guidance in the talks I have given on this fascinating subject over the past 8 years
David KoepsellAugust 14 2014
Mexico City Mexico
Preface to the Second Edition
A lot has happened in nearly every respect since I first decided to try to delve into philosophical issues of gene patenting nearly a decade ago I have learned much the world has changed and I have changed I would very much like to think I have played a role in that change though chances are things would have changed in almost exactly the same way without my small contribution When the first edition came out patenting genes was still a regular part of biotech and only months after the first edition appeared did a surprising and now‐landmark lawsuit alter that significantly Little did I realize the nature of the forces that would be involved in what I had originally assumed was no more than an academic exercise but which became a matter of weighty and heated public debate and finally judicial action
I first became interested in the subject of gene patents when I began reading up on the topic my future wife was researching pharmacogenom-ics To grasp what she did I first needed to study the science and in so doing I also studied the history of that science Along the way I read about the Human Genome Project and learned about the practice of gene patenting that it spawned Having had some experience and interest in general issues of the philosophy of intellectual property (see my 1997 PhD thesis turned 2000 book The Ontology of Cyberspace) my ears perked up when I first read about the notion of patenting genes So I dived into the research and thinking in my ordinary style of philosophical work Although I sometimes teach ethics my primary field is ontology and it is from an ontological approach that I start with everything in philosophy Thus I began to try to get a grip on the nature of the existence of the underlying objects some of which are ldquobrute factsrdquo (molecules exist with or without social institutions or intentionality) and some of which are social objects (like laws rights and other parts of ldquosocial realityrdquo existing only because of
Preface to the Second Edition xi
collective intentionality) The book was an attempt to lay all this out and to connect it together into a theory that is somehow connected to notions of ldquojusticerdquo which I argued bridges the worlds of brute facts and social objects
The conclusions I reached were I thought pretty neat Specifically I worked out an ontology of ldquothe commonsrdquo that I had never heard expressed before and one that connected nicely with the objects involved to show why artifacts and nature ought to be treated differently and how to decide what constitutes an artifact and what constitutes nature and a defense of the viewpoint that unmodified genes were clearly not artifacts It seemed all the more relevant and interesting even perhaps somewhat important in light of the then ongoing practice of gene patenting I was much too focused on the ontological arguments and their seeming relevance to real‐world practices than I was to the scientific and legal terminology with which I was engaging and this was an error When the book was released minor errors I made in using technical terminology from both the science and the law were latched onto by a couple critical reviewers from the Intellectual Property law and teaching worlds and urged as a basis to ignore my substantive arguments They were right to call out the errors and I have attempted to correct them in this edition Regardless the underlying argu-ments I had set forth would become shortly echoed nearly precisely in the lawsuit that the American Civil Liberties Union (ACLU) spearheaded against Myriad Corp over the BRCA1amp2 gene patents
For a brief period of time partly due to lucky timing I was thrust head-long into the public debates about gene patenting with the Myriad case leading the headlines Given numerous opportunities to engage publicly with the issues and ideas I had previously assumed were only academic musings unlikely to alter public policy and given feedback and counterar-guments in those same venues the general arguments could be more finely honed This edition attempts to coalesce them
Perhaps more importantly in the intervening years since I began my musings about the nature of genes artifacts nature and patents I came to learn the very personal impact that gene patents have on peoplersquos lives Because the ACLU chose to sue over the patents on BRCA1amp2 genes there was a ready‐made large and passionate community (mostly women) whose heredity put them at risk of breast and ovarian cancers but who were basically forced into paying monopolistic prices for the only test available for the gene which was patented by Myriad Corp Breast cancer and the threat of inherited tendencies for breast cancer are real They are not legal
xii Preface to the Second Edition
sophistry they are not philosophical musing They kill people or alter their lives irrevocably
I began researching and considering the effects of gene patents believing they were potentially a threat to the conduct of science whose foundational objects I argued were part of a commons‐by‐necessity but I realized after my book came out that real lives were being harmed by patents on genes The Myriad case brought together the theoretical with the actual for me and the dynamics of both the case and the loud and sometimes angry public debate raised my awareness not only about this particular subject but also the power and responsibility of academic research in the sphere of public policy Suddenly ideas seemed more important had relevance outside the academy and could perhaps make a difference in peoplesrsquo lives I began to interact with the activists who were fighting to liberate genes to stop com-panies like Myriad in the courts and engage not just in the philosophical arguments but in those fights I joined with authors of amicus (friend of the court) briefs interviewed and interacted with BRCA1amp2 mutation‐positive women who were actively pursuing an end to a practice that I had only pre-viously considered to be an interesting metaphysical conundrum I also debated Intellectual Property (IP) attorneys and others primarily with backgrounds in biotech industries and learning better the nature of their arguments I came to understand that most of them including Kevin Noonan who once called me a ldquoliarrdquo on his blog but who has now drafted the foreword to this edition that they too generally have the best intentions Many like Dr Noonan truly expect that without gene patents as they existed until recently the sort of innovation we need in biomedical technol-ogies would not occur as it should
Throughout the course of the litigation in Myriad I remained engaged continued to speak to hone my arguments adding to my list of criteria for something to be a creation (artifact) capable of patent ldquodesignrdquo (as well as intention and being man‐made) and finally rejoicing when the decision of the Supreme Court came out as close to what I believed and argued was right as possible I had seen an academic idea mature and bloom into public policy real law enforceable justice While I realistically believe that the first edition of this book had only a very minor role in what finally happened I am proud to have played some part to have foreseen the issues to argue them honestly from what I think is a rational and logical standpoint and see that the world can be changed by ideas
Preface to the Second Edition xiii
There remain issues to discuss and not everything about gene patents has been resolved by Myriad Some still argue that cDNA ought not to be patent‐eligible (in fact I still think it should be under the criteria I have set forth though there are also arguments to be made that it is not somehow ldquodesignedrdquo by man) Moreover we should expect patent attorneys to do their creative best to continue to pursue patents on as much of the genome as they can within the constraints of Myriad Finally Myriad Corp has not given up They are still suing potential competitors under theories of infringement of parts of their patents that might have survived the ACLUrsquos case against them We shall see how they are eventually resolved and what the future holds for companies like theirs who profited mightily from gene patents for decades I describe as much of this recent legal history as possible in this edition
This book is meant to be a definitive version sewing up the past five years since the first edition emerged and so much changed in the world summa-rizing that recent history and refining the arguments I originally made correcting errors and describing where we are where we yet may be and why gene patents as they once were ought never to be again
David KoepsellAugust 14 2014
Mexico City Mexico
Foreword
David and I have had a friendly disagreement about the subject (and even the title) of this book ever since it was first published and I am happy that he asked me to write this Foreword to the Second Edition The issues David raises in the pages to follow continue to be relevant to a discussion of philosophy and patent law with events that have occurred since the first edition justifying (indeed demanding) this update
Without getting into the deep waters of philosophy (Davidrsquos meacutetier not mine) as we have discussed the issues in the book David contends that he takes a deontological approach and has characterized mine as a utilitarian one Accepting that dichotomy I understand the difference to be that David is operating from ldquofirst principlesrdquo about the rules society should impose on human activity and specifically on what the law permits individuals to ldquoownrdquo with regard to genes and more broadly naturally occurring substances I disagree with that approach on several levels perhaps the most germane of which is that if we posit rules we need to impose a rule‐giver and the potential for improvident rules (if not outright abuse of the privilege) makes me wary in some ways I subscribe to Lani Gruinierrsquos suspicions about the effects of the ldquotyranny of the majorityrdquo in this regard
Part of that tyranny is also the tyranny of unintended or intentional ignorance The issue heremdashldquogenerdquo patentingmdashis one at the intersection of molecular biology and modern genetics on the one hand and patent law (an area notorious for its arcane minutiae) I used to joke with my col-leagues about the effect of trying to explain my position to a lay audience of any type and how I distrusted those who advocated that all that was needed was to ldquoeducaterdquo the public the press and policy makers The problem for proponents of gene patenting has been that opponents have gotten the better part of the debate not by making a reasoned philosophical argument such as the one you will find in these pages but instead by making an
Foreword xv
emotional plea to individuals afraid that corporate America was trying to ldquostealrdquo their genes which has proven very effective This process began with an Op‐Ed piece in The New York Times by Michael Crichton wherein he posited a scenario where a patent holder knocks on your door one day and demands payment for the use of ldquoherrdquo patented gene that resides in your liver (Not coincidentally Dr Crichton had just published a novel on the perils of genetic engineering and corporate ownership of human genes complete with an essay as an addendum containing his arguments against the practice And it should be noted that a constant theme in his novels was a mistrust of technology and particularly the ability of humans to use it without dire consequences) Academics like my friend Lori Andrews at Illinois Institute of Technology (IIT)‐Kent School of Law joined in this theme which was picked up eventually by most popular press outlets and became regrettably the canonical narrative on gene patenting culminating in the American Civil Liberties Unionrsquos (ACLUrsquos) ldquoKeep Your Hands Off My Genesrdquo slogan and logo I hope that this essay provides some antidote to this argument which is founded on the literal fear that someone can ldquoownrdquo you (David assures me that his title is allegorical and that he acknowledges that in all countries that have banned slavery no one can ldquoownrdquo another human being or a part of them See the 13th Amendment I assure you that the ACLU has no such illusions about the intended consequences of their ownership rhetoric)
My philosophy is that the principle we should follow is the greatest good to the greatest number while not infringing on individual rights without (at least) compensation As regards patent law this principle is translated into rules that foster the broadest disclosure of technology possible in return for exclusive patent rights and robust‐enough enforcement rights for patents that they provide sufficient certainty to promote investment so his technology is commercialized to benefit the greatest number In my role as a biotechnology patent attorney I have seen how risky investment in biotechnology can be (indeed the evidence is overwhelming that for all its successes biotechrsquos history is littered with the remains of companies that have failed) and how important it is to have a sound patent system of predictable rights go support that investment
The evidence in support of ldquogene patentingrdquo and more broadly natural products patenting is strong the biotechnology industry has promoted innovation in the form of new drugs and diagnostics assays for a genera-tion This may continue despite the recent restrictions on patent protection
xvi Foreword
for genes and natural products (including patent‐restricting decisions in Mayo Collaborative Labs v Prometheus Labs and Assoc of Molecular Pathologists v Myriad Genetics and recently promulgated US Patent and Trademark Office Guidances on Subject Matter Eligibility) In fact these very restrictions suggest that we would benefit from an appreciation of the facts surrounding the past thirty years of gene patenting to understand why these restrictions are not only wrongheaded but dangerous for future innovation
These include debunking several myths First the concern that patents on specific human genes in some way inhibit innovation in basic genetic research is entirely unfounded One reason is that the genetic information itself is not patented while isolated DNA is encompassed by gene patent claims and described in those claims by its sequence the sequence itself is unpatented information that can be used freely for any purpose (eg inter-rogating genetic databases from other species or even human DNA inter alia to find related genes in those databases) Indeed the innovative benefits to gene patenting are evident in at least two ways First scientific publication databases reveal that there have been more than 11 000 scientific papers published on the BRCA1 and BRCA2 genes since the patents claiming them were granted This outcome refutes the prediction that gene patenting would create a ldquotragedy of the anticommonsrdquo where scientific research would be stifled by patenting (see Heller amp Eisenberg 1998 ldquoCan Patents Deter Innovation The Anticommons in Biomedical Researchrdquo Science 280 698ndash701)) a conclusion supported by the overwhelming majority of studies done on this subject (see for example Walsh et al 2003 ldquoScience and the Law Working Through the Patent Problemrdquo Science 299 1020 Walsh et al 2005 ldquoScience and Law View from the Bench Patents and Material Transfersrdquo Science 309 2002ndash03)
In addition policies that the US Patent and Trademark Office adopted in 2001 required applicants to disclose a practical utility for the product of a gene claimed in a patent These requirements were imposed at a time when the standards for scientific journal publication were much less stringent so that identifying a gene by the extent of genetic similarity between the ldquonewrdquo gene and previously discovered genes was enough for publication But it was not enough for a patent which has been held to be ldquonot a hunting license It is not a reward for the search but compensation for its successful conclusionrdquo Thus genes encoding proteins having no known use or biological activity cannot be patented because to do so would allow the
Foreword xvii
gene to be within the exclusive patent right undeservedly the public would not have received its quid pro quo of a useful invention in return for patent exclusivity All such genes not having patent protection are in the public domain (from which they cannot be retrieved for future patenting) and for humans these constitute the vast majority of genes identified inter alia by the Human Genome Project
The role for patenting genes and the related genetic diagnostic methods using this genetic information in the successes of the biotechnology era are evident The industry has produced hundreds of biologic drugs (at an ever‐increasing rate) that have provided effective treatment for a variety of illnesses and decoding the human genome has enabled researchers to iden-tify genes like the BRCA1 and BRCA2 genes that can be used in predictive genetic diagnostic tests Even the much‐maligned Myriad Genetics has played a positive role in the development and prevalence of genetic diagnostic testing It must be remembered that in 1997 (when Myriadrsquos BRCA gene patents were granted) genetic testing was in its infancy and companies like Myriad were under the burden of convincing payers that the tests did the one thing that all insurers public or private require of such tests save them money in the long run by identifying patients with a high probability of becoming ill and costing the insurers much more for treatment than the costs of prophylaxis Moreover Myriad and like com-panies needed to convince doctors that the testing was worthwhile and to establish a network of genetic counselors who could explain to healthy women that they were at much greater risk of developing breast or ovarian cancer than normal under circumstances that resulted in empowerment from the information and not abject fear And in 1997 genetic sequencing technology was not as developed as it is now and the mechanisms and tech-niques needed to minimize or eliminate the occurrence of false positives or negatives had not been conclusively established All these burdens were ones borne by Myriad and these activities produced the world we have today
It is possible as some have argued that BRCA tests may have been devel-oped independently by individual researchers in the absence of patent pro-tection However it is almost certain that such researchers would have been located in medical centers in urban environments Under these circum-stances women living in or near cities such as New York Boston Philadelphia Cleveland Chicago Houston Denver Los Angeles San Francisco Portland and Seattle might have had access to these tests But what of women in
xviii Foreword
Appalachia or the Four Corners region in the Southwest or more generally in rural or other relatively remote locations Would Yale University for example have had any incentive to provide access to the BRCA tests to these women in these far‐off locations Or to provide genetic counseling where the women lived Or to lobby state Medicare administrators or private insurance commissioners to cover the test I think that unlikely Myriad Genetics did all of this as well as perform outreach to the obstetrics and gynecology doctors throughout the United States so that these primary care doctors were aware of the tests Myriad did not ace from altruism but as part of their business plan in order to expand the number of patients who received the test and thus maximize the companyrsquos revenue While it may be counterintuitive to some these circumstances may have been the most effective way not only to pro-mulgate the BRCA tests but also to facilitate acceptance of genetic diagnostic testing for other diseases showing that in this instance Adam Smith rather than Karl Marx provided the most practical solution to the problem of estab-lishing genetic diagnostic testing as a recognized component of a physicianrsquos diagnostic armamentarium
Fortunately the significance and impact of recent US court decisions (spe-cifically the Myriad case) is much less than it would have been ten to thirty years ago Due to patent term rules most patents (and applications) on iso-lated DNA filed in the heyday of the Human Genome Project (approxi-mately 1998ndash2001) are near the end of their actual or potential term indeed a recent study shows that the number of granted patents having at least one claim reciting an isolate DNA comprising a gene peaked in 1999 and has been dropping since 2005 (Graff et al 2013 ldquoNot quite a myriad of gene pat-entsrdquo Nature Biotechnology 31 404ndash410)) These recent decisions in the United States have not harmed the biotechnology industry because they retained patent eligibility for species of DNA that show evidence of the ldquohand of manrdquo and do not occur in nature These include enzymatically pro-duced copies (cDNA) of cellular messenger RNA and should also encom-pass the tools of the recombinant geneticist (eg including recombinant vectors for cloning and expressing genes in heterologous cells) Most impor-tantly the US Supreme Court did not overturn its Diamond v Chakrabarty decision wherein recombinant cells were determined to be patent eligible
Thus in many ways the question of patent eligibility for human genes is a philosophical one However that does not mean that how we think about patent eligibility for isolated DNA is irrelevant to important questions regarding the usefulness of patents for promoting progress and innovation
Foreword xix
Indeed the most pernicious effects of the current trend in the zeitgeist against patenting has been not that genes have become harder to patent but rather that the ability to patent other natural products has been called into question It is the extension of these recent decisions on isolated DNA to all natural products that poses the greatest threat to innovation This threat can be illustrated by a thought experiment for which of these substances should patent protection be withheld
bull A petrochemical with excellent lubrication qualities isolated in pure form and used as improved motor oil
bull Vitamin B12 isolated from beef muscle formulated into a medicament used to cure anemia in children
bull The drug penicillin isolated from a mixture of naturally produced chemicals made by a mold and formulated as a drug to cure syphilis (which is otherwise eventually fatal)
bull Human urinary erythropoietin formulated to treat anemia in kidney dialysis patients
bull The gene responsible for Gaucherrsquos disease a lipid storage disease wherein the gene is used to make the missing protein that is administered to children and that cures an otherwise incurable and fatal disease
The current answer is that none of them are patent‐eligible per se (although there may be ways to claim them that could pass eligibility muster that remains to be seen) Judge Sweet the US District Court judge who first ruled that isolated DNA was not patent‐eligible did so using language carefully crafted to avoid encompassing all natural products into his decision Specifically Judge Sweet distinguished isolated DNA as the ldquophysical embodiments of genetic informationrdquo a property limited to DNA and not shared by other natural products (While an enzymatic protein could be characterized as the physical embodiment of catalysis of a particular chemical reaction that formulation has much less appeal and inherent rationale than Judge Sweetrsquos regarding DNA) Instead of this careful formu-lation the broader language employed by the Supreme Court as well as the broader rationale the Court used in finding genomic DNA unpatentable has made it easier to employ that fractured logic to render patent‐ineligible naturally occurring molecules other than DNA
I would be remiss not to mention the rather comical (but persistent) efforts of former Acting Solicitor General Neal Katyal who included in the
xx Foreword
US Governmentrsquos amicus brief to the Federal Circuit the distinction engine he called a ldquomagic microscoperdquo embodying the concept that if you are able to visualize a natural product (like a genomic DNA molecule) using this mythical microscope then the natural product would not be patent‐eligible whereas if you could not (eg a cDNA molecule) then the natural product could be eligible for patenting Fortunately the disdain with which the Federal Circuit greeted this fantasy (particularly from Judge Moore) prompted its quick abandonment as are argumentative distinction as the case moved forward Nonetheless both the courts and the US Patent and Trademark Office have adopted this standard de facto even as it becomes the theory that dare not speak its name in legal circles
The philosophical point here is that these substances and natural products generally have been deemed patent‐ineligible categorically which while consistent with (and perhaps even mandated by) the deon-tological approach imposes a distinction that cannot be flexibly applied to the individual circumstances Without such flexibility the law is con-strained to use one criterion that the substance can be found in some form in nature to decide patent eligibility instead of making the deter-mination of whether permitting patenting exclusivity satisfies the cri-teria that the invention ldquopromotes progressrdquo as the US Constitution requires and has a benefit to the public that outweighs any categorical disabilities
The potential that using this standard for determining patent eligibility will result in negative practical outcomes that no one in this debate desires is illustrated by a 2012 Report from the National Institutes of Health Natural Product Branch regarding statistics relating to the number of FDA approvals (a total of 1355) for new drugs falling into the following categories
Drug typesource Number
Biological (B) 203Natural product (N) 55Natural product (botanical) (NB) 149Derived from a natural product (ND) 298Totally synthetic (S) 393Total synthesisnatural product (S) 176Vaccine (S) 81
Foreword xxi
These statistics illustrate the consequences of a general ban on patenting naturally derived products of the 1355 drugs approved between 1981 and 2010
bull Fifty percent of all small‐molecule drugs approved between 2000 and 2010 are natural products
bull About 75 of antibacterial drugs are natural products or derived from natural products
bull Almost 80 of small‐molecule anticancer drugs were natural products or derivatives
In addition only 15 of drugs approved during this time frame were so‐called biologic drugs which are also putatively patent‐ineligible This the problems caused by the current interpretation of the law excluding natural product drugs from patent eligibility will be exacerbated in view of reports from every study showing that the percentage of drugs that are biologic drugs has been growing and will be the predominant type of drug devel-oped in the 2011ndash2030 time period
Another ldquothought experimentrdquo illustrating the practical illogic (David can provide his philosophical justifications in the body of the text) of broad natural products patent ineligibility is as follows Suppose a researcher finds a molecule produced by the human body that causes blood pressure homeo-stasis that is lack of this molecule causes or contributes to the disease of high blood pressure The logical consequence of the current natural prod-uct patent ineligibility standards would be that the closer a drug molecule is to the structure of the molecule as it occurs in the body the less patent‐eli-gible it would be Practically speaking there would be no incentive to modify the molecule to confer patent eligibility on the altered molecule because of the unpredictability of such changes on the molecule such as its biological activity half‐life stability antigenicity or other biological prop-erties And there would be even less incentive to develop the molecule as a drug because without patent protection the available regulatory exclusiv-ities would not pass economic muster to sufficiently defray the large development costs (some of which prevent drugs neither safe nor effica-cious from being sold and thus provide their own justification)
There is one further pernicious outcome that can be predicted to arise from a ban on natural products patents (including patents on isolated DNA and genetic diagnostic methods based on such isolated DNA) Natural
xxii Foreword
products are almost by nature complex and an ldquoactive principlerdquo isolated from nature is beneficial because it is isolated Kodak ran an advertisement in the journal Nature in the 1970s showing a scientist in a lab coat holding a 250‐ml flask and standing next to several bushels of green peppers wherein the content of the flask was the purified ldquoessence of green pepperrdquo equivalent to that substance contained in all the peppers in all the bushels and bushels that the scientist was standing beside But this very complexity makes it possible for the ldquoactive principlerdquo (either as a chemical compound or as a diagnostic genetic sequence) to be ldquohidden in plain sightrdquo in ways that may be particularly refractory to reverse engineering
For example even using somewhat dated ldquogene chiprdquo technology genetically diagnostic markers could be encrypted onto a microchip comprising 10 000 unique sequences wherein a computer‐readable bar code would be used to identify the positions of diagnostically relevant sequences on the chip This form of encryption which can be random and confounded by the presence of positive and negative control sequences as well as variable numbers and lengths of sequences specific for the gene (or more likely genes) of interest would be very difficult if not impossible to reverse‐engineer Even if reverse engineering could be done it would be difficult and expensive to undertake and thus make it more likely that the innovator would be able to avoid com-petition (ie it would provide unlimited exclusivity to its purveyor not con-strained by patent term or burdened by the requirement that the invention be disclosed with the specificity required by the Patent Act) While the possi-bility that this type of chip could be made exists with or without patents the absence of patent protection could tip the scales in favor of the extra effort needed and risk entailed in nondisclosure if the reward of extended ldquomonopolyrdquo is great enough But particularly for genetic diagnostic inven-tions the benefits of developing a proprietary database for which a corpora-tion could provide the economic and marketing wherewithal to expeditiously produce would result in a ldquoworst of both worldsrdquo outcome unlimited exclu-sivity based on undisclosed proprietary information that not only is difficult to replicate but whose existence would inhibit competition After all if a company had such a database its outcome for any particular patientrsquos test would be more accurate (and might identify disease riskndashassociated genetic variants not available elsewhere) and this would provide little incentive for a physician to choose an alternative provider to perform the test (and even more malevolently could create a system where the wealthy could afford the best diagnostic testing while the less affluent would be restricted to the more
Foreword xxiii
limited assays offered by companies without access to the ldquoinnovatorrsquosrdquo proprietary database information)
The other aspect of foreclosing patents for certain substances or technology areas categorically is that it upsets a carefully crafted dynamic that has worked extremely well during the biotech era between ldquotruerdquo innovators (typically university professors or small start‐up biotechnology companies) and more established companies capable of commercializing innovation Pundits who worry that permitting patenting will harm innovation miss an important point innovation will happen particularly in universities research institutes and like places because human nature demands it and regardless of whether patent protection is available The intelligent ape in us wants to know and the disparity between how univer-sity professors and patent lawyers are paid should establish how powerful the need to know can be Patenting and the impetus for patenting provided for example by the BayhndashDole Act in the United States prevents the fruits of these inventive efforts from mere predation by commercial concerns The benefits that can be had from a system where private commercializa-tion is encouraged are tempered by the types of corporate shenanigans that raise cogent criticisms of the system But perhaps it is mere human nature that people (in the corporate as well as individual sense) will want to expro-priate technology rather than pay for it and patenting prohibits (or at least retards) this outcome (if not these tendencies) Thus paradoxically limiting patent rights does not free innovation but rather makes it more likely to be kept captive by the entities capable of using such innovation to make a commercial product that is not from the power of building a better mouse-trap but by being able to outcompete smaller innovators merely by their greater economic prowess and resources Conversely patents provide a way for the innovators to protect their innovations and compel corporations to license their inventions producing revenue that can be used to fund future research endeavors This useful cycle has resulted in the successes of the biotechnology era and is something that we abandon at our peril
Thus in my view patents are a useful tool for achieving these societally ben-eficial goals promoting innovation and commercialization and protecting and supporting individuals who use the patent system to protect the products of their labors from being expropriated by others David provides a cogent and honest counterpoint to these thoughts Enjoy reading them
Kevin E NoonanChicago Illinois 2014
Acknowledgments
Many thanks must be given to those whom I have spoken to about the issues discussed herein since the first edition and who helped inform the updates including Tania Simoncelli Luigi Palombi Joanna Rudnick Dan Ravicher Kevin Noonan James Watson and numerous online commenters who helped point out errors and hone my arguments Thank you also to my colleagues at Delft University of Technology where I have worked the past 6 years and continued discussing and sharpening my approach to the ideas in this book and others
I remain grateful to the Yale Interdisciplinary Bioethics Center for appointing me as their Donaghue Initiative Fellow in Research Ethics 2006ndash2007 I drafted a significant portion of this book during that appoint-ment and had the chance to hash out many of these issues with the staff affiliated faculty and others who participated in events that year Special thanks to all the good people at Yale including especially Robert Levine Julius Landwirth Carol Pollard Autumn Ridenour and Jonathan Moser Thanks also to the folks at the New Haven dog park for keeping my dear departed Buttercup and me company during my residency at Yale Many thanks to my wife Vanessa who gave me significant scientific guidance and lots of encouragement as I worked out these issues and drafted the original book and who helped redraft Chapter 3 for this edition Thanks to my 3‐year‐old daughter Amelia whose appearance brought new purpose to my life and my work My parents Eva Hwa and Richard Koepsell provided commentary and feedback on early drafts of chapters and I am as always grateful for their continuing encouragement My dear friend Peter Hare who passed away in 2008 also kept me company bought me lunches and encouraged my work while at Yale hellip I am grateful for his guidance and friendship and will miss him dearly Thanks to Barry Smith who has remained a helpful and encouraging mentor as I pursue the sometimes
Acknowledgments ix
frustrating but often fruitful path of philosophy Thank you also to Denise Riley who helped dig up obscure articles and arranged almost all the research for my initial trip to Yale that hatched the first edition Finally many thanks to anyone I have forgotten including all those who have given me probing questions puzzling scenarios and further guidance in the talks I have given on this fascinating subject over the past 8 years
David KoepsellAugust 14 2014
Mexico City Mexico
Preface to the Second Edition
A lot has happened in nearly every respect since I first decided to try to delve into philosophical issues of gene patenting nearly a decade ago I have learned much the world has changed and I have changed I would very much like to think I have played a role in that change though chances are things would have changed in almost exactly the same way without my small contribution When the first edition came out patenting genes was still a regular part of biotech and only months after the first edition appeared did a surprising and now‐landmark lawsuit alter that significantly Little did I realize the nature of the forces that would be involved in what I had originally assumed was no more than an academic exercise but which became a matter of weighty and heated public debate and finally judicial action
I first became interested in the subject of gene patents when I began reading up on the topic my future wife was researching pharmacogenom-ics To grasp what she did I first needed to study the science and in so doing I also studied the history of that science Along the way I read about the Human Genome Project and learned about the practice of gene patenting that it spawned Having had some experience and interest in general issues of the philosophy of intellectual property (see my 1997 PhD thesis turned 2000 book The Ontology of Cyberspace) my ears perked up when I first read about the notion of patenting genes So I dived into the research and thinking in my ordinary style of philosophical work Although I sometimes teach ethics my primary field is ontology and it is from an ontological approach that I start with everything in philosophy Thus I began to try to get a grip on the nature of the existence of the underlying objects some of which are ldquobrute factsrdquo (molecules exist with or without social institutions or intentionality) and some of which are social objects (like laws rights and other parts of ldquosocial realityrdquo existing only because of
Preface to the Second Edition xi
collective intentionality) The book was an attempt to lay all this out and to connect it together into a theory that is somehow connected to notions of ldquojusticerdquo which I argued bridges the worlds of brute facts and social objects
The conclusions I reached were I thought pretty neat Specifically I worked out an ontology of ldquothe commonsrdquo that I had never heard expressed before and one that connected nicely with the objects involved to show why artifacts and nature ought to be treated differently and how to decide what constitutes an artifact and what constitutes nature and a defense of the viewpoint that unmodified genes were clearly not artifacts It seemed all the more relevant and interesting even perhaps somewhat important in light of the then ongoing practice of gene patenting I was much too focused on the ontological arguments and their seeming relevance to real‐world practices than I was to the scientific and legal terminology with which I was engaging and this was an error When the book was released minor errors I made in using technical terminology from both the science and the law were latched onto by a couple critical reviewers from the Intellectual Property law and teaching worlds and urged as a basis to ignore my substantive arguments They were right to call out the errors and I have attempted to correct them in this edition Regardless the underlying argu-ments I had set forth would become shortly echoed nearly precisely in the lawsuit that the American Civil Liberties Union (ACLU) spearheaded against Myriad Corp over the BRCA1amp2 gene patents
For a brief period of time partly due to lucky timing I was thrust head-long into the public debates about gene patenting with the Myriad case leading the headlines Given numerous opportunities to engage publicly with the issues and ideas I had previously assumed were only academic musings unlikely to alter public policy and given feedback and counterar-guments in those same venues the general arguments could be more finely honed This edition attempts to coalesce them
Perhaps more importantly in the intervening years since I began my musings about the nature of genes artifacts nature and patents I came to learn the very personal impact that gene patents have on peoplersquos lives Because the ACLU chose to sue over the patents on BRCA1amp2 genes there was a ready‐made large and passionate community (mostly women) whose heredity put them at risk of breast and ovarian cancers but who were basically forced into paying monopolistic prices for the only test available for the gene which was patented by Myriad Corp Breast cancer and the threat of inherited tendencies for breast cancer are real They are not legal
xii Preface to the Second Edition
sophistry they are not philosophical musing They kill people or alter their lives irrevocably
I began researching and considering the effects of gene patents believing they were potentially a threat to the conduct of science whose foundational objects I argued were part of a commons‐by‐necessity but I realized after my book came out that real lives were being harmed by patents on genes The Myriad case brought together the theoretical with the actual for me and the dynamics of both the case and the loud and sometimes angry public debate raised my awareness not only about this particular subject but also the power and responsibility of academic research in the sphere of public policy Suddenly ideas seemed more important had relevance outside the academy and could perhaps make a difference in peoplesrsquo lives I began to interact with the activists who were fighting to liberate genes to stop com-panies like Myriad in the courts and engage not just in the philosophical arguments but in those fights I joined with authors of amicus (friend of the court) briefs interviewed and interacted with BRCA1amp2 mutation‐positive women who were actively pursuing an end to a practice that I had only pre-viously considered to be an interesting metaphysical conundrum I also debated Intellectual Property (IP) attorneys and others primarily with backgrounds in biotech industries and learning better the nature of their arguments I came to understand that most of them including Kevin Noonan who once called me a ldquoliarrdquo on his blog but who has now drafted the foreword to this edition that they too generally have the best intentions Many like Dr Noonan truly expect that without gene patents as they existed until recently the sort of innovation we need in biomedical technol-ogies would not occur as it should
Throughout the course of the litigation in Myriad I remained engaged continued to speak to hone my arguments adding to my list of criteria for something to be a creation (artifact) capable of patent ldquodesignrdquo (as well as intention and being man‐made) and finally rejoicing when the decision of the Supreme Court came out as close to what I believed and argued was right as possible I had seen an academic idea mature and bloom into public policy real law enforceable justice While I realistically believe that the first edition of this book had only a very minor role in what finally happened I am proud to have played some part to have foreseen the issues to argue them honestly from what I think is a rational and logical standpoint and see that the world can be changed by ideas
Preface to the Second Edition xiii
There remain issues to discuss and not everything about gene patents has been resolved by Myriad Some still argue that cDNA ought not to be patent‐eligible (in fact I still think it should be under the criteria I have set forth though there are also arguments to be made that it is not somehow ldquodesignedrdquo by man) Moreover we should expect patent attorneys to do their creative best to continue to pursue patents on as much of the genome as they can within the constraints of Myriad Finally Myriad Corp has not given up They are still suing potential competitors under theories of infringement of parts of their patents that might have survived the ACLUrsquos case against them We shall see how they are eventually resolved and what the future holds for companies like theirs who profited mightily from gene patents for decades I describe as much of this recent legal history as possible in this edition
This book is meant to be a definitive version sewing up the past five years since the first edition emerged and so much changed in the world summa-rizing that recent history and refining the arguments I originally made correcting errors and describing where we are where we yet may be and why gene patents as they once were ought never to be again
David KoepsellAugust 14 2014
Mexico City Mexico
Foreword
David and I have had a friendly disagreement about the subject (and even the title) of this book ever since it was first published and I am happy that he asked me to write this Foreword to the Second Edition The issues David raises in the pages to follow continue to be relevant to a discussion of philosophy and patent law with events that have occurred since the first edition justifying (indeed demanding) this update
Without getting into the deep waters of philosophy (Davidrsquos meacutetier not mine) as we have discussed the issues in the book David contends that he takes a deontological approach and has characterized mine as a utilitarian one Accepting that dichotomy I understand the difference to be that David is operating from ldquofirst principlesrdquo about the rules society should impose on human activity and specifically on what the law permits individuals to ldquoownrdquo with regard to genes and more broadly naturally occurring substances I disagree with that approach on several levels perhaps the most germane of which is that if we posit rules we need to impose a rule‐giver and the potential for improvident rules (if not outright abuse of the privilege) makes me wary in some ways I subscribe to Lani Gruinierrsquos suspicions about the effects of the ldquotyranny of the majorityrdquo in this regard
Part of that tyranny is also the tyranny of unintended or intentional ignorance The issue heremdashldquogenerdquo patentingmdashis one at the intersection of molecular biology and modern genetics on the one hand and patent law (an area notorious for its arcane minutiae) I used to joke with my col-leagues about the effect of trying to explain my position to a lay audience of any type and how I distrusted those who advocated that all that was needed was to ldquoeducaterdquo the public the press and policy makers The problem for proponents of gene patenting has been that opponents have gotten the better part of the debate not by making a reasoned philosophical argument such as the one you will find in these pages but instead by making an
Foreword xv
emotional plea to individuals afraid that corporate America was trying to ldquostealrdquo their genes which has proven very effective This process began with an Op‐Ed piece in The New York Times by Michael Crichton wherein he posited a scenario where a patent holder knocks on your door one day and demands payment for the use of ldquoherrdquo patented gene that resides in your liver (Not coincidentally Dr Crichton had just published a novel on the perils of genetic engineering and corporate ownership of human genes complete with an essay as an addendum containing his arguments against the practice And it should be noted that a constant theme in his novels was a mistrust of technology and particularly the ability of humans to use it without dire consequences) Academics like my friend Lori Andrews at Illinois Institute of Technology (IIT)‐Kent School of Law joined in this theme which was picked up eventually by most popular press outlets and became regrettably the canonical narrative on gene patenting culminating in the American Civil Liberties Unionrsquos (ACLUrsquos) ldquoKeep Your Hands Off My Genesrdquo slogan and logo I hope that this essay provides some antidote to this argument which is founded on the literal fear that someone can ldquoownrdquo you (David assures me that his title is allegorical and that he acknowledges that in all countries that have banned slavery no one can ldquoownrdquo another human being or a part of them See the 13th Amendment I assure you that the ACLU has no such illusions about the intended consequences of their ownership rhetoric)
My philosophy is that the principle we should follow is the greatest good to the greatest number while not infringing on individual rights without (at least) compensation As regards patent law this principle is translated into rules that foster the broadest disclosure of technology possible in return for exclusive patent rights and robust‐enough enforcement rights for patents that they provide sufficient certainty to promote investment so his technology is commercialized to benefit the greatest number In my role as a biotechnology patent attorney I have seen how risky investment in biotechnology can be (indeed the evidence is overwhelming that for all its successes biotechrsquos history is littered with the remains of companies that have failed) and how important it is to have a sound patent system of predictable rights go support that investment
The evidence in support of ldquogene patentingrdquo and more broadly natural products patenting is strong the biotechnology industry has promoted innovation in the form of new drugs and diagnostics assays for a genera-tion This may continue despite the recent restrictions on patent protection
xvi Foreword
for genes and natural products (including patent‐restricting decisions in Mayo Collaborative Labs v Prometheus Labs and Assoc of Molecular Pathologists v Myriad Genetics and recently promulgated US Patent and Trademark Office Guidances on Subject Matter Eligibility) In fact these very restrictions suggest that we would benefit from an appreciation of the facts surrounding the past thirty years of gene patenting to understand why these restrictions are not only wrongheaded but dangerous for future innovation
These include debunking several myths First the concern that patents on specific human genes in some way inhibit innovation in basic genetic research is entirely unfounded One reason is that the genetic information itself is not patented while isolated DNA is encompassed by gene patent claims and described in those claims by its sequence the sequence itself is unpatented information that can be used freely for any purpose (eg inter-rogating genetic databases from other species or even human DNA inter alia to find related genes in those databases) Indeed the innovative benefits to gene patenting are evident in at least two ways First scientific publication databases reveal that there have been more than 11 000 scientific papers published on the BRCA1 and BRCA2 genes since the patents claiming them were granted This outcome refutes the prediction that gene patenting would create a ldquotragedy of the anticommonsrdquo where scientific research would be stifled by patenting (see Heller amp Eisenberg 1998 ldquoCan Patents Deter Innovation The Anticommons in Biomedical Researchrdquo Science 280 698ndash701)) a conclusion supported by the overwhelming majority of studies done on this subject (see for example Walsh et al 2003 ldquoScience and the Law Working Through the Patent Problemrdquo Science 299 1020 Walsh et al 2005 ldquoScience and Law View from the Bench Patents and Material Transfersrdquo Science 309 2002ndash03)
In addition policies that the US Patent and Trademark Office adopted in 2001 required applicants to disclose a practical utility for the product of a gene claimed in a patent These requirements were imposed at a time when the standards for scientific journal publication were much less stringent so that identifying a gene by the extent of genetic similarity between the ldquonewrdquo gene and previously discovered genes was enough for publication But it was not enough for a patent which has been held to be ldquonot a hunting license It is not a reward for the search but compensation for its successful conclusionrdquo Thus genes encoding proteins having no known use or biological activity cannot be patented because to do so would allow the
Foreword xvii
gene to be within the exclusive patent right undeservedly the public would not have received its quid pro quo of a useful invention in return for patent exclusivity All such genes not having patent protection are in the public domain (from which they cannot be retrieved for future patenting) and for humans these constitute the vast majority of genes identified inter alia by the Human Genome Project
The role for patenting genes and the related genetic diagnostic methods using this genetic information in the successes of the biotechnology era are evident The industry has produced hundreds of biologic drugs (at an ever‐increasing rate) that have provided effective treatment for a variety of illnesses and decoding the human genome has enabled researchers to iden-tify genes like the BRCA1 and BRCA2 genes that can be used in predictive genetic diagnostic tests Even the much‐maligned Myriad Genetics has played a positive role in the development and prevalence of genetic diagnostic testing It must be remembered that in 1997 (when Myriadrsquos BRCA gene patents were granted) genetic testing was in its infancy and companies like Myriad were under the burden of convincing payers that the tests did the one thing that all insurers public or private require of such tests save them money in the long run by identifying patients with a high probability of becoming ill and costing the insurers much more for treatment than the costs of prophylaxis Moreover Myriad and like com-panies needed to convince doctors that the testing was worthwhile and to establish a network of genetic counselors who could explain to healthy women that they were at much greater risk of developing breast or ovarian cancer than normal under circumstances that resulted in empowerment from the information and not abject fear And in 1997 genetic sequencing technology was not as developed as it is now and the mechanisms and tech-niques needed to minimize or eliminate the occurrence of false positives or negatives had not been conclusively established All these burdens were ones borne by Myriad and these activities produced the world we have today
It is possible as some have argued that BRCA tests may have been devel-oped independently by individual researchers in the absence of patent pro-tection However it is almost certain that such researchers would have been located in medical centers in urban environments Under these circum-stances women living in or near cities such as New York Boston Philadelphia Cleveland Chicago Houston Denver Los Angeles San Francisco Portland and Seattle might have had access to these tests But what of women in
xviii Foreword
Appalachia or the Four Corners region in the Southwest or more generally in rural or other relatively remote locations Would Yale University for example have had any incentive to provide access to the BRCA tests to these women in these far‐off locations Or to provide genetic counseling where the women lived Or to lobby state Medicare administrators or private insurance commissioners to cover the test I think that unlikely Myriad Genetics did all of this as well as perform outreach to the obstetrics and gynecology doctors throughout the United States so that these primary care doctors were aware of the tests Myriad did not ace from altruism but as part of their business plan in order to expand the number of patients who received the test and thus maximize the companyrsquos revenue While it may be counterintuitive to some these circumstances may have been the most effective way not only to pro-mulgate the BRCA tests but also to facilitate acceptance of genetic diagnostic testing for other diseases showing that in this instance Adam Smith rather than Karl Marx provided the most practical solution to the problem of estab-lishing genetic diagnostic testing as a recognized component of a physicianrsquos diagnostic armamentarium
Fortunately the significance and impact of recent US court decisions (spe-cifically the Myriad case) is much less than it would have been ten to thirty years ago Due to patent term rules most patents (and applications) on iso-lated DNA filed in the heyday of the Human Genome Project (approxi-mately 1998ndash2001) are near the end of their actual or potential term indeed a recent study shows that the number of granted patents having at least one claim reciting an isolate DNA comprising a gene peaked in 1999 and has been dropping since 2005 (Graff et al 2013 ldquoNot quite a myriad of gene pat-entsrdquo Nature Biotechnology 31 404ndash410)) These recent decisions in the United States have not harmed the biotechnology industry because they retained patent eligibility for species of DNA that show evidence of the ldquohand of manrdquo and do not occur in nature These include enzymatically pro-duced copies (cDNA) of cellular messenger RNA and should also encom-pass the tools of the recombinant geneticist (eg including recombinant vectors for cloning and expressing genes in heterologous cells) Most impor-tantly the US Supreme Court did not overturn its Diamond v Chakrabarty decision wherein recombinant cells were determined to be patent eligible
Thus in many ways the question of patent eligibility for human genes is a philosophical one However that does not mean that how we think about patent eligibility for isolated DNA is irrelevant to important questions regarding the usefulness of patents for promoting progress and innovation
Foreword xix
Indeed the most pernicious effects of the current trend in the zeitgeist against patenting has been not that genes have become harder to patent but rather that the ability to patent other natural products has been called into question It is the extension of these recent decisions on isolated DNA to all natural products that poses the greatest threat to innovation This threat can be illustrated by a thought experiment for which of these substances should patent protection be withheld
bull A petrochemical with excellent lubrication qualities isolated in pure form and used as improved motor oil
bull Vitamin B12 isolated from beef muscle formulated into a medicament used to cure anemia in children
bull The drug penicillin isolated from a mixture of naturally produced chemicals made by a mold and formulated as a drug to cure syphilis (which is otherwise eventually fatal)
bull Human urinary erythropoietin formulated to treat anemia in kidney dialysis patients
bull The gene responsible for Gaucherrsquos disease a lipid storage disease wherein the gene is used to make the missing protein that is administered to children and that cures an otherwise incurable and fatal disease
The current answer is that none of them are patent‐eligible per se (although there may be ways to claim them that could pass eligibility muster that remains to be seen) Judge Sweet the US District Court judge who first ruled that isolated DNA was not patent‐eligible did so using language carefully crafted to avoid encompassing all natural products into his decision Specifically Judge Sweet distinguished isolated DNA as the ldquophysical embodiments of genetic informationrdquo a property limited to DNA and not shared by other natural products (While an enzymatic protein could be characterized as the physical embodiment of catalysis of a particular chemical reaction that formulation has much less appeal and inherent rationale than Judge Sweetrsquos regarding DNA) Instead of this careful formu-lation the broader language employed by the Supreme Court as well as the broader rationale the Court used in finding genomic DNA unpatentable has made it easier to employ that fractured logic to render patent‐ineligible naturally occurring molecules other than DNA
I would be remiss not to mention the rather comical (but persistent) efforts of former Acting Solicitor General Neal Katyal who included in the
xx Foreword
US Governmentrsquos amicus brief to the Federal Circuit the distinction engine he called a ldquomagic microscoperdquo embodying the concept that if you are able to visualize a natural product (like a genomic DNA molecule) using this mythical microscope then the natural product would not be patent‐eligible whereas if you could not (eg a cDNA molecule) then the natural product could be eligible for patenting Fortunately the disdain with which the Federal Circuit greeted this fantasy (particularly from Judge Moore) prompted its quick abandonment as are argumentative distinction as the case moved forward Nonetheless both the courts and the US Patent and Trademark Office have adopted this standard de facto even as it becomes the theory that dare not speak its name in legal circles
The philosophical point here is that these substances and natural products generally have been deemed patent‐ineligible categorically which while consistent with (and perhaps even mandated by) the deon-tological approach imposes a distinction that cannot be flexibly applied to the individual circumstances Without such flexibility the law is con-strained to use one criterion that the substance can be found in some form in nature to decide patent eligibility instead of making the deter-mination of whether permitting patenting exclusivity satisfies the cri-teria that the invention ldquopromotes progressrdquo as the US Constitution requires and has a benefit to the public that outweighs any categorical disabilities
The potential that using this standard for determining patent eligibility will result in negative practical outcomes that no one in this debate desires is illustrated by a 2012 Report from the National Institutes of Health Natural Product Branch regarding statistics relating to the number of FDA approvals (a total of 1355) for new drugs falling into the following categories
Drug typesource Number
Biological (B) 203Natural product (N) 55Natural product (botanical) (NB) 149Derived from a natural product (ND) 298Totally synthetic (S) 393Total synthesisnatural product (S) 176Vaccine (S) 81
Foreword xxi
These statistics illustrate the consequences of a general ban on patenting naturally derived products of the 1355 drugs approved between 1981 and 2010
bull Fifty percent of all small‐molecule drugs approved between 2000 and 2010 are natural products
bull About 75 of antibacterial drugs are natural products or derived from natural products
bull Almost 80 of small‐molecule anticancer drugs were natural products or derivatives
In addition only 15 of drugs approved during this time frame were so‐called biologic drugs which are also putatively patent‐ineligible This the problems caused by the current interpretation of the law excluding natural product drugs from patent eligibility will be exacerbated in view of reports from every study showing that the percentage of drugs that are biologic drugs has been growing and will be the predominant type of drug devel-oped in the 2011ndash2030 time period
Another ldquothought experimentrdquo illustrating the practical illogic (David can provide his philosophical justifications in the body of the text) of broad natural products patent ineligibility is as follows Suppose a researcher finds a molecule produced by the human body that causes blood pressure homeo-stasis that is lack of this molecule causes or contributes to the disease of high blood pressure The logical consequence of the current natural prod-uct patent ineligibility standards would be that the closer a drug molecule is to the structure of the molecule as it occurs in the body the less patent‐eli-gible it would be Practically speaking there would be no incentive to modify the molecule to confer patent eligibility on the altered molecule because of the unpredictability of such changes on the molecule such as its biological activity half‐life stability antigenicity or other biological prop-erties And there would be even less incentive to develop the molecule as a drug because without patent protection the available regulatory exclusiv-ities would not pass economic muster to sufficiently defray the large development costs (some of which prevent drugs neither safe nor effica-cious from being sold and thus provide their own justification)
There is one further pernicious outcome that can be predicted to arise from a ban on natural products patents (including patents on isolated DNA and genetic diagnostic methods based on such isolated DNA) Natural
xxii Foreword
products are almost by nature complex and an ldquoactive principlerdquo isolated from nature is beneficial because it is isolated Kodak ran an advertisement in the journal Nature in the 1970s showing a scientist in a lab coat holding a 250‐ml flask and standing next to several bushels of green peppers wherein the content of the flask was the purified ldquoessence of green pepperrdquo equivalent to that substance contained in all the peppers in all the bushels and bushels that the scientist was standing beside But this very complexity makes it possible for the ldquoactive principlerdquo (either as a chemical compound or as a diagnostic genetic sequence) to be ldquohidden in plain sightrdquo in ways that may be particularly refractory to reverse engineering
For example even using somewhat dated ldquogene chiprdquo technology genetically diagnostic markers could be encrypted onto a microchip comprising 10 000 unique sequences wherein a computer‐readable bar code would be used to identify the positions of diagnostically relevant sequences on the chip This form of encryption which can be random and confounded by the presence of positive and negative control sequences as well as variable numbers and lengths of sequences specific for the gene (or more likely genes) of interest would be very difficult if not impossible to reverse‐engineer Even if reverse engineering could be done it would be difficult and expensive to undertake and thus make it more likely that the innovator would be able to avoid com-petition (ie it would provide unlimited exclusivity to its purveyor not con-strained by patent term or burdened by the requirement that the invention be disclosed with the specificity required by the Patent Act) While the possi-bility that this type of chip could be made exists with or without patents the absence of patent protection could tip the scales in favor of the extra effort needed and risk entailed in nondisclosure if the reward of extended ldquomonopolyrdquo is great enough But particularly for genetic diagnostic inven-tions the benefits of developing a proprietary database for which a corpora-tion could provide the economic and marketing wherewithal to expeditiously produce would result in a ldquoworst of both worldsrdquo outcome unlimited exclu-sivity based on undisclosed proprietary information that not only is difficult to replicate but whose existence would inhibit competition After all if a company had such a database its outcome for any particular patientrsquos test would be more accurate (and might identify disease riskndashassociated genetic variants not available elsewhere) and this would provide little incentive for a physician to choose an alternative provider to perform the test (and even more malevolently could create a system where the wealthy could afford the best diagnostic testing while the less affluent would be restricted to the more
Foreword xxiii
limited assays offered by companies without access to the ldquoinnovatorrsquosrdquo proprietary database information)
The other aspect of foreclosing patents for certain substances or technology areas categorically is that it upsets a carefully crafted dynamic that has worked extremely well during the biotech era between ldquotruerdquo innovators (typically university professors or small start‐up biotechnology companies) and more established companies capable of commercializing innovation Pundits who worry that permitting patenting will harm innovation miss an important point innovation will happen particularly in universities research institutes and like places because human nature demands it and regardless of whether patent protection is available The intelligent ape in us wants to know and the disparity between how univer-sity professors and patent lawyers are paid should establish how powerful the need to know can be Patenting and the impetus for patenting provided for example by the BayhndashDole Act in the United States prevents the fruits of these inventive efforts from mere predation by commercial concerns The benefits that can be had from a system where private commercializa-tion is encouraged are tempered by the types of corporate shenanigans that raise cogent criticisms of the system But perhaps it is mere human nature that people (in the corporate as well as individual sense) will want to expro-priate technology rather than pay for it and patenting prohibits (or at least retards) this outcome (if not these tendencies) Thus paradoxically limiting patent rights does not free innovation but rather makes it more likely to be kept captive by the entities capable of using such innovation to make a commercial product that is not from the power of building a better mouse-trap but by being able to outcompete smaller innovators merely by their greater economic prowess and resources Conversely patents provide a way for the innovators to protect their innovations and compel corporations to license their inventions producing revenue that can be used to fund future research endeavors This useful cycle has resulted in the successes of the biotechnology era and is something that we abandon at our peril
Thus in my view patents are a useful tool for achieving these societally ben-eficial goals promoting innovation and commercialization and protecting and supporting individuals who use the patent system to protect the products of their labors from being expropriated by others David provides a cogent and honest counterpoint to these thoughts Enjoy reading them
Kevin E NoonanChicago Illinois 2014
Acknowledgments ix
frustrating but often fruitful path of philosophy Thank you also to Denise Riley who helped dig up obscure articles and arranged almost all the research for my initial trip to Yale that hatched the first edition Finally many thanks to anyone I have forgotten including all those who have given me probing questions puzzling scenarios and further guidance in the talks I have given on this fascinating subject over the past 8 years
David KoepsellAugust 14 2014
Mexico City Mexico
Preface to the Second Edition
A lot has happened in nearly every respect since I first decided to try to delve into philosophical issues of gene patenting nearly a decade ago I have learned much the world has changed and I have changed I would very much like to think I have played a role in that change though chances are things would have changed in almost exactly the same way without my small contribution When the first edition came out patenting genes was still a regular part of biotech and only months after the first edition appeared did a surprising and now‐landmark lawsuit alter that significantly Little did I realize the nature of the forces that would be involved in what I had originally assumed was no more than an academic exercise but which became a matter of weighty and heated public debate and finally judicial action
I first became interested in the subject of gene patents when I began reading up on the topic my future wife was researching pharmacogenom-ics To grasp what she did I first needed to study the science and in so doing I also studied the history of that science Along the way I read about the Human Genome Project and learned about the practice of gene patenting that it spawned Having had some experience and interest in general issues of the philosophy of intellectual property (see my 1997 PhD thesis turned 2000 book The Ontology of Cyberspace) my ears perked up when I first read about the notion of patenting genes So I dived into the research and thinking in my ordinary style of philosophical work Although I sometimes teach ethics my primary field is ontology and it is from an ontological approach that I start with everything in philosophy Thus I began to try to get a grip on the nature of the existence of the underlying objects some of which are ldquobrute factsrdquo (molecules exist with or without social institutions or intentionality) and some of which are social objects (like laws rights and other parts of ldquosocial realityrdquo existing only because of
Preface to the Second Edition xi
collective intentionality) The book was an attempt to lay all this out and to connect it together into a theory that is somehow connected to notions of ldquojusticerdquo which I argued bridges the worlds of brute facts and social objects
The conclusions I reached were I thought pretty neat Specifically I worked out an ontology of ldquothe commonsrdquo that I had never heard expressed before and one that connected nicely with the objects involved to show why artifacts and nature ought to be treated differently and how to decide what constitutes an artifact and what constitutes nature and a defense of the viewpoint that unmodified genes were clearly not artifacts It seemed all the more relevant and interesting even perhaps somewhat important in light of the then ongoing practice of gene patenting I was much too focused on the ontological arguments and their seeming relevance to real‐world practices than I was to the scientific and legal terminology with which I was engaging and this was an error When the book was released minor errors I made in using technical terminology from both the science and the law were latched onto by a couple critical reviewers from the Intellectual Property law and teaching worlds and urged as a basis to ignore my substantive arguments They were right to call out the errors and I have attempted to correct them in this edition Regardless the underlying argu-ments I had set forth would become shortly echoed nearly precisely in the lawsuit that the American Civil Liberties Union (ACLU) spearheaded against Myriad Corp over the BRCA1amp2 gene patents
For a brief period of time partly due to lucky timing I was thrust head-long into the public debates about gene patenting with the Myriad case leading the headlines Given numerous opportunities to engage publicly with the issues and ideas I had previously assumed were only academic musings unlikely to alter public policy and given feedback and counterar-guments in those same venues the general arguments could be more finely honed This edition attempts to coalesce them
Perhaps more importantly in the intervening years since I began my musings about the nature of genes artifacts nature and patents I came to learn the very personal impact that gene patents have on peoplersquos lives Because the ACLU chose to sue over the patents on BRCA1amp2 genes there was a ready‐made large and passionate community (mostly women) whose heredity put them at risk of breast and ovarian cancers but who were basically forced into paying monopolistic prices for the only test available for the gene which was patented by Myriad Corp Breast cancer and the threat of inherited tendencies for breast cancer are real They are not legal
xii Preface to the Second Edition
sophistry they are not philosophical musing They kill people or alter their lives irrevocably
I began researching and considering the effects of gene patents believing they were potentially a threat to the conduct of science whose foundational objects I argued were part of a commons‐by‐necessity but I realized after my book came out that real lives were being harmed by patents on genes The Myriad case brought together the theoretical with the actual for me and the dynamics of both the case and the loud and sometimes angry public debate raised my awareness not only about this particular subject but also the power and responsibility of academic research in the sphere of public policy Suddenly ideas seemed more important had relevance outside the academy and could perhaps make a difference in peoplesrsquo lives I began to interact with the activists who were fighting to liberate genes to stop com-panies like Myriad in the courts and engage not just in the philosophical arguments but in those fights I joined with authors of amicus (friend of the court) briefs interviewed and interacted with BRCA1amp2 mutation‐positive women who were actively pursuing an end to a practice that I had only pre-viously considered to be an interesting metaphysical conundrum I also debated Intellectual Property (IP) attorneys and others primarily with backgrounds in biotech industries and learning better the nature of their arguments I came to understand that most of them including Kevin Noonan who once called me a ldquoliarrdquo on his blog but who has now drafted the foreword to this edition that they too generally have the best intentions Many like Dr Noonan truly expect that without gene patents as they existed until recently the sort of innovation we need in biomedical technol-ogies would not occur as it should
Throughout the course of the litigation in Myriad I remained engaged continued to speak to hone my arguments adding to my list of criteria for something to be a creation (artifact) capable of patent ldquodesignrdquo (as well as intention and being man‐made) and finally rejoicing when the decision of the Supreme Court came out as close to what I believed and argued was right as possible I had seen an academic idea mature and bloom into public policy real law enforceable justice While I realistically believe that the first edition of this book had only a very minor role in what finally happened I am proud to have played some part to have foreseen the issues to argue them honestly from what I think is a rational and logical standpoint and see that the world can be changed by ideas
Preface to the Second Edition xiii
There remain issues to discuss and not everything about gene patents has been resolved by Myriad Some still argue that cDNA ought not to be patent‐eligible (in fact I still think it should be under the criteria I have set forth though there are also arguments to be made that it is not somehow ldquodesignedrdquo by man) Moreover we should expect patent attorneys to do their creative best to continue to pursue patents on as much of the genome as they can within the constraints of Myriad Finally Myriad Corp has not given up They are still suing potential competitors under theories of infringement of parts of their patents that might have survived the ACLUrsquos case against them We shall see how they are eventually resolved and what the future holds for companies like theirs who profited mightily from gene patents for decades I describe as much of this recent legal history as possible in this edition
This book is meant to be a definitive version sewing up the past five years since the first edition emerged and so much changed in the world summa-rizing that recent history and refining the arguments I originally made correcting errors and describing where we are where we yet may be and why gene patents as they once were ought never to be again
David KoepsellAugust 14 2014
Mexico City Mexico
Foreword
David and I have had a friendly disagreement about the subject (and even the title) of this book ever since it was first published and I am happy that he asked me to write this Foreword to the Second Edition The issues David raises in the pages to follow continue to be relevant to a discussion of philosophy and patent law with events that have occurred since the first edition justifying (indeed demanding) this update
Without getting into the deep waters of philosophy (Davidrsquos meacutetier not mine) as we have discussed the issues in the book David contends that he takes a deontological approach and has characterized mine as a utilitarian one Accepting that dichotomy I understand the difference to be that David is operating from ldquofirst principlesrdquo about the rules society should impose on human activity and specifically on what the law permits individuals to ldquoownrdquo with regard to genes and more broadly naturally occurring substances I disagree with that approach on several levels perhaps the most germane of which is that if we posit rules we need to impose a rule‐giver and the potential for improvident rules (if not outright abuse of the privilege) makes me wary in some ways I subscribe to Lani Gruinierrsquos suspicions about the effects of the ldquotyranny of the majorityrdquo in this regard
Part of that tyranny is also the tyranny of unintended or intentional ignorance The issue heremdashldquogenerdquo patentingmdashis one at the intersection of molecular biology and modern genetics on the one hand and patent law (an area notorious for its arcane minutiae) I used to joke with my col-leagues about the effect of trying to explain my position to a lay audience of any type and how I distrusted those who advocated that all that was needed was to ldquoeducaterdquo the public the press and policy makers The problem for proponents of gene patenting has been that opponents have gotten the better part of the debate not by making a reasoned philosophical argument such as the one you will find in these pages but instead by making an
Foreword xv
emotional plea to individuals afraid that corporate America was trying to ldquostealrdquo their genes which has proven very effective This process began with an Op‐Ed piece in The New York Times by Michael Crichton wherein he posited a scenario where a patent holder knocks on your door one day and demands payment for the use of ldquoherrdquo patented gene that resides in your liver (Not coincidentally Dr Crichton had just published a novel on the perils of genetic engineering and corporate ownership of human genes complete with an essay as an addendum containing his arguments against the practice And it should be noted that a constant theme in his novels was a mistrust of technology and particularly the ability of humans to use it without dire consequences) Academics like my friend Lori Andrews at Illinois Institute of Technology (IIT)‐Kent School of Law joined in this theme which was picked up eventually by most popular press outlets and became regrettably the canonical narrative on gene patenting culminating in the American Civil Liberties Unionrsquos (ACLUrsquos) ldquoKeep Your Hands Off My Genesrdquo slogan and logo I hope that this essay provides some antidote to this argument which is founded on the literal fear that someone can ldquoownrdquo you (David assures me that his title is allegorical and that he acknowledges that in all countries that have banned slavery no one can ldquoownrdquo another human being or a part of them See the 13th Amendment I assure you that the ACLU has no such illusions about the intended consequences of their ownership rhetoric)
My philosophy is that the principle we should follow is the greatest good to the greatest number while not infringing on individual rights without (at least) compensation As regards patent law this principle is translated into rules that foster the broadest disclosure of technology possible in return for exclusive patent rights and robust‐enough enforcement rights for patents that they provide sufficient certainty to promote investment so his technology is commercialized to benefit the greatest number In my role as a biotechnology patent attorney I have seen how risky investment in biotechnology can be (indeed the evidence is overwhelming that for all its successes biotechrsquos history is littered with the remains of companies that have failed) and how important it is to have a sound patent system of predictable rights go support that investment
The evidence in support of ldquogene patentingrdquo and more broadly natural products patenting is strong the biotechnology industry has promoted innovation in the form of new drugs and diagnostics assays for a genera-tion This may continue despite the recent restrictions on patent protection
xvi Foreword
for genes and natural products (including patent‐restricting decisions in Mayo Collaborative Labs v Prometheus Labs and Assoc of Molecular Pathologists v Myriad Genetics and recently promulgated US Patent and Trademark Office Guidances on Subject Matter Eligibility) In fact these very restrictions suggest that we would benefit from an appreciation of the facts surrounding the past thirty years of gene patenting to understand why these restrictions are not only wrongheaded but dangerous for future innovation
These include debunking several myths First the concern that patents on specific human genes in some way inhibit innovation in basic genetic research is entirely unfounded One reason is that the genetic information itself is not patented while isolated DNA is encompassed by gene patent claims and described in those claims by its sequence the sequence itself is unpatented information that can be used freely for any purpose (eg inter-rogating genetic databases from other species or even human DNA inter alia to find related genes in those databases) Indeed the innovative benefits to gene patenting are evident in at least two ways First scientific publication databases reveal that there have been more than 11 000 scientific papers published on the BRCA1 and BRCA2 genes since the patents claiming them were granted This outcome refutes the prediction that gene patenting would create a ldquotragedy of the anticommonsrdquo where scientific research would be stifled by patenting (see Heller amp Eisenberg 1998 ldquoCan Patents Deter Innovation The Anticommons in Biomedical Researchrdquo Science 280 698ndash701)) a conclusion supported by the overwhelming majority of studies done on this subject (see for example Walsh et al 2003 ldquoScience and the Law Working Through the Patent Problemrdquo Science 299 1020 Walsh et al 2005 ldquoScience and Law View from the Bench Patents and Material Transfersrdquo Science 309 2002ndash03)
In addition policies that the US Patent and Trademark Office adopted in 2001 required applicants to disclose a practical utility for the product of a gene claimed in a patent These requirements were imposed at a time when the standards for scientific journal publication were much less stringent so that identifying a gene by the extent of genetic similarity between the ldquonewrdquo gene and previously discovered genes was enough for publication But it was not enough for a patent which has been held to be ldquonot a hunting license It is not a reward for the search but compensation for its successful conclusionrdquo Thus genes encoding proteins having no known use or biological activity cannot be patented because to do so would allow the
Foreword xvii
gene to be within the exclusive patent right undeservedly the public would not have received its quid pro quo of a useful invention in return for patent exclusivity All such genes not having patent protection are in the public domain (from which they cannot be retrieved for future patenting) and for humans these constitute the vast majority of genes identified inter alia by the Human Genome Project
The role for patenting genes and the related genetic diagnostic methods using this genetic information in the successes of the biotechnology era are evident The industry has produced hundreds of biologic drugs (at an ever‐increasing rate) that have provided effective treatment for a variety of illnesses and decoding the human genome has enabled researchers to iden-tify genes like the BRCA1 and BRCA2 genes that can be used in predictive genetic diagnostic tests Even the much‐maligned Myriad Genetics has played a positive role in the development and prevalence of genetic diagnostic testing It must be remembered that in 1997 (when Myriadrsquos BRCA gene patents were granted) genetic testing was in its infancy and companies like Myriad were under the burden of convincing payers that the tests did the one thing that all insurers public or private require of such tests save them money in the long run by identifying patients with a high probability of becoming ill and costing the insurers much more for treatment than the costs of prophylaxis Moreover Myriad and like com-panies needed to convince doctors that the testing was worthwhile and to establish a network of genetic counselors who could explain to healthy women that they were at much greater risk of developing breast or ovarian cancer than normal under circumstances that resulted in empowerment from the information and not abject fear And in 1997 genetic sequencing technology was not as developed as it is now and the mechanisms and tech-niques needed to minimize or eliminate the occurrence of false positives or negatives had not been conclusively established All these burdens were ones borne by Myriad and these activities produced the world we have today
It is possible as some have argued that BRCA tests may have been devel-oped independently by individual researchers in the absence of patent pro-tection However it is almost certain that such researchers would have been located in medical centers in urban environments Under these circum-stances women living in or near cities such as New York Boston Philadelphia Cleveland Chicago Houston Denver Los Angeles San Francisco Portland and Seattle might have had access to these tests But what of women in
xviii Foreword
Appalachia or the Four Corners region in the Southwest or more generally in rural or other relatively remote locations Would Yale University for example have had any incentive to provide access to the BRCA tests to these women in these far‐off locations Or to provide genetic counseling where the women lived Or to lobby state Medicare administrators or private insurance commissioners to cover the test I think that unlikely Myriad Genetics did all of this as well as perform outreach to the obstetrics and gynecology doctors throughout the United States so that these primary care doctors were aware of the tests Myriad did not ace from altruism but as part of their business plan in order to expand the number of patients who received the test and thus maximize the companyrsquos revenue While it may be counterintuitive to some these circumstances may have been the most effective way not only to pro-mulgate the BRCA tests but also to facilitate acceptance of genetic diagnostic testing for other diseases showing that in this instance Adam Smith rather than Karl Marx provided the most practical solution to the problem of estab-lishing genetic diagnostic testing as a recognized component of a physicianrsquos diagnostic armamentarium
Fortunately the significance and impact of recent US court decisions (spe-cifically the Myriad case) is much less than it would have been ten to thirty years ago Due to patent term rules most patents (and applications) on iso-lated DNA filed in the heyday of the Human Genome Project (approxi-mately 1998ndash2001) are near the end of their actual or potential term indeed a recent study shows that the number of granted patents having at least one claim reciting an isolate DNA comprising a gene peaked in 1999 and has been dropping since 2005 (Graff et al 2013 ldquoNot quite a myriad of gene pat-entsrdquo Nature Biotechnology 31 404ndash410)) These recent decisions in the United States have not harmed the biotechnology industry because they retained patent eligibility for species of DNA that show evidence of the ldquohand of manrdquo and do not occur in nature These include enzymatically pro-duced copies (cDNA) of cellular messenger RNA and should also encom-pass the tools of the recombinant geneticist (eg including recombinant vectors for cloning and expressing genes in heterologous cells) Most impor-tantly the US Supreme Court did not overturn its Diamond v Chakrabarty decision wherein recombinant cells were determined to be patent eligible
Thus in many ways the question of patent eligibility for human genes is a philosophical one However that does not mean that how we think about patent eligibility for isolated DNA is irrelevant to important questions regarding the usefulness of patents for promoting progress and innovation
Foreword xix
Indeed the most pernicious effects of the current trend in the zeitgeist against patenting has been not that genes have become harder to patent but rather that the ability to patent other natural products has been called into question It is the extension of these recent decisions on isolated DNA to all natural products that poses the greatest threat to innovation This threat can be illustrated by a thought experiment for which of these substances should patent protection be withheld
bull A petrochemical with excellent lubrication qualities isolated in pure form and used as improved motor oil
bull Vitamin B12 isolated from beef muscle formulated into a medicament used to cure anemia in children
bull The drug penicillin isolated from a mixture of naturally produced chemicals made by a mold and formulated as a drug to cure syphilis (which is otherwise eventually fatal)
bull Human urinary erythropoietin formulated to treat anemia in kidney dialysis patients
bull The gene responsible for Gaucherrsquos disease a lipid storage disease wherein the gene is used to make the missing protein that is administered to children and that cures an otherwise incurable and fatal disease
The current answer is that none of them are patent‐eligible per se (although there may be ways to claim them that could pass eligibility muster that remains to be seen) Judge Sweet the US District Court judge who first ruled that isolated DNA was not patent‐eligible did so using language carefully crafted to avoid encompassing all natural products into his decision Specifically Judge Sweet distinguished isolated DNA as the ldquophysical embodiments of genetic informationrdquo a property limited to DNA and not shared by other natural products (While an enzymatic protein could be characterized as the physical embodiment of catalysis of a particular chemical reaction that formulation has much less appeal and inherent rationale than Judge Sweetrsquos regarding DNA) Instead of this careful formu-lation the broader language employed by the Supreme Court as well as the broader rationale the Court used in finding genomic DNA unpatentable has made it easier to employ that fractured logic to render patent‐ineligible naturally occurring molecules other than DNA
I would be remiss not to mention the rather comical (but persistent) efforts of former Acting Solicitor General Neal Katyal who included in the
xx Foreword
US Governmentrsquos amicus brief to the Federal Circuit the distinction engine he called a ldquomagic microscoperdquo embodying the concept that if you are able to visualize a natural product (like a genomic DNA molecule) using this mythical microscope then the natural product would not be patent‐eligible whereas if you could not (eg a cDNA molecule) then the natural product could be eligible for patenting Fortunately the disdain with which the Federal Circuit greeted this fantasy (particularly from Judge Moore) prompted its quick abandonment as are argumentative distinction as the case moved forward Nonetheless both the courts and the US Patent and Trademark Office have adopted this standard de facto even as it becomes the theory that dare not speak its name in legal circles
The philosophical point here is that these substances and natural products generally have been deemed patent‐ineligible categorically which while consistent with (and perhaps even mandated by) the deon-tological approach imposes a distinction that cannot be flexibly applied to the individual circumstances Without such flexibility the law is con-strained to use one criterion that the substance can be found in some form in nature to decide patent eligibility instead of making the deter-mination of whether permitting patenting exclusivity satisfies the cri-teria that the invention ldquopromotes progressrdquo as the US Constitution requires and has a benefit to the public that outweighs any categorical disabilities
The potential that using this standard for determining patent eligibility will result in negative practical outcomes that no one in this debate desires is illustrated by a 2012 Report from the National Institutes of Health Natural Product Branch regarding statistics relating to the number of FDA approvals (a total of 1355) for new drugs falling into the following categories
Drug typesource Number
Biological (B) 203Natural product (N) 55Natural product (botanical) (NB) 149Derived from a natural product (ND) 298Totally synthetic (S) 393Total synthesisnatural product (S) 176Vaccine (S) 81
Foreword xxi
These statistics illustrate the consequences of a general ban on patenting naturally derived products of the 1355 drugs approved between 1981 and 2010
bull Fifty percent of all small‐molecule drugs approved between 2000 and 2010 are natural products
bull About 75 of antibacterial drugs are natural products or derived from natural products
bull Almost 80 of small‐molecule anticancer drugs were natural products or derivatives
In addition only 15 of drugs approved during this time frame were so‐called biologic drugs which are also putatively patent‐ineligible This the problems caused by the current interpretation of the law excluding natural product drugs from patent eligibility will be exacerbated in view of reports from every study showing that the percentage of drugs that are biologic drugs has been growing and will be the predominant type of drug devel-oped in the 2011ndash2030 time period
Another ldquothought experimentrdquo illustrating the practical illogic (David can provide his philosophical justifications in the body of the text) of broad natural products patent ineligibility is as follows Suppose a researcher finds a molecule produced by the human body that causes blood pressure homeo-stasis that is lack of this molecule causes or contributes to the disease of high blood pressure The logical consequence of the current natural prod-uct patent ineligibility standards would be that the closer a drug molecule is to the structure of the molecule as it occurs in the body the less patent‐eli-gible it would be Practically speaking there would be no incentive to modify the molecule to confer patent eligibility on the altered molecule because of the unpredictability of such changes on the molecule such as its biological activity half‐life stability antigenicity or other biological prop-erties And there would be even less incentive to develop the molecule as a drug because without patent protection the available regulatory exclusiv-ities would not pass economic muster to sufficiently defray the large development costs (some of which prevent drugs neither safe nor effica-cious from being sold and thus provide their own justification)
There is one further pernicious outcome that can be predicted to arise from a ban on natural products patents (including patents on isolated DNA and genetic diagnostic methods based on such isolated DNA) Natural
xxii Foreword
products are almost by nature complex and an ldquoactive principlerdquo isolated from nature is beneficial because it is isolated Kodak ran an advertisement in the journal Nature in the 1970s showing a scientist in a lab coat holding a 250‐ml flask and standing next to several bushels of green peppers wherein the content of the flask was the purified ldquoessence of green pepperrdquo equivalent to that substance contained in all the peppers in all the bushels and bushels that the scientist was standing beside But this very complexity makes it possible for the ldquoactive principlerdquo (either as a chemical compound or as a diagnostic genetic sequence) to be ldquohidden in plain sightrdquo in ways that may be particularly refractory to reverse engineering
For example even using somewhat dated ldquogene chiprdquo technology genetically diagnostic markers could be encrypted onto a microchip comprising 10 000 unique sequences wherein a computer‐readable bar code would be used to identify the positions of diagnostically relevant sequences on the chip This form of encryption which can be random and confounded by the presence of positive and negative control sequences as well as variable numbers and lengths of sequences specific for the gene (or more likely genes) of interest would be very difficult if not impossible to reverse‐engineer Even if reverse engineering could be done it would be difficult and expensive to undertake and thus make it more likely that the innovator would be able to avoid com-petition (ie it would provide unlimited exclusivity to its purveyor not con-strained by patent term or burdened by the requirement that the invention be disclosed with the specificity required by the Patent Act) While the possi-bility that this type of chip could be made exists with or without patents the absence of patent protection could tip the scales in favor of the extra effort needed and risk entailed in nondisclosure if the reward of extended ldquomonopolyrdquo is great enough But particularly for genetic diagnostic inven-tions the benefits of developing a proprietary database for which a corpora-tion could provide the economic and marketing wherewithal to expeditiously produce would result in a ldquoworst of both worldsrdquo outcome unlimited exclu-sivity based on undisclosed proprietary information that not only is difficult to replicate but whose existence would inhibit competition After all if a company had such a database its outcome for any particular patientrsquos test would be more accurate (and might identify disease riskndashassociated genetic variants not available elsewhere) and this would provide little incentive for a physician to choose an alternative provider to perform the test (and even more malevolently could create a system where the wealthy could afford the best diagnostic testing while the less affluent would be restricted to the more
Foreword xxiii
limited assays offered by companies without access to the ldquoinnovatorrsquosrdquo proprietary database information)
The other aspect of foreclosing patents for certain substances or technology areas categorically is that it upsets a carefully crafted dynamic that has worked extremely well during the biotech era between ldquotruerdquo innovators (typically university professors or small start‐up biotechnology companies) and more established companies capable of commercializing innovation Pundits who worry that permitting patenting will harm innovation miss an important point innovation will happen particularly in universities research institutes and like places because human nature demands it and regardless of whether patent protection is available The intelligent ape in us wants to know and the disparity between how univer-sity professors and patent lawyers are paid should establish how powerful the need to know can be Patenting and the impetus for patenting provided for example by the BayhndashDole Act in the United States prevents the fruits of these inventive efforts from mere predation by commercial concerns The benefits that can be had from a system where private commercializa-tion is encouraged are tempered by the types of corporate shenanigans that raise cogent criticisms of the system But perhaps it is mere human nature that people (in the corporate as well as individual sense) will want to expro-priate technology rather than pay for it and patenting prohibits (or at least retards) this outcome (if not these tendencies) Thus paradoxically limiting patent rights does not free innovation but rather makes it more likely to be kept captive by the entities capable of using such innovation to make a commercial product that is not from the power of building a better mouse-trap but by being able to outcompete smaller innovators merely by their greater economic prowess and resources Conversely patents provide a way for the innovators to protect their innovations and compel corporations to license their inventions producing revenue that can be used to fund future research endeavors This useful cycle has resulted in the successes of the biotechnology era and is something that we abandon at our peril
Thus in my view patents are a useful tool for achieving these societally ben-eficial goals promoting innovation and commercialization and protecting and supporting individuals who use the patent system to protect the products of their labors from being expropriated by others David provides a cogent and honest counterpoint to these thoughts Enjoy reading them
Kevin E NoonanChicago Illinois 2014
Preface to the Second Edition
A lot has happened in nearly every respect since I first decided to try to delve into philosophical issues of gene patenting nearly a decade ago I have learned much the world has changed and I have changed I would very much like to think I have played a role in that change though chances are things would have changed in almost exactly the same way without my small contribution When the first edition came out patenting genes was still a regular part of biotech and only months after the first edition appeared did a surprising and now‐landmark lawsuit alter that significantly Little did I realize the nature of the forces that would be involved in what I had originally assumed was no more than an academic exercise but which became a matter of weighty and heated public debate and finally judicial action
I first became interested in the subject of gene patents when I began reading up on the topic my future wife was researching pharmacogenom-ics To grasp what she did I first needed to study the science and in so doing I also studied the history of that science Along the way I read about the Human Genome Project and learned about the practice of gene patenting that it spawned Having had some experience and interest in general issues of the philosophy of intellectual property (see my 1997 PhD thesis turned 2000 book The Ontology of Cyberspace) my ears perked up when I first read about the notion of patenting genes So I dived into the research and thinking in my ordinary style of philosophical work Although I sometimes teach ethics my primary field is ontology and it is from an ontological approach that I start with everything in philosophy Thus I began to try to get a grip on the nature of the existence of the underlying objects some of which are ldquobrute factsrdquo (molecules exist with or without social institutions or intentionality) and some of which are social objects (like laws rights and other parts of ldquosocial realityrdquo existing only because of
Preface to the Second Edition xi
collective intentionality) The book was an attempt to lay all this out and to connect it together into a theory that is somehow connected to notions of ldquojusticerdquo which I argued bridges the worlds of brute facts and social objects
The conclusions I reached were I thought pretty neat Specifically I worked out an ontology of ldquothe commonsrdquo that I had never heard expressed before and one that connected nicely with the objects involved to show why artifacts and nature ought to be treated differently and how to decide what constitutes an artifact and what constitutes nature and a defense of the viewpoint that unmodified genes were clearly not artifacts It seemed all the more relevant and interesting even perhaps somewhat important in light of the then ongoing practice of gene patenting I was much too focused on the ontological arguments and their seeming relevance to real‐world practices than I was to the scientific and legal terminology with which I was engaging and this was an error When the book was released minor errors I made in using technical terminology from both the science and the law were latched onto by a couple critical reviewers from the Intellectual Property law and teaching worlds and urged as a basis to ignore my substantive arguments They were right to call out the errors and I have attempted to correct them in this edition Regardless the underlying argu-ments I had set forth would become shortly echoed nearly precisely in the lawsuit that the American Civil Liberties Union (ACLU) spearheaded against Myriad Corp over the BRCA1amp2 gene patents
For a brief period of time partly due to lucky timing I was thrust head-long into the public debates about gene patenting with the Myriad case leading the headlines Given numerous opportunities to engage publicly with the issues and ideas I had previously assumed were only academic musings unlikely to alter public policy and given feedback and counterar-guments in those same venues the general arguments could be more finely honed This edition attempts to coalesce them
Perhaps more importantly in the intervening years since I began my musings about the nature of genes artifacts nature and patents I came to learn the very personal impact that gene patents have on peoplersquos lives Because the ACLU chose to sue over the patents on BRCA1amp2 genes there was a ready‐made large and passionate community (mostly women) whose heredity put them at risk of breast and ovarian cancers but who were basically forced into paying monopolistic prices for the only test available for the gene which was patented by Myriad Corp Breast cancer and the threat of inherited tendencies for breast cancer are real They are not legal
xii Preface to the Second Edition
sophistry they are not philosophical musing They kill people or alter their lives irrevocably
I began researching and considering the effects of gene patents believing they were potentially a threat to the conduct of science whose foundational objects I argued were part of a commons‐by‐necessity but I realized after my book came out that real lives were being harmed by patents on genes The Myriad case brought together the theoretical with the actual for me and the dynamics of both the case and the loud and sometimes angry public debate raised my awareness not only about this particular subject but also the power and responsibility of academic research in the sphere of public policy Suddenly ideas seemed more important had relevance outside the academy and could perhaps make a difference in peoplesrsquo lives I began to interact with the activists who were fighting to liberate genes to stop com-panies like Myriad in the courts and engage not just in the philosophical arguments but in those fights I joined with authors of amicus (friend of the court) briefs interviewed and interacted with BRCA1amp2 mutation‐positive women who were actively pursuing an end to a practice that I had only pre-viously considered to be an interesting metaphysical conundrum I also debated Intellectual Property (IP) attorneys and others primarily with backgrounds in biotech industries and learning better the nature of their arguments I came to understand that most of them including Kevin Noonan who once called me a ldquoliarrdquo on his blog but who has now drafted the foreword to this edition that they too generally have the best intentions Many like Dr Noonan truly expect that without gene patents as they existed until recently the sort of innovation we need in biomedical technol-ogies would not occur as it should
Throughout the course of the litigation in Myriad I remained engaged continued to speak to hone my arguments adding to my list of criteria for something to be a creation (artifact) capable of patent ldquodesignrdquo (as well as intention and being man‐made) and finally rejoicing when the decision of the Supreme Court came out as close to what I believed and argued was right as possible I had seen an academic idea mature and bloom into public policy real law enforceable justice While I realistically believe that the first edition of this book had only a very minor role in what finally happened I am proud to have played some part to have foreseen the issues to argue them honestly from what I think is a rational and logical standpoint and see that the world can be changed by ideas
Preface to the Second Edition xiii
There remain issues to discuss and not everything about gene patents has been resolved by Myriad Some still argue that cDNA ought not to be patent‐eligible (in fact I still think it should be under the criteria I have set forth though there are also arguments to be made that it is not somehow ldquodesignedrdquo by man) Moreover we should expect patent attorneys to do their creative best to continue to pursue patents on as much of the genome as they can within the constraints of Myriad Finally Myriad Corp has not given up They are still suing potential competitors under theories of infringement of parts of their patents that might have survived the ACLUrsquos case against them We shall see how they are eventually resolved and what the future holds for companies like theirs who profited mightily from gene patents for decades I describe as much of this recent legal history as possible in this edition
This book is meant to be a definitive version sewing up the past five years since the first edition emerged and so much changed in the world summa-rizing that recent history and refining the arguments I originally made correcting errors and describing where we are where we yet may be and why gene patents as they once were ought never to be again
David KoepsellAugust 14 2014
Mexico City Mexico
Foreword
David and I have had a friendly disagreement about the subject (and even the title) of this book ever since it was first published and I am happy that he asked me to write this Foreword to the Second Edition The issues David raises in the pages to follow continue to be relevant to a discussion of philosophy and patent law with events that have occurred since the first edition justifying (indeed demanding) this update
Without getting into the deep waters of philosophy (Davidrsquos meacutetier not mine) as we have discussed the issues in the book David contends that he takes a deontological approach and has characterized mine as a utilitarian one Accepting that dichotomy I understand the difference to be that David is operating from ldquofirst principlesrdquo about the rules society should impose on human activity and specifically on what the law permits individuals to ldquoownrdquo with regard to genes and more broadly naturally occurring substances I disagree with that approach on several levels perhaps the most germane of which is that if we posit rules we need to impose a rule‐giver and the potential for improvident rules (if not outright abuse of the privilege) makes me wary in some ways I subscribe to Lani Gruinierrsquos suspicions about the effects of the ldquotyranny of the majorityrdquo in this regard
Part of that tyranny is also the tyranny of unintended or intentional ignorance The issue heremdashldquogenerdquo patentingmdashis one at the intersection of molecular biology and modern genetics on the one hand and patent law (an area notorious for its arcane minutiae) I used to joke with my col-leagues about the effect of trying to explain my position to a lay audience of any type and how I distrusted those who advocated that all that was needed was to ldquoeducaterdquo the public the press and policy makers The problem for proponents of gene patenting has been that opponents have gotten the better part of the debate not by making a reasoned philosophical argument such as the one you will find in these pages but instead by making an
Foreword xv
emotional plea to individuals afraid that corporate America was trying to ldquostealrdquo their genes which has proven very effective This process began with an Op‐Ed piece in The New York Times by Michael Crichton wherein he posited a scenario where a patent holder knocks on your door one day and demands payment for the use of ldquoherrdquo patented gene that resides in your liver (Not coincidentally Dr Crichton had just published a novel on the perils of genetic engineering and corporate ownership of human genes complete with an essay as an addendum containing his arguments against the practice And it should be noted that a constant theme in his novels was a mistrust of technology and particularly the ability of humans to use it without dire consequences) Academics like my friend Lori Andrews at Illinois Institute of Technology (IIT)‐Kent School of Law joined in this theme which was picked up eventually by most popular press outlets and became regrettably the canonical narrative on gene patenting culminating in the American Civil Liberties Unionrsquos (ACLUrsquos) ldquoKeep Your Hands Off My Genesrdquo slogan and logo I hope that this essay provides some antidote to this argument which is founded on the literal fear that someone can ldquoownrdquo you (David assures me that his title is allegorical and that he acknowledges that in all countries that have banned slavery no one can ldquoownrdquo another human being or a part of them See the 13th Amendment I assure you that the ACLU has no such illusions about the intended consequences of their ownership rhetoric)
My philosophy is that the principle we should follow is the greatest good to the greatest number while not infringing on individual rights without (at least) compensation As regards patent law this principle is translated into rules that foster the broadest disclosure of technology possible in return for exclusive patent rights and robust‐enough enforcement rights for patents that they provide sufficient certainty to promote investment so his technology is commercialized to benefit the greatest number In my role as a biotechnology patent attorney I have seen how risky investment in biotechnology can be (indeed the evidence is overwhelming that for all its successes biotechrsquos history is littered with the remains of companies that have failed) and how important it is to have a sound patent system of predictable rights go support that investment
The evidence in support of ldquogene patentingrdquo and more broadly natural products patenting is strong the biotechnology industry has promoted innovation in the form of new drugs and diagnostics assays for a genera-tion This may continue despite the recent restrictions on patent protection
xvi Foreword
for genes and natural products (including patent‐restricting decisions in Mayo Collaborative Labs v Prometheus Labs and Assoc of Molecular Pathologists v Myriad Genetics and recently promulgated US Patent and Trademark Office Guidances on Subject Matter Eligibility) In fact these very restrictions suggest that we would benefit from an appreciation of the facts surrounding the past thirty years of gene patenting to understand why these restrictions are not only wrongheaded but dangerous for future innovation
These include debunking several myths First the concern that patents on specific human genes in some way inhibit innovation in basic genetic research is entirely unfounded One reason is that the genetic information itself is not patented while isolated DNA is encompassed by gene patent claims and described in those claims by its sequence the sequence itself is unpatented information that can be used freely for any purpose (eg inter-rogating genetic databases from other species or even human DNA inter alia to find related genes in those databases) Indeed the innovative benefits to gene patenting are evident in at least two ways First scientific publication databases reveal that there have been more than 11 000 scientific papers published on the BRCA1 and BRCA2 genes since the patents claiming them were granted This outcome refutes the prediction that gene patenting would create a ldquotragedy of the anticommonsrdquo where scientific research would be stifled by patenting (see Heller amp Eisenberg 1998 ldquoCan Patents Deter Innovation The Anticommons in Biomedical Researchrdquo Science 280 698ndash701)) a conclusion supported by the overwhelming majority of studies done on this subject (see for example Walsh et al 2003 ldquoScience and the Law Working Through the Patent Problemrdquo Science 299 1020 Walsh et al 2005 ldquoScience and Law View from the Bench Patents and Material Transfersrdquo Science 309 2002ndash03)
In addition policies that the US Patent and Trademark Office adopted in 2001 required applicants to disclose a practical utility for the product of a gene claimed in a patent These requirements were imposed at a time when the standards for scientific journal publication were much less stringent so that identifying a gene by the extent of genetic similarity between the ldquonewrdquo gene and previously discovered genes was enough for publication But it was not enough for a patent which has been held to be ldquonot a hunting license It is not a reward for the search but compensation for its successful conclusionrdquo Thus genes encoding proteins having no known use or biological activity cannot be patented because to do so would allow the
Foreword xvii
gene to be within the exclusive patent right undeservedly the public would not have received its quid pro quo of a useful invention in return for patent exclusivity All such genes not having patent protection are in the public domain (from which they cannot be retrieved for future patenting) and for humans these constitute the vast majority of genes identified inter alia by the Human Genome Project
The role for patenting genes and the related genetic diagnostic methods using this genetic information in the successes of the biotechnology era are evident The industry has produced hundreds of biologic drugs (at an ever‐increasing rate) that have provided effective treatment for a variety of illnesses and decoding the human genome has enabled researchers to iden-tify genes like the BRCA1 and BRCA2 genes that can be used in predictive genetic diagnostic tests Even the much‐maligned Myriad Genetics has played a positive role in the development and prevalence of genetic diagnostic testing It must be remembered that in 1997 (when Myriadrsquos BRCA gene patents were granted) genetic testing was in its infancy and companies like Myriad were under the burden of convincing payers that the tests did the one thing that all insurers public or private require of such tests save them money in the long run by identifying patients with a high probability of becoming ill and costing the insurers much more for treatment than the costs of prophylaxis Moreover Myriad and like com-panies needed to convince doctors that the testing was worthwhile and to establish a network of genetic counselors who could explain to healthy women that they were at much greater risk of developing breast or ovarian cancer than normal under circumstances that resulted in empowerment from the information and not abject fear And in 1997 genetic sequencing technology was not as developed as it is now and the mechanisms and tech-niques needed to minimize or eliminate the occurrence of false positives or negatives had not been conclusively established All these burdens were ones borne by Myriad and these activities produced the world we have today
It is possible as some have argued that BRCA tests may have been devel-oped independently by individual researchers in the absence of patent pro-tection However it is almost certain that such researchers would have been located in medical centers in urban environments Under these circum-stances women living in or near cities such as New York Boston Philadelphia Cleveland Chicago Houston Denver Los Angeles San Francisco Portland and Seattle might have had access to these tests But what of women in
xviii Foreword
Appalachia or the Four Corners region in the Southwest or more generally in rural or other relatively remote locations Would Yale University for example have had any incentive to provide access to the BRCA tests to these women in these far‐off locations Or to provide genetic counseling where the women lived Or to lobby state Medicare administrators or private insurance commissioners to cover the test I think that unlikely Myriad Genetics did all of this as well as perform outreach to the obstetrics and gynecology doctors throughout the United States so that these primary care doctors were aware of the tests Myriad did not ace from altruism but as part of their business plan in order to expand the number of patients who received the test and thus maximize the companyrsquos revenue While it may be counterintuitive to some these circumstances may have been the most effective way not only to pro-mulgate the BRCA tests but also to facilitate acceptance of genetic diagnostic testing for other diseases showing that in this instance Adam Smith rather than Karl Marx provided the most practical solution to the problem of estab-lishing genetic diagnostic testing as a recognized component of a physicianrsquos diagnostic armamentarium
Fortunately the significance and impact of recent US court decisions (spe-cifically the Myriad case) is much less than it would have been ten to thirty years ago Due to patent term rules most patents (and applications) on iso-lated DNA filed in the heyday of the Human Genome Project (approxi-mately 1998ndash2001) are near the end of their actual or potential term indeed a recent study shows that the number of granted patents having at least one claim reciting an isolate DNA comprising a gene peaked in 1999 and has been dropping since 2005 (Graff et al 2013 ldquoNot quite a myriad of gene pat-entsrdquo Nature Biotechnology 31 404ndash410)) These recent decisions in the United States have not harmed the biotechnology industry because they retained patent eligibility for species of DNA that show evidence of the ldquohand of manrdquo and do not occur in nature These include enzymatically pro-duced copies (cDNA) of cellular messenger RNA and should also encom-pass the tools of the recombinant geneticist (eg including recombinant vectors for cloning and expressing genes in heterologous cells) Most impor-tantly the US Supreme Court did not overturn its Diamond v Chakrabarty decision wherein recombinant cells were determined to be patent eligible
Thus in many ways the question of patent eligibility for human genes is a philosophical one However that does not mean that how we think about patent eligibility for isolated DNA is irrelevant to important questions regarding the usefulness of patents for promoting progress and innovation
Foreword xix
Indeed the most pernicious effects of the current trend in the zeitgeist against patenting has been not that genes have become harder to patent but rather that the ability to patent other natural products has been called into question It is the extension of these recent decisions on isolated DNA to all natural products that poses the greatest threat to innovation This threat can be illustrated by a thought experiment for which of these substances should patent protection be withheld
bull A petrochemical with excellent lubrication qualities isolated in pure form and used as improved motor oil
bull Vitamin B12 isolated from beef muscle formulated into a medicament used to cure anemia in children
bull The drug penicillin isolated from a mixture of naturally produced chemicals made by a mold and formulated as a drug to cure syphilis (which is otherwise eventually fatal)
bull Human urinary erythropoietin formulated to treat anemia in kidney dialysis patients
bull The gene responsible for Gaucherrsquos disease a lipid storage disease wherein the gene is used to make the missing protein that is administered to children and that cures an otherwise incurable and fatal disease
The current answer is that none of them are patent‐eligible per se (although there may be ways to claim them that could pass eligibility muster that remains to be seen) Judge Sweet the US District Court judge who first ruled that isolated DNA was not patent‐eligible did so using language carefully crafted to avoid encompassing all natural products into his decision Specifically Judge Sweet distinguished isolated DNA as the ldquophysical embodiments of genetic informationrdquo a property limited to DNA and not shared by other natural products (While an enzymatic protein could be characterized as the physical embodiment of catalysis of a particular chemical reaction that formulation has much less appeal and inherent rationale than Judge Sweetrsquos regarding DNA) Instead of this careful formu-lation the broader language employed by the Supreme Court as well as the broader rationale the Court used in finding genomic DNA unpatentable has made it easier to employ that fractured logic to render patent‐ineligible naturally occurring molecules other than DNA
I would be remiss not to mention the rather comical (but persistent) efforts of former Acting Solicitor General Neal Katyal who included in the
xx Foreword
US Governmentrsquos amicus brief to the Federal Circuit the distinction engine he called a ldquomagic microscoperdquo embodying the concept that if you are able to visualize a natural product (like a genomic DNA molecule) using this mythical microscope then the natural product would not be patent‐eligible whereas if you could not (eg a cDNA molecule) then the natural product could be eligible for patenting Fortunately the disdain with which the Federal Circuit greeted this fantasy (particularly from Judge Moore) prompted its quick abandonment as are argumentative distinction as the case moved forward Nonetheless both the courts and the US Patent and Trademark Office have adopted this standard de facto even as it becomes the theory that dare not speak its name in legal circles
The philosophical point here is that these substances and natural products generally have been deemed patent‐ineligible categorically which while consistent with (and perhaps even mandated by) the deon-tological approach imposes a distinction that cannot be flexibly applied to the individual circumstances Without such flexibility the law is con-strained to use one criterion that the substance can be found in some form in nature to decide patent eligibility instead of making the deter-mination of whether permitting patenting exclusivity satisfies the cri-teria that the invention ldquopromotes progressrdquo as the US Constitution requires and has a benefit to the public that outweighs any categorical disabilities
The potential that using this standard for determining patent eligibility will result in negative practical outcomes that no one in this debate desires is illustrated by a 2012 Report from the National Institutes of Health Natural Product Branch regarding statistics relating to the number of FDA approvals (a total of 1355) for new drugs falling into the following categories
Drug typesource Number
Biological (B) 203Natural product (N) 55Natural product (botanical) (NB) 149Derived from a natural product (ND) 298Totally synthetic (S) 393Total synthesisnatural product (S) 176Vaccine (S) 81
Foreword xxi
These statistics illustrate the consequences of a general ban on patenting naturally derived products of the 1355 drugs approved between 1981 and 2010
bull Fifty percent of all small‐molecule drugs approved between 2000 and 2010 are natural products
bull About 75 of antibacterial drugs are natural products or derived from natural products
bull Almost 80 of small‐molecule anticancer drugs were natural products or derivatives
In addition only 15 of drugs approved during this time frame were so‐called biologic drugs which are also putatively patent‐ineligible This the problems caused by the current interpretation of the law excluding natural product drugs from patent eligibility will be exacerbated in view of reports from every study showing that the percentage of drugs that are biologic drugs has been growing and will be the predominant type of drug devel-oped in the 2011ndash2030 time period
Another ldquothought experimentrdquo illustrating the practical illogic (David can provide his philosophical justifications in the body of the text) of broad natural products patent ineligibility is as follows Suppose a researcher finds a molecule produced by the human body that causes blood pressure homeo-stasis that is lack of this molecule causes or contributes to the disease of high blood pressure The logical consequence of the current natural prod-uct patent ineligibility standards would be that the closer a drug molecule is to the structure of the molecule as it occurs in the body the less patent‐eli-gible it would be Practically speaking there would be no incentive to modify the molecule to confer patent eligibility on the altered molecule because of the unpredictability of such changes on the molecule such as its biological activity half‐life stability antigenicity or other biological prop-erties And there would be even less incentive to develop the molecule as a drug because without patent protection the available regulatory exclusiv-ities would not pass economic muster to sufficiently defray the large development costs (some of which prevent drugs neither safe nor effica-cious from being sold and thus provide their own justification)
There is one further pernicious outcome that can be predicted to arise from a ban on natural products patents (including patents on isolated DNA and genetic diagnostic methods based on such isolated DNA) Natural
xxii Foreword
products are almost by nature complex and an ldquoactive principlerdquo isolated from nature is beneficial because it is isolated Kodak ran an advertisement in the journal Nature in the 1970s showing a scientist in a lab coat holding a 250‐ml flask and standing next to several bushels of green peppers wherein the content of the flask was the purified ldquoessence of green pepperrdquo equivalent to that substance contained in all the peppers in all the bushels and bushels that the scientist was standing beside But this very complexity makes it possible for the ldquoactive principlerdquo (either as a chemical compound or as a diagnostic genetic sequence) to be ldquohidden in plain sightrdquo in ways that may be particularly refractory to reverse engineering
For example even using somewhat dated ldquogene chiprdquo technology genetically diagnostic markers could be encrypted onto a microchip comprising 10 000 unique sequences wherein a computer‐readable bar code would be used to identify the positions of diagnostically relevant sequences on the chip This form of encryption which can be random and confounded by the presence of positive and negative control sequences as well as variable numbers and lengths of sequences specific for the gene (or more likely genes) of interest would be very difficult if not impossible to reverse‐engineer Even if reverse engineering could be done it would be difficult and expensive to undertake and thus make it more likely that the innovator would be able to avoid com-petition (ie it would provide unlimited exclusivity to its purveyor not con-strained by patent term or burdened by the requirement that the invention be disclosed with the specificity required by the Patent Act) While the possi-bility that this type of chip could be made exists with or without patents the absence of patent protection could tip the scales in favor of the extra effort needed and risk entailed in nondisclosure if the reward of extended ldquomonopolyrdquo is great enough But particularly for genetic diagnostic inven-tions the benefits of developing a proprietary database for which a corpora-tion could provide the economic and marketing wherewithal to expeditiously produce would result in a ldquoworst of both worldsrdquo outcome unlimited exclu-sivity based on undisclosed proprietary information that not only is difficult to replicate but whose existence would inhibit competition After all if a company had such a database its outcome for any particular patientrsquos test would be more accurate (and might identify disease riskndashassociated genetic variants not available elsewhere) and this would provide little incentive for a physician to choose an alternative provider to perform the test (and even more malevolently could create a system where the wealthy could afford the best diagnostic testing while the less affluent would be restricted to the more
Foreword xxiii
limited assays offered by companies without access to the ldquoinnovatorrsquosrdquo proprietary database information)
The other aspect of foreclosing patents for certain substances or technology areas categorically is that it upsets a carefully crafted dynamic that has worked extremely well during the biotech era between ldquotruerdquo innovators (typically university professors or small start‐up biotechnology companies) and more established companies capable of commercializing innovation Pundits who worry that permitting patenting will harm innovation miss an important point innovation will happen particularly in universities research institutes and like places because human nature demands it and regardless of whether patent protection is available The intelligent ape in us wants to know and the disparity between how univer-sity professors and patent lawyers are paid should establish how powerful the need to know can be Patenting and the impetus for patenting provided for example by the BayhndashDole Act in the United States prevents the fruits of these inventive efforts from mere predation by commercial concerns The benefits that can be had from a system where private commercializa-tion is encouraged are tempered by the types of corporate shenanigans that raise cogent criticisms of the system But perhaps it is mere human nature that people (in the corporate as well as individual sense) will want to expro-priate technology rather than pay for it and patenting prohibits (or at least retards) this outcome (if not these tendencies) Thus paradoxically limiting patent rights does not free innovation but rather makes it more likely to be kept captive by the entities capable of using such innovation to make a commercial product that is not from the power of building a better mouse-trap but by being able to outcompete smaller innovators merely by their greater economic prowess and resources Conversely patents provide a way for the innovators to protect their innovations and compel corporations to license their inventions producing revenue that can be used to fund future research endeavors This useful cycle has resulted in the successes of the biotechnology era and is something that we abandon at our peril
Thus in my view patents are a useful tool for achieving these societally ben-eficial goals promoting innovation and commercialization and protecting and supporting individuals who use the patent system to protect the products of their labors from being expropriated by others David provides a cogent and honest counterpoint to these thoughts Enjoy reading them
Kevin E NoonanChicago Illinois 2014
Preface to the Second Edition xi
collective intentionality) The book was an attempt to lay all this out and to connect it together into a theory that is somehow connected to notions of ldquojusticerdquo which I argued bridges the worlds of brute facts and social objects
The conclusions I reached were I thought pretty neat Specifically I worked out an ontology of ldquothe commonsrdquo that I had never heard expressed before and one that connected nicely with the objects involved to show why artifacts and nature ought to be treated differently and how to decide what constitutes an artifact and what constitutes nature and a defense of the viewpoint that unmodified genes were clearly not artifacts It seemed all the more relevant and interesting even perhaps somewhat important in light of the then ongoing practice of gene patenting I was much too focused on the ontological arguments and their seeming relevance to real‐world practices than I was to the scientific and legal terminology with which I was engaging and this was an error When the book was released minor errors I made in using technical terminology from both the science and the law were latched onto by a couple critical reviewers from the Intellectual Property law and teaching worlds and urged as a basis to ignore my substantive arguments They were right to call out the errors and I have attempted to correct them in this edition Regardless the underlying argu-ments I had set forth would become shortly echoed nearly precisely in the lawsuit that the American Civil Liberties Union (ACLU) spearheaded against Myriad Corp over the BRCA1amp2 gene patents
For a brief period of time partly due to lucky timing I was thrust head-long into the public debates about gene patenting with the Myriad case leading the headlines Given numerous opportunities to engage publicly with the issues and ideas I had previously assumed were only academic musings unlikely to alter public policy and given feedback and counterar-guments in those same venues the general arguments could be more finely honed This edition attempts to coalesce them
Perhaps more importantly in the intervening years since I began my musings about the nature of genes artifacts nature and patents I came to learn the very personal impact that gene patents have on peoplersquos lives Because the ACLU chose to sue over the patents on BRCA1amp2 genes there was a ready‐made large and passionate community (mostly women) whose heredity put them at risk of breast and ovarian cancers but who were basically forced into paying monopolistic prices for the only test available for the gene which was patented by Myriad Corp Breast cancer and the threat of inherited tendencies for breast cancer are real They are not legal
xii Preface to the Second Edition
sophistry they are not philosophical musing They kill people or alter their lives irrevocably
I began researching and considering the effects of gene patents believing they were potentially a threat to the conduct of science whose foundational objects I argued were part of a commons‐by‐necessity but I realized after my book came out that real lives were being harmed by patents on genes The Myriad case brought together the theoretical with the actual for me and the dynamics of both the case and the loud and sometimes angry public debate raised my awareness not only about this particular subject but also the power and responsibility of academic research in the sphere of public policy Suddenly ideas seemed more important had relevance outside the academy and could perhaps make a difference in peoplesrsquo lives I began to interact with the activists who were fighting to liberate genes to stop com-panies like Myriad in the courts and engage not just in the philosophical arguments but in those fights I joined with authors of amicus (friend of the court) briefs interviewed and interacted with BRCA1amp2 mutation‐positive women who were actively pursuing an end to a practice that I had only pre-viously considered to be an interesting metaphysical conundrum I also debated Intellectual Property (IP) attorneys and others primarily with backgrounds in biotech industries and learning better the nature of their arguments I came to understand that most of them including Kevin Noonan who once called me a ldquoliarrdquo on his blog but who has now drafted the foreword to this edition that they too generally have the best intentions Many like Dr Noonan truly expect that without gene patents as they existed until recently the sort of innovation we need in biomedical technol-ogies would not occur as it should
Throughout the course of the litigation in Myriad I remained engaged continued to speak to hone my arguments adding to my list of criteria for something to be a creation (artifact) capable of patent ldquodesignrdquo (as well as intention and being man‐made) and finally rejoicing when the decision of the Supreme Court came out as close to what I believed and argued was right as possible I had seen an academic idea mature and bloom into public policy real law enforceable justice While I realistically believe that the first edition of this book had only a very minor role in what finally happened I am proud to have played some part to have foreseen the issues to argue them honestly from what I think is a rational and logical standpoint and see that the world can be changed by ideas
Preface to the Second Edition xiii
There remain issues to discuss and not everything about gene patents has been resolved by Myriad Some still argue that cDNA ought not to be patent‐eligible (in fact I still think it should be under the criteria I have set forth though there are also arguments to be made that it is not somehow ldquodesignedrdquo by man) Moreover we should expect patent attorneys to do their creative best to continue to pursue patents on as much of the genome as they can within the constraints of Myriad Finally Myriad Corp has not given up They are still suing potential competitors under theories of infringement of parts of their patents that might have survived the ACLUrsquos case against them We shall see how they are eventually resolved and what the future holds for companies like theirs who profited mightily from gene patents for decades I describe as much of this recent legal history as possible in this edition
This book is meant to be a definitive version sewing up the past five years since the first edition emerged and so much changed in the world summa-rizing that recent history and refining the arguments I originally made correcting errors and describing where we are where we yet may be and why gene patents as they once were ought never to be again
David KoepsellAugust 14 2014
Mexico City Mexico
Foreword
David and I have had a friendly disagreement about the subject (and even the title) of this book ever since it was first published and I am happy that he asked me to write this Foreword to the Second Edition The issues David raises in the pages to follow continue to be relevant to a discussion of philosophy and patent law with events that have occurred since the first edition justifying (indeed demanding) this update
Without getting into the deep waters of philosophy (Davidrsquos meacutetier not mine) as we have discussed the issues in the book David contends that he takes a deontological approach and has characterized mine as a utilitarian one Accepting that dichotomy I understand the difference to be that David is operating from ldquofirst principlesrdquo about the rules society should impose on human activity and specifically on what the law permits individuals to ldquoownrdquo with regard to genes and more broadly naturally occurring substances I disagree with that approach on several levels perhaps the most germane of which is that if we posit rules we need to impose a rule‐giver and the potential for improvident rules (if not outright abuse of the privilege) makes me wary in some ways I subscribe to Lani Gruinierrsquos suspicions about the effects of the ldquotyranny of the majorityrdquo in this regard
Part of that tyranny is also the tyranny of unintended or intentional ignorance The issue heremdashldquogenerdquo patentingmdashis one at the intersection of molecular biology and modern genetics on the one hand and patent law (an area notorious for its arcane minutiae) I used to joke with my col-leagues about the effect of trying to explain my position to a lay audience of any type and how I distrusted those who advocated that all that was needed was to ldquoeducaterdquo the public the press and policy makers The problem for proponents of gene patenting has been that opponents have gotten the better part of the debate not by making a reasoned philosophical argument such as the one you will find in these pages but instead by making an
Foreword xv
emotional plea to individuals afraid that corporate America was trying to ldquostealrdquo their genes which has proven very effective This process began with an Op‐Ed piece in The New York Times by Michael Crichton wherein he posited a scenario where a patent holder knocks on your door one day and demands payment for the use of ldquoherrdquo patented gene that resides in your liver (Not coincidentally Dr Crichton had just published a novel on the perils of genetic engineering and corporate ownership of human genes complete with an essay as an addendum containing his arguments against the practice And it should be noted that a constant theme in his novels was a mistrust of technology and particularly the ability of humans to use it without dire consequences) Academics like my friend Lori Andrews at Illinois Institute of Technology (IIT)‐Kent School of Law joined in this theme which was picked up eventually by most popular press outlets and became regrettably the canonical narrative on gene patenting culminating in the American Civil Liberties Unionrsquos (ACLUrsquos) ldquoKeep Your Hands Off My Genesrdquo slogan and logo I hope that this essay provides some antidote to this argument which is founded on the literal fear that someone can ldquoownrdquo you (David assures me that his title is allegorical and that he acknowledges that in all countries that have banned slavery no one can ldquoownrdquo another human being or a part of them See the 13th Amendment I assure you that the ACLU has no such illusions about the intended consequences of their ownership rhetoric)
My philosophy is that the principle we should follow is the greatest good to the greatest number while not infringing on individual rights without (at least) compensation As regards patent law this principle is translated into rules that foster the broadest disclosure of technology possible in return for exclusive patent rights and robust‐enough enforcement rights for patents that they provide sufficient certainty to promote investment so his technology is commercialized to benefit the greatest number In my role as a biotechnology patent attorney I have seen how risky investment in biotechnology can be (indeed the evidence is overwhelming that for all its successes biotechrsquos history is littered with the remains of companies that have failed) and how important it is to have a sound patent system of predictable rights go support that investment
The evidence in support of ldquogene patentingrdquo and more broadly natural products patenting is strong the biotechnology industry has promoted innovation in the form of new drugs and diagnostics assays for a genera-tion This may continue despite the recent restrictions on patent protection
xvi Foreword
for genes and natural products (including patent‐restricting decisions in Mayo Collaborative Labs v Prometheus Labs and Assoc of Molecular Pathologists v Myriad Genetics and recently promulgated US Patent and Trademark Office Guidances on Subject Matter Eligibility) In fact these very restrictions suggest that we would benefit from an appreciation of the facts surrounding the past thirty years of gene patenting to understand why these restrictions are not only wrongheaded but dangerous for future innovation
These include debunking several myths First the concern that patents on specific human genes in some way inhibit innovation in basic genetic research is entirely unfounded One reason is that the genetic information itself is not patented while isolated DNA is encompassed by gene patent claims and described in those claims by its sequence the sequence itself is unpatented information that can be used freely for any purpose (eg inter-rogating genetic databases from other species or even human DNA inter alia to find related genes in those databases) Indeed the innovative benefits to gene patenting are evident in at least two ways First scientific publication databases reveal that there have been more than 11 000 scientific papers published on the BRCA1 and BRCA2 genes since the patents claiming them were granted This outcome refutes the prediction that gene patenting would create a ldquotragedy of the anticommonsrdquo where scientific research would be stifled by patenting (see Heller amp Eisenberg 1998 ldquoCan Patents Deter Innovation The Anticommons in Biomedical Researchrdquo Science 280 698ndash701)) a conclusion supported by the overwhelming majority of studies done on this subject (see for example Walsh et al 2003 ldquoScience and the Law Working Through the Patent Problemrdquo Science 299 1020 Walsh et al 2005 ldquoScience and Law View from the Bench Patents and Material Transfersrdquo Science 309 2002ndash03)
In addition policies that the US Patent and Trademark Office adopted in 2001 required applicants to disclose a practical utility for the product of a gene claimed in a patent These requirements were imposed at a time when the standards for scientific journal publication were much less stringent so that identifying a gene by the extent of genetic similarity between the ldquonewrdquo gene and previously discovered genes was enough for publication But it was not enough for a patent which has been held to be ldquonot a hunting license It is not a reward for the search but compensation for its successful conclusionrdquo Thus genes encoding proteins having no known use or biological activity cannot be patented because to do so would allow the
Foreword xvii
gene to be within the exclusive patent right undeservedly the public would not have received its quid pro quo of a useful invention in return for patent exclusivity All such genes not having patent protection are in the public domain (from which they cannot be retrieved for future patenting) and for humans these constitute the vast majority of genes identified inter alia by the Human Genome Project
The role for patenting genes and the related genetic diagnostic methods using this genetic information in the successes of the biotechnology era are evident The industry has produced hundreds of biologic drugs (at an ever‐increasing rate) that have provided effective treatment for a variety of illnesses and decoding the human genome has enabled researchers to iden-tify genes like the BRCA1 and BRCA2 genes that can be used in predictive genetic diagnostic tests Even the much‐maligned Myriad Genetics has played a positive role in the development and prevalence of genetic diagnostic testing It must be remembered that in 1997 (when Myriadrsquos BRCA gene patents were granted) genetic testing was in its infancy and companies like Myriad were under the burden of convincing payers that the tests did the one thing that all insurers public or private require of such tests save them money in the long run by identifying patients with a high probability of becoming ill and costing the insurers much more for treatment than the costs of prophylaxis Moreover Myriad and like com-panies needed to convince doctors that the testing was worthwhile and to establish a network of genetic counselors who could explain to healthy women that they were at much greater risk of developing breast or ovarian cancer than normal under circumstances that resulted in empowerment from the information and not abject fear And in 1997 genetic sequencing technology was not as developed as it is now and the mechanisms and tech-niques needed to minimize or eliminate the occurrence of false positives or negatives had not been conclusively established All these burdens were ones borne by Myriad and these activities produced the world we have today
It is possible as some have argued that BRCA tests may have been devel-oped independently by individual researchers in the absence of patent pro-tection However it is almost certain that such researchers would have been located in medical centers in urban environments Under these circum-stances women living in or near cities such as New York Boston Philadelphia Cleveland Chicago Houston Denver Los Angeles San Francisco Portland and Seattle might have had access to these tests But what of women in
xviii Foreword
Appalachia or the Four Corners region in the Southwest or more generally in rural or other relatively remote locations Would Yale University for example have had any incentive to provide access to the BRCA tests to these women in these far‐off locations Or to provide genetic counseling where the women lived Or to lobby state Medicare administrators or private insurance commissioners to cover the test I think that unlikely Myriad Genetics did all of this as well as perform outreach to the obstetrics and gynecology doctors throughout the United States so that these primary care doctors were aware of the tests Myriad did not ace from altruism but as part of their business plan in order to expand the number of patients who received the test and thus maximize the companyrsquos revenue While it may be counterintuitive to some these circumstances may have been the most effective way not only to pro-mulgate the BRCA tests but also to facilitate acceptance of genetic diagnostic testing for other diseases showing that in this instance Adam Smith rather than Karl Marx provided the most practical solution to the problem of estab-lishing genetic diagnostic testing as a recognized component of a physicianrsquos diagnostic armamentarium
Fortunately the significance and impact of recent US court decisions (spe-cifically the Myriad case) is much less than it would have been ten to thirty years ago Due to patent term rules most patents (and applications) on iso-lated DNA filed in the heyday of the Human Genome Project (approxi-mately 1998ndash2001) are near the end of their actual or potential term indeed a recent study shows that the number of granted patents having at least one claim reciting an isolate DNA comprising a gene peaked in 1999 and has been dropping since 2005 (Graff et al 2013 ldquoNot quite a myriad of gene pat-entsrdquo Nature Biotechnology 31 404ndash410)) These recent decisions in the United States have not harmed the biotechnology industry because they retained patent eligibility for species of DNA that show evidence of the ldquohand of manrdquo and do not occur in nature These include enzymatically pro-duced copies (cDNA) of cellular messenger RNA and should also encom-pass the tools of the recombinant geneticist (eg including recombinant vectors for cloning and expressing genes in heterologous cells) Most impor-tantly the US Supreme Court did not overturn its Diamond v Chakrabarty decision wherein recombinant cells were determined to be patent eligible
Thus in many ways the question of patent eligibility for human genes is a philosophical one However that does not mean that how we think about patent eligibility for isolated DNA is irrelevant to important questions regarding the usefulness of patents for promoting progress and innovation
Foreword xix
Indeed the most pernicious effects of the current trend in the zeitgeist against patenting has been not that genes have become harder to patent but rather that the ability to patent other natural products has been called into question It is the extension of these recent decisions on isolated DNA to all natural products that poses the greatest threat to innovation This threat can be illustrated by a thought experiment for which of these substances should patent protection be withheld
bull A petrochemical with excellent lubrication qualities isolated in pure form and used as improved motor oil
bull Vitamin B12 isolated from beef muscle formulated into a medicament used to cure anemia in children
bull The drug penicillin isolated from a mixture of naturally produced chemicals made by a mold and formulated as a drug to cure syphilis (which is otherwise eventually fatal)
bull Human urinary erythropoietin formulated to treat anemia in kidney dialysis patients
bull The gene responsible for Gaucherrsquos disease a lipid storage disease wherein the gene is used to make the missing protein that is administered to children and that cures an otherwise incurable and fatal disease
The current answer is that none of them are patent‐eligible per se (although there may be ways to claim them that could pass eligibility muster that remains to be seen) Judge Sweet the US District Court judge who first ruled that isolated DNA was not patent‐eligible did so using language carefully crafted to avoid encompassing all natural products into his decision Specifically Judge Sweet distinguished isolated DNA as the ldquophysical embodiments of genetic informationrdquo a property limited to DNA and not shared by other natural products (While an enzymatic protein could be characterized as the physical embodiment of catalysis of a particular chemical reaction that formulation has much less appeal and inherent rationale than Judge Sweetrsquos regarding DNA) Instead of this careful formu-lation the broader language employed by the Supreme Court as well as the broader rationale the Court used in finding genomic DNA unpatentable has made it easier to employ that fractured logic to render patent‐ineligible naturally occurring molecules other than DNA
I would be remiss not to mention the rather comical (but persistent) efforts of former Acting Solicitor General Neal Katyal who included in the
xx Foreword
US Governmentrsquos amicus brief to the Federal Circuit the distinction engine he called a ldquomagic microscoperdquo embodying the concept that if you are able to visualize a natural product (like a genomic DNA molecule) using this mythical microscope then the natural product would not be patent‐eligible whereas if you could not (eg a cDNA molecule) then the natural product could be eligible for patenting Fortunately the disdain with which the Federal Circuit greeted this fantasy (particularly from Judge Moore) prompted its quick abandonment as are argumentative distinction as the case moved forward Nonetheless both the courts and the US Patent and Trademark Office have adopted this standard de facto even as it becomes the theory that dare not speak its name in legal circles
The philosophical point here is that these substances and natural products generally have been deemed patent‐ineligible categorically which while consistent with (and perhaps even mandated by) the deon-tological approach imposes a distinction that cannot be flexibly applied to the individual circumstances Without such flexibility the law is con-strained to use one criterion that the substance can be found in some form in nature to decide patent eligibility instead of making the deter-mination of whether permitting patenting exclusivity satisfies the cri-teria that the invention ldquopromotes progressrdquo as the US Constitution requires and has a benefit to the public that outweighs any categorical disabilities
The potential that using this standard for determining patent eligibility will result in negative practical outcomes that no one in this debate desires is illustrated by a 2012 Report from the National Institutes of Health Natural Product Branch regarding statistics relating to the number of FDA approvals (a total of 1355) for new drugs falling into the following categories
Drug typesource Number
Biological (B) 203Natural product (N) 55Natural product (botanical) (NB) 149Derived from a natural product (ND) 298Totally synthetic (S) 393Total synthesisnatural product (S) 176Vaccine (S) 81
Foreword xxi
These statistics illustrate the consequences of a general ban on patenting naturally derived products of the 1355 drugs approved between 1981 and 2010
bull Fifty percent of all small‐molecule drugs approved between 2000 and 2010 are natural products
bull About 75 of antibacterial drugs are natural products or derived from natural products
bull Almost 80 of small‐molecule anticancer drugs were natural products or derivatives
In addition only 15 of drugs approved during this time frame were so‐called biologic drugs which are also putatively patent‐ineligible This the problems caused by the current interpretation of the law excluding natural product drugs from patent eligibility will be exacerbated in view of reports from every study showing that the percentage of drugs that are biologic drugs has been growing and will be the predominant type of drug devel-oped in the 2011ndash2030 time period
Another ldquothought experimentrdquo illustrating the practical illogic (David can provide his philosophical justifications in the body of the text) of broad natural products patent ineligibility is as follows Suppose a researcher finds a molecule produced by the human body that causes blood pressure homeo-stasis that is lack of this molecule causes or contributes to the disease of high blood pressure The logical consequence of the current natural prod-uct patent ineligibility standards would be that the closer a drug molecule is to the structure of the molecule as it occurs in the body the less patent‐eli-gible it would be Practically speaking there would be no incentive to modify the molecule to confer patent eligibility on the altered molecule because of the unpredictability of such changes on the molecule such as its biological activity half‐life stability antigenicity or other biological prop-erties And there would be even less incentive to develop the molecule as a drug because without patent protection the available regulatory exclusiv-ities would not pass economic muster to sufficiently defray the large development costs (some of which prevent drugs neither safe nor effica-cious from being sold and thus provide their own justification)
There is one further pernicious outcome that can be predicted to arise from a ban on natural products patents (including patents on isolated DNA and genetic diagnostic methods based on such isolated DNA) Natural
xxii Foreword
products are almost by nature complex and an ldquoactive principlerdquo isolated from nature is beneficial because it is isolated Kodak ran an advertisement in the journal Nature in the 1970s showing a scientist in a lab coat holding a 250‐ml flask and standing next to several bushels of green peppers wherein the content of the flask was the purified ldquoessence of green pepperrdquo equivalent to that substance contained in all the peppers in all the bushels and bushels that the scientist was standing beside But this very complexity makes it possible for the ldquoactive principlerdquo (either as a chemical compound or as a diagnostic genetic sequence) to be ldquohidden in plain sightrdquo in ways that may be particularly refractory to reverse engineering
For example even using somewhat dated ldquogene chiprdquo technology genetically diagnostic markers could be encrypted onto a microchip comprising 10 000 unique sequences wherein a computer‐readable bar code would be used to identify the positions of diagnostically relevant sequences on the chip This form of encryption which can be random and confounded by the presence of positive and negative control sequences as well as variable numbers and lengths of sequences specific for the gene (or more likely genes) of interest would be very difficult if not impossible to reverse‐engineer Even if reverse engineering could be done it would be difficult and expensive to undertake and thus make it more likely that the innovator would be able to avoid com-petition (ie it would provide unlimited exclusivity to its purveyor not con-strained by patent term or burdened by the requirement that the invention be disclosed with the specificity required by the Patent Act) While the possi-bility that this type of chip could be made exists with or without patents the absence of patent protection could tip the scales in favor of the extra effort needed and risk entailed in nondisclosure if the reward of extended ldquomonopolyrdquo is great enough But particularly for genetic diagnostic inven-tions the benefits of developing a proprietary database for which a corpora-tion could provide the economic and marketing wherewithal to expeditiously produce would result in a ldquoworst of both worldsrdquo outcome unlimited exclu-sivity based on undisclosed proprietary information that not only is difficult to replicate but whose existence would inhibit competition After all if a company had such a database its outcome for any particular patientrsquos test would be more accurate (and might identify disease riskndashassociated genetic variants not available elsewhere) and this would provide little incentive for a physician to choose an alternative provider to perform the test (and even more malevolently could create a system where the wealthy could afford the best diagnostic testing while the less affluent would be restricted to the more
Foreword xxiii
limited assays offered by companies without access to the ldquoinnovatorrsquosrdquo proprietary database information)
The other aspect of foreclosing patents for certain substances or technology areas categorically is that it upsets a carefully crafted dynamic that has worked extremely well during the biotech era between ldquotruerdquo innovators (typically university professors or small start‐up biotechnology companies) and more established companies capable of commercializing innovation Pundits who worry that permitting patenting will harm innovation miss an important point innovation will happen particularly in universities research institutes and like places because human nature demands it and regardless of whether patent protection is available The intelligent ape in us wants to know and the disparity between how univer-sity professors and patent lawyers are paid should establish how powerful the need to know can be Patenting and the impetus for patenting provided for example by the BayhndashDole Act in the United States prevents the fruits of these inventive efforts from mere predation by commercial concerns The benefits that can be had from a system where private commercializa-tion is encouraged are tempered by the types of corporate shenanigans that raise cogent criticisms of the system But perhaps it is mere human nature that people (in the corporate as well as individual sense) will want to expro-priate technology rather than pay for it and patenting prohibits (or at least retards) this outcome (if not these tendencies) Thus paradoxically limiting patent rights does not free innovation but rather makes it more likely to be kept captive by the entities capable of using such innovation to make a commercial product that is not from the power of building a better mouse-trap but by being able to outcompete smaller innovators merely by their greater economic prowess and resources Conversely patents provide a way for the innovators to protect their innovations and compel corporations to license their inventions producing revenue that can be used to fund future research endeavors This useful cycle has resulted in the successes of the biotechnology era and is something that we abandon at our peril
Thus in my view patents are a useful tool for achieving these societally ben-eficial goals promoting innovation and commercialization and protecting and supporting individuals who use the patent system to protect the products of their labors from being expropriated by others David provides a cogent and honest counterpoint to these thoughts Enjoy reading them
Kevin E NoonanChicago Illinois 2014
xii Preface to the Second Edition
sophistry they are not philosophical musing They kill people or alter their lives irrevocably
I began researching and considering the effects of gene patents believing they were potentially a threat to the conduct of science whose foundational objects I argued were part of a commons‐by‐necessity but I realized after my book came out that real lives were being harmed by patents on genes The Myriad case brought together the theoretical with the actual for me and the dynamics of both the case and the loud and sometimes angry public debate raised my awareness not only about this particular subject but also the power and responsibility of academic research in the sphere of public policy Suddenly ideas seemed more important had relevance outside the academy and could perhaps make a difference in peoplesrsquo lives I began to interact with the activists who were fighting to liberate genes to stop com-panies like Myriad in the courts and engage not just in the philosophical arguments but in those fights I joined with authors of amicus (friend of the court) briefs interviewed and interacted with BRCA1amp2 mutation‐positive women who were actively pursuing an end to a practice that I had only pre-viously considered to be an interesting metaphysical conundrum I also debated Intellectual Property (IP) attorneys and others primarily with backgrounds in biotech industries and learning better the nature of their arguments I came to understand that most of them including Kevin Noonan who once called me a ldquoliarrdquo on his blog but who has now drafted the foreword to this edition that they too generally have the best intentions Many like Dr Noonan truly expect that without gene patents as they existed until recently the sort of innovation we need in biomedical technol-ogies would not occur as it should
Throughout the course of the litigation in Myriad I remained engaged continued to speak to hone my arguments adding to my list of criteria for something to be a creation (artifact) capable of patent ldquodesignrdquo (as well as intention and being man‐made) and finally rejoicing when the decision of the Supreme Court came out as close to what I believed and argued was right as possible I had seen an academic idea mature and bloom into public policy real law enforceable justice While I realistically believe that the first edition of this book had only a very minor role in what finally happened I am proud to have played some part to have foreseen the issues to argue them honestly from what I think is a rational and logical standpoint and see that the world can be changed by ideas
Preface to the Second Edition xiii
There remain issues to discuss and not everything about gene patents has been resolved by Myriad Some still argue that cDNA ought not to be patent‐eligible (in fact I still think it should be under the criteria I have set forth though there are also arguments to be made that it is not somehow ldquodesignedrdquo by man) Moreover we should expect patent attorneys to do their creative best to continue to pursue patents on as much of the genome as they can within the constraints of Myriad Finally Myriad Corp has not given up They are still suing potential competitors under theories of infringement of parts of their patents that might have survived the ACLUrsquos case against them We shall see how they are eventually resolved and what the future holds for companies like theirs who profited mightily from gene patents for decades I describe as much of this recent legal history as possible in this edition
This book is meant to be a definitive version sewing up the past five years since the first edition emerged and so much changed in the world summa-rizing that recent history and refining the arguments I originally made correcting errors and describing where we are where we yet may be and why gene patents as they once were ought never to be again
David KoepsellAugust 14 2014
Mexico City Mexico
Foreword
David and I have had a friendly disagreement about the subject (and even the title) of this book ever since it was first published and I am happy that he asked me to write this Foreword to the Second Edition The issues David raises in the pages to follow continue to be relevant to a discussion of philosophy and patent law with events that have occurred since the first edition justifying (indeed demanding) this update
Without getting into the deep waters of philosophy (Davidrsquos meacutetier not mine) as we have discussed the issues in the book David contends that he takes a deontological approach and has characterized mine as a utilitarian one Accepting that dichotomy I understand the difference to be that David is operating from ldquofirst principlesrdquo about the rules society should impose on human activity and specifically on what the law permits individuals to ldquoownrdquo with regard to genes and more broadly naturally occurring substances I disagree with that approach on several levels perhaps the most germane of which is that if we posit rules we need to impose a rule‐giver and the potential for improvident rules (if not outright abuse of the privilege) makes me wary in some ways I subscribe to Lani Gruinierrsquos suspicions about the effects of the ldquotyranny of the majorityrdquo in this regard
Part of that tyranny is also the tyranny of unintended or intentional ignorance The issue heremdashldquogenerdquo patentingmdashis one at the intersection of molecular biology and modern genetics on the one hand and patent law (an area notorious for its arcane minutiae) I used to joke with my col-leagues about the effect of trying to explain my position to a lay audience of any type and how I distrusted those who advocated that all that was needed was to ldquoeducaterdquo the public the press and policy makers The problem for proponents of gene patenting has been that opponents have gotten the better part of the debate not by making a reasoned philosophical argument such as the one you will find in these pages but instead by making an
Foreword xv
emotional plea to individuals afraid that corporate America was trying to ldquostealrdquo their genes which has proven very effective This process began with an Op‐Ed piece in The New York Times by Michael Crichton wherein he posited a scenario where a patent holder knocks on your door one day and demands payment for the use of ldquoherrdquo patented gene that resides in your liver (Not coincidentally Dr Crichton had just published a novel on the perils of genetic engineering and corporate ownership of human genes complete with an essay as an addendum containing his arguments against the practice And it should be noted that a constant theme in his novels was a mistrust of technology and particularly the ability of humans to use it without dire consequences) Academics like my friend Lori Andrews at Illinois Institute of Technology (IIT)‐Kent School of Law joined in this theme which was picked up eventually by most popular press outlets and became regrettably the canonical narrative on gene patenting culminating in the American Civil Liberties Unionrsquos (ACLUrsquos) ldquoKeep Your Hands Off My Genesrdquo slogan and logo I hope that this essay provides some antidote to this argument which is founded on the literal fear that someone can ldquoownrdquo you (David assures me that his title is allegorical and that he acknowledges that in all countries that have banned slavery no one can ldquoownrdquo another human being or a part of them See the 13th Amendment I assure you that the ACLU has no such illusions about the intended consequences of their ownership rhetoric)
My philosophy is that the principle we should follow is the greatest good to the greatest number while not infringing on individual rights without (at least) compensation As regards patent law this principle is translated into rules that foster the broadest disclosure of technology possible in return for exclusive patent rights and robust‐enough enforcement rights for patents that they provide sufficient certainty to promote investment so his technology is commercialized to benefit the greatest number In my role as a biotechnology patent attorney I have seen how risky investment in biotechnology can be (indeed the evidence is overwhelming that for all its successes biotechrsquos history is littered with the remains of companies that have failed) and how important it is to have a sound patent system of predictable rights go support that investment
The evidence in support of ldquogene patentingrdquo and more broadly natural products patenting is strong the biotechnology industry has promoted innovation in the form of new drugs and diagnostics assays for a genera-tion This may continue despite the recent restrictions on patent protection
xvi Foreword
for genes and natural products (including patent‐restricting decisions in Mayo Collaborative Labs v Prometheus Labs and Assoc of Molecular Pathologists v Myriad Genetics and recently promulgated US Patent and Trademark Office Guidances on Subject Matter Eligibility) In fact these very restrictions suggest that we would benefit from an appreciation of the facts surrounding the past thirty years of gene patenting to understand why these restrictions are not only wrongheaded but dangerous for future innovation
These include debunking several myths First the concern that patents on specific human genes in some way inhibit innovation in basic genetic research is entirely unfounded One reason is that the genetic information itself is not patented while isolated DNA is encompassed by gene patent claims and described in those claims by its sequence the sequence itself is unpatented information that can be used freely for any purpose (eg inter-rogating genetic databases from other species or even human DNA inter alia to find related genes in those databases) Indeed the innovative benefits to gene patenting are evident in at least two ways First scientific publication databases reveal that there have been more than 11 000 scientific papers published on the BRCA1 and BRCA2 genes since the patents claiming them were granted This outcome refutes the prediction that gene patenting would create a ldquotragedy of the anticommonsrdquo where scientific research would be stifled by patenting (see Heller amp Eisenberg 1998 ldquoCan Patents Deter Innovation The Anticommons in Biomedical Researchrdquo Science 280 698ndash701)) a conclusion supported by the overwhelming majority of studies done on this subject (see for example Walsh et al 2003 ldquoScience and the Law Working Through the Patent Problemrdquo Science 299 1020 Walsh et al 2005 ldquoScience and Law View from the Bench Patents and Material Transfersrdquo Science 309 2002ndash03)
In addition policies that the US Patent and Trademark Office adopted in 2001 required applicants to disclose a practical utility for the product of a gene claimed in a patent These requirements were imposed at a time when the standards for scientific journal publication were much less stringent so that identifying a gene by the extent of genetic similarity between the ldquonewrdquo gene and previously discovered genes was enough for publication But it was not enough for a patent which has been held to be ldquonot a hunting license It is not a reward for the search but compensation for its successful conclusionrdquo Thus genes encoding proteins having no known use or biological activity cannot be patented because to do so would allow the
Foreword xvii
gene to be within the exclusive patent right undeservedly the public would not have received its quid pro quo of a useful invention in return for patent exclusivity All such genes not having patent protection are in the public domain (from which they cannot be retrieved for future patenting) and for humans these constitute the vast majority of genes identified inter alia by the Human Genome Project
The role for patenting genes and the related genetic diagnostic methods using this genetic information in the successes of the biotechnology era are evident The industry has produced hundreds of biologic drugs (at an ever‐increasing rate) that have provided effective treatment for a variety of illnesses and decoding the human genome has enabled researchers to iden-tify genes like the BRCA1 and BRCA2 genes that can be used in predictive genetic diagnostic tests Even the much‐maligned Myriad Genetics has played a positive role in the development and prevalence of genetic diagnostic testing It must be remembered that in 1997 (when Myriadrsquos BRCA gene patents were granted) genetic testing was in its infancy and companies like Myriad were under the burden of convincing payers that the tests did the one thing that all insurers public or private require of such tests save them money in the long run by identifying patients with a high probability of becoming ill and costing the insurers much more for treatment than the costs of prophylaxis Moreover Myriad and like com-panies needed to convince doctors that the testing was worthwhile and to establish a network of genetic counselors who could explain to healthy women that they were at much greater risk of developing breast or ovarian cancer than normal under circumstances that resulted in empowerment from the information and not abject fear And in 1997 genetic sequencing technology was not as developed as it is now and the mechanisms and tech-niques needed to minimize or eliminate the occurrence of false positives or negatives had not been conclusively established All these burdens were ones borne by Myriad and these activities produced the world we have today
It is possible as some have argued that BRCA tests may have been devel-oped independently by individual researchers in the absence of patent pro-tection However it is almost certain that such researchers would have been located in medical centers in urban environments Under these circum-stances women living in or near cities such as New York Boston Philadelphia Cleveland Chicago Houston Denver Los Angeles San Francisco Portland and Seattle might have had access to these tests But what of women in
xviii Foreword
Appalachia or the Four Corners region in the Southwest or more generally in rural or other relatively remote locations Would Yale University for example have had any incentive to provide access to the BRCA tests to these women in these far‐off locations Or to provide genetic counseling where the women lived Or to lobby state Medicare administrators or private insurance commissioners to cover the test I think that unlikely Myriad Genetics did all of this as well as perform outreach to the obstetrics and gynecology doctors throughout the United States so that these primary care doctors were aware of the tests Myriad did not ace from altruism but as part of their business plan in order to expand the number of patients who received the test and thus maximize the companyrsquos revenue While it may be counterintuitive to some these circumstances may have been the most effective way not only to pro-mulgate the BRCA tests but also to facilitate acceptance of genetic diagnostic testing for other diseases showing that in this instance Adam Smith rather than Karl Marx provided the most practical solution to the problem of estab-lishing genetic diagnostic testing as a recognized component of a physicianrsquos diagnostic armamentarium
Fortunately the significance and impact of recent US court decisions (spe-cifically the Myriad case) is much less than it would have been ten to thirty years ago Due to patent term rules most patents (and applications) on iso-lated DNA filed in the heyday of the Human Genome Project (approxi-mately 1998ndash2001) are near the end of their actual or potential term indeed a recent study shows that the number of granted patents having at least one claim reciting an isolate DNA comprising a gene peaked in 1999 and has been dropping since 2005 (Graff et al 2013 ldquoNot quite a myriad of gene pat-entsrdquo Nature Biotechnology 31 404ndash410)) These recent decisions in the United States have not harmed the biotechnology industry because they retained patent eligibility for species of DNA that show evidence of the ldquohand of manrdquo and do not occur in nature These include enzymatically pro-duced copies (cDNA) of cellular messenger RNA and should also encom-pass the tools of the recombinant geneticist (eg including recombinant vectors for cloning and expressing genes in heterologous cells) Most impor-tantly the US Supreme Court did not overturn its Diamond v Chakrabarty decision wherein recombinant cells were determined to be patent eligible
Thus in many ways the question of patent eligibility for human genes is a philosophical one However that does not mean that how we think about patent eligibility for isolated DNA is irrelevant to important questions regarding the usefulness of patents for promoting progress and innovation
Foreword xix
Indeed the most pernicious effects of the current trend in the zeitgeist against patenting has been not that genes have become harder to patent but rather that the ability to patent other natural products has been called into question It is the extension of these recent decisions on isolated DNA to all natural products that poses the greatest threat to innovation This threat can be illustrated by a thought experiment for which of these substances should patent protection be withheld
bull A petrochemical with excellent lubrication qualities isolated in pure form and used as improved motor oil
bull Vitamin B12 isolated from beef muscle formulated into a medicament used to cure anemia in children
bull The drug penicillin isolated from a mixture of naturally produced chemicals made by a mold and formulated as a drug to cure syphilis (which is otherwise eventually fatal)
bull Human urinary erythropoietin formulated to treat anemia in kidney dialysis patients
bull The gene responsible for Gaucherrsquos disease a lipid storage disease wherein the gene is used to make the missing protein that is administered to children and that cures an otherwise incurable and fatal disease
The current answer is that none of them are patent‐eligible per se (although there may be ways to claim them that could pass eligibility muster that remains to be seen) Judge Sweet the US District Court judge who first ruled that isolated DNA was not patent‐eligible did so using language carefully crafted to avoid encompassing all natural products into his decision Specifically Judge Sweet distinguished isolated DNA as the ldquophysical embodiments of genetic informationrdquo a property limited to DNA and not shared by other natural products (While an enzymatic protein could be characterized as the physical embodiment of catalysis of a particular chemical reaction that formulation has much less appeal and inherent rationale than Judge Sweetrsquos regarding DNA) Instead of this careful formu-lation the broader language employed by the Supreme Court as well as the broader rationale the Court used in finding genomic DNA unpatentable has made it easier to employ that fractured logic to render patent‐ineligible naturally occurring molecules other than DNA
I would be remiss not to mention the rather comical (but persistent) efforts of former Acting Solicitor General Neal Katyal who included in the
xx Foreword
US Governmentrsquos amicus brief to the Federal Circuit the distinction engine he called a ldquomagic microscoperdquo embodying the concept that if you are able to visualize a natural product (like a genomic DNA molecule) using this mythical microscope then the natural product would not be patent‐eligible whereas if you could not (eg a cDNA molecule) then the natural product could be eligible for patenting Fortunately the disdain with which the Federal Circuit greeted this fantasy (particularly from Judge Moore) prompted its quick abandonment as are argumentative distinction as the case moved forward Nonetheless both the courts and the US Patent and Trademark Office have adopted this standard de facto even as it becomes the theory that dare not speak its name in legal circles
The philosophical point here is that these substances and natural products generally have been deemed patent‐ineligible categorically which while consistent with (and perhaps even mandated by) the deon-tological approach imposes a distinction that cannot be flexibly applied to the individual circumstances Without such flexibility the law is con-strained to use one criterion that the substance can be found in some form in nature to decide patent eligibility instead of making the deter-mination of whether permitting patenting exclusivity satisfies the cri-teria that the invention ldquopromotes progressrdquo as the US Constitution requires and has a benefit to the public that outweighs any categorical disabilities
The potential that using this standard for determining patent eligibility will result in negative practical outcomes that no one in this debate desires is illustrated by a 2012 Report from the National Institutes of Health Natural Product Branch regarding statistics relating to the number of FDA approvals (a total of 1355) for new drugs falling into the following categories
Drug typesource Number
Biological (B) 203Natural product (N) 55Natural product (botanical) (NB) 149Derived from a natural product (ND) 298Totally synthetic (S) 393Total synthesisnatural product (S) 176Vaccine (S) 81
Foreword xxi
These statistics illustrate the consequences of a general ban on patenting naturally derived products of the 1355 drugs approved between 1981 and 2010
bull Fifty percent of all small‐molecule drugs approved between 2000 and 2010 are natural products
bull About 75 of antibacterial drugs are natural products or derived from natural products
bull Almost 80 of small‐molecule anticancer drugs were natural products or derivatives
In addition only 15 of drugs approved during this time frame were so‐called biologic drugs which are also putatively patent‐ineligible This the problems caused by the current interpretation of the law excluding natural product drugs from patent eligibility will be exacerbated in view of reports from every study showing that the percentage of drugs that are biologic drugs has been growing and will be the predominant type of drug devel-oped in the 2011ndash2030 time period
Another ldquothought experimentrdquo illustrating the practical illogic (David can provide his philosophical justifications in the body of the text) of broad natural products patent ineligibility is as follows Suppose a researcher finds a molecule produced by the human body that causes blood pressure homeo-stasis that is lack of this molecule causes or contributes to the disease of high blood pressure The logical consequence of the current natural prod-uct patent ineligibility standards would be that the closer a drug molecule is to the structure of the molecule as it occurs in the body the less patent‐eli-gible it would be Practically speaking there would be no incentive to modify the molecule to confer patent eligibility on the altered molecule because of the unpredictability of such changes on the molecule such as its biological activity half‐life stability antigenicity or other biological prop-erties And there would be even less incentive to develop the molecule as a drug because without patent protection the available regulatory exclusiv-ities would not pass economic muster to sufficiently defray the large development costs (some of which prevent drugs neither safe nor effica-cious from being sold and thus provide their own justification)
There is one further pernicious outcome that can be predicted to arise from a ban on natural products patents (including patents on isolated DNA and genetic diagnostic methods based on such isolated DNA) Natural
xxii Foreword
products are almost by nature complex and an ldquoactive principlerdquo isolated from nature is beneficial because it is isolated Kodak ran an advertisement in the journal Nature in the 1970s showing a scientist in a lab coat holding a 250‐ml flask and standing next to several bushels of green peppers wherein the content of the flask was the purified ldquoessence of green pepperrdquo equivalent to that substance contained in all the peppers in all the bushels and bushels that the scientist was standing beside But this very complexity makes it possible for the ldquoactive principlerdquo (either as a chemical compound or as a diagnostic genetic sequence) to be ldquohidden in plain sightrdquo in ways that may be particularly refractory to reverse engineering
For example even using somewhat dated ldquogene chiprdquo technology genetically diagnostic markers could be encrypted onto a microchip comprising 10 000 unique sequences wherein a computer‐readable bar code would be used to identify the positions of diagnostically relevant sequences on the chip This form of encryption which can be random and confounded by the presence of positive and negative control sequences as well as variable numbers and lengths of sequences specific for the gene (or more likely genes) of interest would be very difficult if not impossible to reverse‐engineer Even if reverse engineering could be done it would be difficult and expensive to undertake and thus make it more likely that the innovator would be able to avoid com-petition (ie it would provide unlimited exclusivity to its purveyor not con-strained by patent term or burdened by the requirement that the invention be disclosed with the specificity required by the Patent Act) While the possi-bility that this type of chip could be made exists with or without patents the absence of patent protection could tip the scales in favor of the extra effort needed and risk entailed in nondisclosure if the reward of extended ldquomonopolyrdquo is great enough But particularly for genetic diagnostic inven-tions the benefits of developing a proprietary database for which a corpora-tion could provide the economic and marketing wherewithal to expeditiously produce would result in a ldquoworst of both worldsrdquo outcome unlimited exclu-sivity based on undisclosed proprietary information that not only is difficult to replicate but whose existence would inhibit competition After all if a company had such a database its outcome for any particular patientrsquos test would be more accurate (and might identify disease riskndashassociated genetic variants not available elsewhere) and this would provide little incentive for a physician to choose an alternative provider to perform the test (and even more malevolently could create a system where the wealthy could afford the best diagnostic testing while the less affluent would be restricted to the more
Foreword xxiii
limited assays offered by companies without access to the ldquoinnovatorrsquosrdquo proprietary database information)
The other aspect of foreclosing patents for certain substances or technology areas categorically is that it upsets a carefully crafted dynamic that has worked extremely well during the biotech era between ldquotruerdquo innovators (typically university professors or small start‐up biotechnology companies) and more established companies capable of commercializing innovation Pundits who worry that permitting patenting will harm innovation miss an important point innovation will happen particularly in universities research institutes and like places because human nature demands it and regardless of whether patent protection is available The intelligent ape in us wants to know and the disparity between how univer-sity professors and patent lawyers are paid should establish how powerful the need to know can be Patenting and the impetus for patenting provided for example by the BayhndashDole Act in the United States prevents the fruits of these inventive efforts from mere predation by commercial concerns The benefits that can be had from a system where private commercializa-tion is encouraged are tempered by the types of corporate shenanigans that raise cogent criticisms of the system But perhaps it is mere human nature that people (in the corporate as well as individual sense) will want to expro-priate technology rather than pay for it and patenting prohibits (or at least retards) this outcome (if not these tendencies) Thus paradoxically limiting patent rights does not free innovation but rather makes it more likely to be kept captive by the entities capable of using such innovation to make a commercial product that is not from the power of building a better mouse-trap but by being able to outcompete smaller innovators merely by their greater economic prowess and resources Conversely patents provide a way for the innovators to protect their innovations and compel corporations to license their inventions producing revenue that can be used to fund future research endeavors This useful cycle has resulted in the successes of the biotechnology era and is something that we abandon at our peril
Thus in my view patents are a useful tool for achieving these societally ben-eficial goals promoting innovation and commercialization and protecting and supporting individuals who use the patent system to protect the products of their labors from being expropriated by others David provides a cogent and honest counterpoint to these thoughts Enjoy reading them
Kevin E NoonanChicago Illinois 2014
Preface to the Second Edition xiii
There remain issues to discuss and not everything about gene patents has been resolved by Myriad Some still argue that cDNA ought not to be patent‐eligible (in fact I still think it should be under the criteria I have set forth though there are also arguments to be made that it is not somehow ldquodesignedrdquo by man) Moreover we should expect patent attorneys to do their creative best to continue to pursue patents on as much of the genome as they can within the constraints of Myriad Finally Myriad Corp has not given up They are still suing potential competitors under theories of infringement of parts of their patents that might have survived the ACLUrsquos case against them We shall see how they are eventually resolved and what the future holds for companies like theirs who profited mightily from gene patents for decades I describe as much of this recent legal history as possible in this edition
This book is meant to be a definitive version sewing up the past five years since the first edition emerged and so much changed in the world summa-rizing that recent history and refining the arguments I originally made correcting errors and describing where we are where we yet may be and why gene patents as they once were ought never to be again
David KoepsellAugust 14 2014
Mexico City Mexico
Foreword
David and I have had a friendly disagreement about the subject (and even the title) of this book ever since it was first published and I am happy that he asked me to write this Foreword to the Second Edition The issues David raises in the pages to follow continue to be relevant to a discussion of philosophy and patent law with events that have occurred since the first edition justifying (indeed demanding) this update
Without getting into the deep waters of philosophy (Davidrsquos meacutetier not mine) as we have discussed the issues in the book David contends that he takes a deontological approach and has characterized mine as a utilitarian one Accepting that dichotomy I understand the difference to be that David is operating from ldquofirst principlesrdquo about the rules society should impose on human activity and specifically on what the law permits individuals to ldquoownrdquo with regard to genes and more broadly naturally occurring substances I disagree with that approach on several levels perhaps the most germane of which is that if we posit rules we need to impose a rule‐giver and the potential for improvident rules (if not outright abuse of the privilege) makes me wary in some ways I subscribe to Lani Gruinierrsquos suspicions about the effects of the ldquotyranny of the majorityrdquo in this regard
Part of that tyranny is also the tyranny of unintended or intentional ignorance The issue heremdashldquogenerdquo patentingmdashis one at the intersection of molecular biology and modern genetics on the one hand and patent law (an area notorious for its arcane minutiae) I used to joke with my col-leagues about the effect of trying to explain my position to a lay audience of any type and how I distrusted those who advocated that all that was needed was to ldquoeducaterdquo the public the press and policy makers The problem for proponents of gene patenting has been that opponents have gotten the better part of the debate not by making a reasoned philosophical argument such as the one you will find in these pages but instead by making an
Foreword xv
emotional plea to individuals afraid that corporate America was trying to ldquostealrdquo their genes which has proven very effective This process began with an Op‐Ed piece in The New York Times by Michael Crichton wherein he posited a scenario where a patent holder knocks on your door one day and demands payment for the use of ldquoherrdquo patented gene that resides in your liver (Not coincidentally Dr Crichton had just published a novel on the perils of genetic engineering and corporate ownership of human genes complete with an essay as an addendum containing his arguments against the practice And it should be noted that a constant theme in his novels was a mistrust of technology and particularly the ability of humans to use it without dire consequences) Academics like my friend Lori Andrews at Illinois Institute of Technology (IIT)‐Kent School of Law joined in this theme which was picked up eventually by most popular press outlets and became regrettably the canonical narrative on gene patenting culminating in the American Civil Liberties Unionrsquos (ACLUrsquos) ldquoKeep Your Hands Off My Genesrdquo slogan and logo I hope that this essay provides some antidote to this argument which is founded on the literal fear that someone can ldquoownrdquo you (David assures me that his title is allegorical and that he acknowledges that in all countries that have banned slavery no one can ldquoownrdquo another human being or a part of them See the 13th Amendment I assure you that the ACLU has no such illusions about the intended consequences of their ownership rhetoric)
My philosophy is that the principle we should follow is the greatest good to the greatest number while not infringing on individual rights without (at least) compensation As regards patent law this principle is translated into rules that foster the broadest disclosure of technology possible in return for exclusive patent rights and robust‐enough enforcement rights for patents that they provide sufficient certainty to promote investment so his technology is commercialized to benefit the greatest number In my role as a biotechnology patent attorney I have seen how risky investment in biotechnology can be (indeed the evidence is overwhelming that for all its successes biotechrsquos history is littered with the remains of companies that have failed) and how important it is to have a sound patent system of predictable rights go support that investment
The evidence in support of ldquogene patentingrdquo and more broadly natural products patenting is strong the biotechnology industry has promoted innovation in the form of new drugs and diagnostics assays for a genera-tion This may continue despite the recent restrictions on patent protection
xvi Foreword
for genes and natural products (including patent‐restricting decisions in Mayo Collaborative Labs v Prometheus Labs and Assoc of Molecular Pathologists v Myriad Genetics and recently promulgated US Patent and Trademark Office Guidances on Subject Matter Eligibility) In fact these very restrictions suggest that we would benefit from an appreciation of the facts surrounding the past thirty years of gene patenting to understand why these restrictions are not only wrongheaded but dangerous for future innovation
These include debunking several myths First the concern that patents on specific human genes in some way inhibit innovation in basic genetic research is entirely unfounded One reason is that the genetic information itself is not patented while isolated DNA is encompassed by gene patent claims and described in those claims by its sequence the sequence itself is unpatented information that can be used freely for any purpose (eg inter-rogating genetic databases from other species or even human DNA inter alia to find related genes in those databases) Indeed the innovative benefits to gene patenting are evident in at least two ways First scientific publication databases reveal that there have been more than 11 000 scientific papers published on the BRCA1 and BRCA2 genes since the patents claiming them were granted This outcome refutes the prediction that gene patenting would create a ldquotragedy of the anticommonsrdquo where scientific research would be stifled by patenting (see Heller amp Eisenberg 1998 ldquoCan Patents Deter Innovation The Anticommons in Biomedical Researchrdquo Science 280 698ndash701)) a conclusion supported by the overwhelming majority of studies done on this subject (see for example Walsh et al 2003 ldquoScience and the Law Working Through the Patent Problemrdquo Science 299 1020 Walsh et al 2005 ldquoScience and Law View from the Bench Patents and Material Transfersrdquo Science 309 2002ndash03)
In addition policies that the US Patent and Trademark Office adopted in 2001 required applicants to disclose a practical utility for the product of a gene claimed in a patent These requirements were imposed at a time when the standards for scientific journal publication were much less stringent so that identifying a gene by the extent of genetic similarity between the ldquonewrdquo gene and previously discovered genes was enough for publication But it was not enough for a patent which has been held to be ldquonot a hunting license It is not a reward for the search but compensation for its successful conclusionrdquo Thus genes encoding proteins having no known use or biological activity cannot be patented because to do so would allow the
Foreword xvii
gene to be within the exclusive patent right undeservedly the public would not have received its quid pro quo of a useful invention in return for patent exclusivity All such genes not having patent protection are in the public domain (from which they cannot be retrieved for future patenting) and for humans these constitute the vast majority of genes identified inter alia by the Human Genome Project
The role for patenting genes and the related genetic diagnostic methods using this genetic information in the successes of the biotechnology era are evident The industry has produced hundreds of biologic drugs (at an ever‐increasing rate) that have provided effective treatment for a variety of illnesses and decoding the human genome has enabled researchers to iden-tify genes like the BRCA1 and BRCA2 genes that can be used in predictive genetic diagnostic tests Even the much‐maligned Myriad Genetics has played a positive role in the development and prevalence of genetic diagnostic testing It must be remembered that in 1997 (when Myriadrsquos BRCA gene patents were granted) genetic testing was in its infancy and companies like Myriad were under the burden of convincing payers that the tests did the one thing that all insurers public or private require of such tests save them money in the long run by identifying patients with a high probability of becoming ill and costing the insurers much more for treatment than the costs of prophylaxis Moreover Myriad and like com-panies needed to convince doctors that the testing was worthwhile and to establish a network of genetic counselors who could explain to healthy women that they were at much greater risk of developing breast or ovarian cancer than normal under circumstances that resulted in empowerment from the information and not abject fear And in 1997 genetic sequencing technology was not as developed as it is now and the mechanisms and tech-niques needed to minimize or eliminate the occurrence of false positives or negatives had not been conclusively established All these burdens were ones borne by Myriad and these activities produced the world we have today
It is possible as some have argued that BRCA tests may have been devel-oped independently by individual researchers in the absence of patent pro-tection However it is almost certain that such researchers would have been located in medical centers in urban environments Under these circum-stances women living in or near cities such as New York Boston Philadelphia Cleveland Chicago Houston Denver Los Angeles San Francisco Portland and Seattle might have had access to these tests But what of women in
xviii Foreword
Appalachia or the Four Corners region in the Southwest or more generally in rural or other relatively remote locations Would Yale University for example have had any incentive to provide access to the BRCA tests to these women in these far‐off locations Or to provide genetic counseling where the women lived Or to lobby state Medicare administrators or private insurance commissioners to cover the test I think that unlikely Myriad Genetics did all of this as well as perform outreach to the obstetrics and gynecology doctors throughout the United States so that these primary care doctors were aware of the tests Myriad did not ace from altruism but as part of their business plan in order to expand the number of patients who received the test and thus maximize the companyrsquos revenue While it may be counterintuitive to some these circumstances may have been the most effective way not only to pro-mulgate the BRCA tests but also to facilitate acceptance of genetic diagnostic testing for other diseases showing that in this instance Adam Smith rather than Karl Marx provided the most practical solution to the problem of estab-lishing genetic diagnostic testing as a recognized component of a physicianrsquos diagnostic armamentarium
Fortunately the significance and impact of recent US court decisions (spe-cifically the Myriad case) is much less than it would have been ten to thirty years ago Due to patent term rules most patents (and applications) on iso-lated DNA filed in the heyday of the Human Genome Project (approxi-mately 1998ndash2001) are near the end of their actual or potential term indeed a recent study shows that the number of granted patents having at least one claim reciting an isolate DNA comprising a gene peaked in 1999 and has been dropping since 2005 (Graff et al 2013 ldquoNot quite a myriad of gene pat-entsrdquo Nature Biotechnology 31 404ndash410)) These recent decisions in the United States have not harmed the biotechnology industry because they retained patent eligibility for species of DNA that show evidence of the ldquohand of manrdquo and do not occur in nature These include enzymatically pro-duced copies (cDNA) of cellular messenger RNA and should also encom-pass the tools of the recombinant geneticist (eg including recombinant vectors for cloning and expressing genes in heterologous cells) Most impor-tantly the US Supreme Court did not overturn its Diamond v Chakrabarty decision wherein recombinant cells were determined to be patent eligible
Thus in many ways the question of patent eligibility for human genes is a philosophical one However that does not mean that how we think about patent eligibility for isolated DNA is irrelevant to important questions regarding the usefulness of patents for promoting progress and innovation
Foreword xix
Indeed the most pernicious effects of the current trend in the zeitgeist against patenting has been not that genes have become harder to patent but rather that the ability to patent other natural products has been called into question It is the extension of these recent decisions on isolated DNA to all natural products that poses the greatest threat to innovation This threat can be illustrated by a thought experiment for which of these substances should patent protection be withheld
bull A petrochemical with excellent lubrication qualities isolated in pure form and used as improved motor oil
bull Vitamin B12 isolated from beef muscle formulated into a medicament used to cure anemia in children
bull The drug penicillin isolated from a mixture of naturally produced chemicals made by a mold and formulated as a drug to cure syphilis (which is otherwise eventually fatal)
bull Human urinary erythropoietin formulated to treat anemia in kidney dialysis patients
bull The gene responsible for Gaucherrsquos disease a lipid storage disease wherein the gene is used to make the missing protein that is administered to children and that cures an otherwise incurable and fatal disease
The current answer is that none of them are patent‐eligible per se (although there may be ways to claim them that could pass eligibility muster that remains to be seen) Judge Sweet the US District Court judge who first ruled that isolated DNA was not patent‐eligible did so using language carefully crafted to avoid encompassing all natural products into his decision Specifically Judge Sweet distinguished isolated DNA as the ldquophysical embodiments of genetic informationrdquo a property limited to DNA and not shared by other natural products (While an enzymatic protein could be characterized as the physical embodiment of catalysis of a particular chemical reaction that formulation has much less appeal and inherent rationale than Judge Sweetrsquos regarding DNA) Instead of this careful formu-lation the broader language employed by the Supreme Court as well as the broader rationale the Court used in finding genomic DNA unpatentable has made it easier to employ that fractured logic to render patent‐ineligible naturally occurring molecules other than DNA
I would be remiss not to mention the rather comical (but persistent) efforts of former Acting Solicitor General Neal Katyal who included in the
xx Foreword
US Governmentrsquos amicus brief to the Federal Circuit the distinction engine he called a ldquomagic microscoperdquo embodying the concept that if you are able to visualize a natural product (like a genomic DNA molecule) using this mythical microscope then the natural product would not be patent‐eligible whereas if you could not (eg a cDNA molecule) then the natural product could be eligible for patenting Fortunately the disdain with which the Federal Circuit greeted this fantasy (particularly from Judge Moore) prompted its quick abandonment as are argumentative distinction as the case moved forward Nonetheless both the courts and the US Patent and Trademark Office have adopted this standard de facto even as it becomes the theory that dare not speak its name in legal circles
The philosophical point here is that these substances and natural products generally have been deemed patent‐ineligible categorically which while consistent with (and perhaps even mandated by) the deon-tological approach imposes a distinction that cannot be flexibly applied to the individual circumstances Without such flexibility the law is con-strained to use one criterion that the substance can be found in some form in nature to decide patent eligibility instead of making the deter-mination of whether permitting patenting exclusivity satisfies the cri-teria that the invention ldquopromotes progressrdquo as the US Constitution requires and has a benefit to the public that outweighs any categorical disabilities
The potential that using this standard for determining patent eligibility will result in negative practical outcomes that no one in this debate desires is illustrated by a 2012 Report from the National Institutes of Health Natural Product Branch regarding statistics relating to the number of FDA approvals (a total of 1355) for new drugs falling into the following categories
Drug typesource Number
Biological (B) 203Natural product (N) 55Natural product (botanical) (NB) 149Derived from a natural product (ND) 298Totally synthetic (S) 393Total synthesisnatural product (S) 176Vaccine (S) 81
Foreword xxi
These statistics illustrate the consequences of a general ban on patenting naturally derived products of the 1355 drugs approved between 1981 and 2010
bull Fifty percent of all small‐molecule drugs approved between 2000 and 2010 are natural products
bull About 75 of antibacterial drugs are natural products or derived from natural products
bull Almost 80 of small‐molecule anticancer drugs were natural products or derivatives
In addition only 15 of drugs approved during this time frame were so‐called biologic drugs which are also putatively patent‐ineligible This the problems caused by the current interpretation of the law excluding natural product drugs from patent eligibility will be exacerbated in view of reports from every study showing that the percentage of drugs that are biologic drugs has been growing and will be the predominant type of drug devel-oped in the 2011ndash2030 time period
Another ldquothought experimentrdquo illustrating the practical illogic (David can provide his philosophical justifications in the body of the text) of broad natural products patent ineligibility is as follows Suppose a researcher finds a molecule produced by the human body that causes blood pressure homeo-stasis that is lack of this molecule causes or contributes to the disease of high blood pressure The logical consequence of the current natural prod-uct patent ineligibility standards would be that the closer a drug molecule is to the structure of the molecule as it occurs in the body the less patent‐eli-gible it would be Practically speaking there would be no incentive to modify the molecule to confer patent eligibility on the altered molecule because of the unpredictability of such changes on the molecule such as its biological activity half‐life stability antigenicity or other biological prop-erties And there would be even less incentive to develop the molecule as a drug because without patent protection the available regulatory exclusiv-ities would not pass economic muster to sufficiently defray the large development costs (some of which prevent drugs neither safe nor effica-cious from being sold and thus provide their own justification)
There is one further pernicious outcome that can be predicted to arise from a ban on natural products patents (including patents on isolated DNA and genetic diagnostic methods based on such isolated DNA) Natural
xxii Foreword
products are almost by nature complex and an ldquoactive principlerdquo isolated from nature is beneficial because it is isolated Kodak ran an advertisement in the journal Nature in the 1970s showing a scientist in a lab coat holding a 250‐ml flask and standing next to several bushels of green peppers wherein the content of the flask was the purified ldquoessence of green pepperrdquo equivalent to that substance contained in all the peppers in all the bushels and bushels that the scientist was standing beside But this very complexity makes it possible for the ldquoactive principlerdquo (either as a chemical compound or as a diagnostic genetic sequence) to be ldquohidden in plain sightrdquo in ways that may be particularly refractory to reverse engineering
For example even using somewhat dated ldquogene chiprdquo technology genetically diagnostic markers could be encrypted onto a microchip comprising 10 000 unique sequences wherein a computer‐readable bar code would be used to identify the positions of diagnostically relevant sequences on the chip This form of encryption which can be random and confounded by the presence of positive and negative control sequences as well as variable numbers and lengths of sequences specific for the gene (or more likely genes) of interest would be very difficult if not impossible to reverse‐engineer Even if reverse engineering could be done it would be difficult and expensive to undertake and thus make it more likely that the innovator would be able to avoid com-petition (ie it would provide unlimited exclusivity to its purveyor not con-strained by patent term or burdened by the requirement that the invention be disclosed with the specificity required by the Patent Act) While the possi-bility that this type of chip could be made exists with or without patents the absence of patent protection could tip the scales in favor of the extra effort needed and risk entailed in nondisclosure if the reward of extended ldquomonopolyrdquo is great enough But particularly for genetic diagnostic inven-tions the benefits of developing a proprietary database for which a corpora-tion could provide the economic and marketing wherewithal to expeditiously produce would result in a ldquoworst of both worldsrdquo outcome unlimited exclu-sivity based on undisclosed proprietary information that not only is difficult to replicate but whose existence would inhibit competition After all if a company had such a database its outcome for any particular patientrsquos test would be more accurate (and might identify disease riskndashassociated genetic variants not available elsewhere) and this would provide little incentive for a physician to choose an alternative provider to perform the test (and even more malevolently could create a system where the wealthy could afford the best diagnostic testing while the less affluent would be restricted to the more
Foreword xxiii
limited assays offered by companies without access to the ldquoinnovatorrsquosrdquo proprietary database information)
The other aspect of foreclosing patents for certain substances or technology areas categorically is that it upsets a carefully crafted dynamic that has worked extremely well during the biotech era between ldquotruerdquo innovators (typically university professors or small start‐up biotechnology companies) and more established companies capable of commercializing innovation Pundits who worry that permitting patenting will harm innovation miss an important point innovation will happen particularly in universities research institutes and like places because human nature demands it and regardless of whether patent protection is available The intelligent ape in us wants to know and the disparity between how univer-sity professors and patent lawyers are paid should establish how powerful the need to know can be Patenting and the impetus for patenting provided for example by the BayhndashDole Act in the United States prevents the fruits of these inventive efforts from mere predation by commercial concerns The benefits that can be had from a system where private commercializa-tion is encouraged are tempered by the types of corporate shenanigans that raise cogent criticisms of the system But perhaps it is mere human nature that people (in the corporate as well as individual sense) will want to expro-priate technology rather than pay for it and patenting prohibits (or at least retards) this outcome (if not these tendencies) Thus paradoxically limiting patent rights does not free innovation but rather makes it more likely to be kept captive by the entities capable of using such innovation to make a commercial product that is not from the power of building a better mouse-trap but by being able to outcompete smaller innovators merely by their greater economic prowess and resources Conversely patents provide a way for the innovators to protect their innovations and compel corporations to license their inventions producing revenue that can be used to fund future research endeavors This useful cycle has resulted in the successes of the biotechnology era and is something that we abandon at our peril
Thus in my view patents are a useful tool for achieving these societally ben-eficial goals promoting innovation and commercialization and protecting and supporting individuals who use the patent system to protect the products of their labors from being expropriated by others David provides a cogent and honest counterpoint to these thoughts Enjoy reading them
Kevin E NoonanChicago Illinois 2014
Foreword
David and I have had a friendly disagreement about the subject (and even the title) of this book ever since it was first published and I am happy that he asked me to write this Foreword to the Second Edition The issues David raises in the pages to follow continue to be relevant to a discussion of philosophy and patent law with events that have occurred since the first edition justifying (indeed demanding) this update
Without getting into the deep waters of philosophy (Davidrsquos meacutetier not mine) as we have discussed the issues in the book David contends that he takes a deontological approach and has characterized mine as a utilitarian one Accepting that dichotomy I understand the difference to be that David is operating from ldquofirst principlesrdquo about the rules society should impose on human activity and specifically on what the law permits individuals to ldquoownrdquo with regard to genes and more broadly naturally occurring substances I disagree with that approach on several levels perhaps the most germane of which is that if we posit rules we need to impose a rule‐giver and the potential for improvident rules (if not outright abuse of the privilege) makes me wary in some ways I subscribe to Lani Gruinierrsquos suspicions about the effects of the ldquotyranny of the majorityrdquo in this regard
Part of that tyranny is also the tyranny of unintended or intentional ignorance The issue heremdashldquogenerdquo patentingmdashis one at the intersection of molecular biology and modern genetics on the one hand and patent law (an area notorious for its arcane minutiae) I used to joke with my col-leagues about the effect of trying to explain my position to a lay audience of any type and how I distrusted those who advocated that all that was needed was to ldquoeducaterdquo the public the press and policy makers The problem for proponents of gene patenting has been that opponents have gotten the better part of the debate not by making a reasoned philosophical argument such as the one you will find in these pages but instead by making an
Foreword xv
emotional plea to individuals afraid that corporate America was trying to ldquostealrdquo their genes which has proven very effective This process began with an Op‐Ed piece in The New York Times by Michael Crichton wherein he posited a scenario where a patent holder knocks on your door one day and demands payment for the use of ldquoherrdquo patented gene that resides in your liver (Not coincidentally Dr Crichton had just published a novel on the perils of genetic engineering and corporate ownership of human genes complete with an essay as an addendum containing his arguments against the practice And it should be noted that a constant theme in his novels was a mistrust of technology and particularly the ability of humans to use it without dire consequences) Academics like my friend Lori Andrews at Illinois Institute of Technology (IIT)‐Kent School of Law joined in this theme which was picked up eventually by most popular press outlets and became regrettably the canonical narrative on gene patenting culminating in the American Civil Liberties Unionrsquos (ACLUrsquos) ldquoKeep Your Hands Off My Genesrdquo slogan and logo I hope that this essay provides some antidote to this argument which is founded on the literal fear that someone can ldquoownrdquo you (David assures me that his title is allegorical and that he acknowledges that in all countries that have banned slavery no one can ldquoownrdquo another human being or a part of them See the 13th Amendment I assure you that the ACLU has no such illusions about the intended consequences of their ownership rhetoric)
My philosophy is that the principle we should follow is the greatest good to the greatest number while not infringing on individual rights without (at least) compensation As regards patent law this principle is translated into rules that foster the broadest disclosure of technology possible in return for exclusive patent rights and robust‐enough enforcement rights for patents that they provide sufficient certainty to promote investment so his technology is commercialized to benefit the greatest number In my role as a biotechnology patent attorney I have seen how risky investment in biotechnology can be (indeed the evidence is overwhelming that for all its successes biotechrsquos history is littered with the remains of companies that have failed) and how important it is to have a sound patent system of predictable rights go support that investment
The evidence in support of ldquogene patentingrdquo and more broadly natural products patenting is strong the biotechnology industry has promoted innovation in the form of new drugs and diagnostics assays for a genera-tion This may continue despite the recent restrictions on patent protection
xvi Foreword
for genes and natural products (including patent‐restricting decisions in Mayo Collaborative Labs v Prometheus Labs and Assoc of Molecular Pathologists v Myriad Genetics and recently promulgated US Patent and Trademark Office Guidances on Subject Matter Eligibility) In fact these very restrictions suggest that we would benefit from an appreciation of the facts surrounding the past thirty years of gene patenting to understand why these restrictions are not only wrongheaded but dangerous for future innovation
These include debunking several myths First the concern that patents on specific human genes in some way inhibit innovation in basic genetic research is entirely unfounded One reason is that the genetic information itself is not patented while isolated DNA is encompassed by gene patent claims and described in those claims by its sequence the sequence itself is unpatented information that can be used freely for any purpose (eg inter-rogating genetic databases from other species or even human DNA inter alia to find related genes in those databases) Indeed the innovative benefits to gene patenting are evident in at least two ways First scientific publication databases reveal that there have been more than 11 000 scientific papers published on the BRCA1 and BRCA2 genes since the patents claiming them were granted This outcome refutes the prediction that gene patenting would create a ldquotragedy of the anticommonsrdquo where scientific research would be stifled by patenting (see Heller amp Eisenberg 1998 ldquoCan Patents Deter Innovation The Anticommons in Biomedical Researchrdquo Science 280 698ndash701)) a conclusion supported by the overwhelming majority of studies done on this subject (see for example Walsh et al 2003 ldquoScience and the Law Working Through the Patent Problemrdquo Science 299 1020 Walsh et al 2005 ldquoScience and Law View from the Bench Patents and Material Transfersrdquo Science 309 2002ndash03)
In addition policies that the US Patent and Trademark Office adopted in 2001 required applicants to disclose a practical utility for the product of a gene claimed in a patent These requirements were imposed at a time when the standards for scientific journal publication were much less stringent so that identifying a gene by the extent of genetic similarity between the ldquonewrdquo gene and previously discovered genes was enough for publication But it was not enough for a patent which has been held to be ldquonot a hunting license It is not a reward for the search but compensation for its successful conclusionrdquo Thus genes encoding proteins having no known use or biological activity cannot be patented because to do so would allow the
Foreword xvii
gene to be within the exclusive patent right undeservedly the public would not have received its quid pro quo of a useful invention in return for patent exclusivity All such genes not having patent protection are in the public domain (from which they cannot be retrieved for future patenting) and for humans these constitute the vast majority of genes identified inter alia by the Human Genome Project
The role for patenting genes and the related genetic diagnostic methods using this genetic information in the successes of the biotechnology era are evident The industry has produced hundreds of biologic drugs (at an ever‐increasing rate) that have provided effective treatment for a variety of illnesses and decoding the human genome has enabled researchers to iden-tify genes like the BRCA1 and BRCA2 genes that can be used in predictive genetic diagnostic tests Even the much‐maligned Myriad Genetics has played a positive role in the development and prevalence of genetic diagnostic testing It must be remembered that in 1997 (when Myriadrsquos BRCA gene patents were granted) genetic testing was in its infancy and companies like Myriad were under the burden of convincing payers that the tests did the one thing that all insurers public or private require of such tests save them money in the long run by identifying patients with a high probability of becoming ill and costing the insurers much more for treatment than the costs of prophylaxis Moreover Myriad and like com-panies needed to convince doctors that the testing was worthwhile and to establish a network of genetic counselors who could explain to healthy women that they were at much greater risk of developing breast or ovarian cancer than normal under circumstances that resulted in empowerment from the information and not abject fear And in 1997 genetic sequencing technology was not as developed as it is now and the mechanisms and tech-niques needed to minimize or eliminate the occurrence of false positives or negatives had not been conclusively established All these burdens were ones borne by Myriad and these activities produced the world we have today
It is possible as some have argued that BRCA tests may have been devel-oped independently by individual researchers in the absence of patent pro-tection However it is almost certain that such researchers would have been located in medical centers in urban environments Under these circum-stances women living in or near cities such as New York Boston Philadelphia Cleveland Chicago Houston Denver Los Angeles San Francisco Portland and Seattle might have had access to these tests But what of women in
xviii Foreword
Appalachia or the Four Corners region in the Southwest or more generally in rural or other relatively remote locations Would Yale University for example have had any incentive to provide access to the BRCA tests to these women in these far‐off locations Or to provide genetic counseling where the women lived Or to lobby state Medicare administrators or private insurance commissioners to cover the test I think that unlikely Myriad Genetics did all of this as well as perform outreach to the obstetrics and gynecology doctors throughout the United States so that these primary care doctors were aware of the tests Myriad did not ace from altruism but as part of their business plan in order to expand the number of patients who received the test and thus maximize the companyrsquos revenue While it may be counterintuitive to some these circumstances may have been the most effective way not only to pro-mulgate the BRCA tests but also to facilitate acceptance of genetic diagnostic testing for other diseases showing that in this instance Adam Smith rather than Karl Marx provided the most practical solution to the problem of estab-lishing genetic diagnostic testing as a recognized component of a physicianrsquos diagnostic armamentarium
Fortunately the significance and impact of recent US court decisions (spe-cifically the Myriad case) is much less than it would have been ten to thirty years ago Due to patent term rules most patents (and applications) on iso-lated DNA filed in the heyday of the Human Genome Project (approxi-mately 1998ndash2001) are near the end of their actual or potential term indeed a recent study shows that the number of granted patents having at least one claim reciting an isolate DNA comprising a gene peaked in 1999 and has been dropping since 2005 (Graff et al 2013 ldquoNot quite a myriad of gene pat-entsrdquo Nature Biotechnology 31 404ndash410)) These recent decisions in the United States have not harmed the biotechnology industry because they retained patent eligibility for species of DNA that show evidence of the ldquohand of manrdquo and do not occur in nature These include enzymatically pro-duced copies (cDNA) of cellular messenger RNA and should also encom-pass the tools of the recombinant geneticist (eg including recombinant vectors for cloning and expressing genes in heterologous cells) Most impor-tantly the US Supreme Court did not overturn its Diamond v Chakrabarty decision wherein recombinant cells were determined to be patent eligible
Thus in many ways the question of patent eligibility for human genes is a philosophical one However that does not mean that how we think about patent eligibility for isolated DNA is irrelevant to important questions regarding the usefulness of patents for promoting progress and innovation
Foreword xix
Indeed the most pernicious effects of the current trend in the zeitgeist against patenting has been not that genes have become harder to patent but rather that the ability to patent other natural products has been called into question It is the extension of these recent decisions on isolated DNA to all natural products that poses the greatest threat to innovation This threat can be illustrated by a thought experiment for which of these substances should patent protection be withheld
bull A petrochemical with excellent lubrication qualities isolated in pure form and used as improved motor oil
bull Vitamin B12 isolated from beef muscle formulated into a medicament used to cure anemia in children
bull The drug penicillin isolated from a mixture of naturally produced chemicals made by a mold and formulated as a drug to cure syphilis (which is otherwise eventually fatal)
bull Human urinary erythropoietin formulated to treat anemia in kidney dialysis patients
bull The gene responsible for Gaucherrsquos disease a lipid storage disease wherein the gene is used to make the missing protein that is administered to children and that cures an otherwise incurable and fatal disease
The current answer is that none of them are patent‐eligible per se (although there may be ways to claim them that could pass eligibility muster that remains to be seen) Judge Sweet the US District Court judge who first ruled that isolated DNA was not patent‐eligible did so using language carefully crafted to avoid encompassing all natural products into his decision Specifically Judge Sweet distinguished isolated DNA as the ldquophysical embodiments of genetic informationrdquo a property limited to DNA and not shared by other natural products (While an enzymatic protein could be characterized as the physical embodiment of catalysis of a particular chemical reaction that formulation has much less appeal and inherent rationale than Judge Sweetrsquos regarding DNA) Instead of this careful formu-lation the broader language employed by the Supreme Court as well as the broader rationale the Court used in finding genomic DNA unpatentable has made it easier to employ that fractured logic to render patent‐ineligible naturally occurring molecules other than DNA
I would be remiss not to mention the rather comical (but persistent) efforts of former Acting Solicitor General Neal Katyal who included in the
xx Foreword
US Governmentrsquos amicus brief to the Federal Circuit the distinction engine he called a ldquomagic microscoperdquo embodying the concept that if you are able to visualize a natural product (like a genomic DNA molecule) using this mythical microscope then the natural product would not be patent‐eligible whereas if you could not (eg a cDNA molecule) then the natural product could be eligible for patenting Fortunately the disdain with which the Federal Circuit greeted this fantasy (particularly from Judge Moore) prompted its quick abandonment as are argumentative distinction as the case moved forward Nonetheless both the courts and the US Patent and Trademark Office have adopted this standard de facto even as it becomes the theory that dare not speak its name in legal circles
The philosophical point here is that these substances and natural products generally have been deemed patent‐ineligible categorically which while consistent with (and perhaps even mandated by) the deon-tological approach imposes a distinction that cannot be flexibly applied to the individual circumstances Without such flexibility the law is con-strained to use one criterion that the substance can be found in some form in nature to decide patent eligibility instead of making the deter-mination of whether permitting patenting exclusivity satisfies the cri-teria that the invention ldquopromotes progressrdquo as the US Constitution requires and has a benefit to the public that outweighs any categorical disabilities
The potential that using this standard for determining patent eligibility will result in negative practical outcomes that no one in this debate desires is illustrated by a 2012 Report from the National Institutes of Health Natural Product Branch regarding statistics relating to the number of FDA approvals (a total of 1355) for new drugs falling into the following categories
Drug typesource Number
Biological (B) 203Natural product (N) 55Natural product (botanical) (NB) 149Derived from a natural product (ND) 298Totally synthetic (S) 393Total synthesisnatural product (S) 176Vaccine (S) 81
Foreword xxi
These statistics illustrate the consequences of a general ban on patenting naturally derived products of the 1355 drugs approved between 1981 and 2010
bull Fifty percent of all small‐molecule drugs approved between 2000 and 2010 are natural products
bull About 75 of antibacterial drugs are natural products or derived from natural products
bull Almost 80 of small‐molecule anticancer drugs were natural products or derivatives
In addition only 15 of drugs approved during this time frame were so‐called biologic drugs which are also putatively patent‐ineligible This the problems caused by the current interpretation of the law excluding natural product drugs from patent eligibility will be exacerbated in view of reports from every study showing that the percentage of drugs that are biologic drugs has been growing and will be the predominant type of drug devel-oped in the 2011ndash2030 time period
Another ldquothought experimentrdquo illustrating the practical illogic (David can provide his philosophical justifications in the body of the text) of broad natural products patent ineligibility is as follows Suppose a researcher finds a molecule produced by the human body that causes blood pressure homeo-stasis that is lack of this molecule causes or contributes to the disease of high blood pressure The logical consequence of the current natural prod-uct patent ineligibility standards would be that the closer a drug molecule is to the structure of the molecule as it occurs in the body the less patent‐eli-gible it would be Practically speaking there would be no incentive to modify the molecule to confer patent eligibility on the altered molecule because of the unpredictability of such changes on the molecule such as its biological activity half‐life stability antigenicity or other biological prop-erties And there would be even less incentive to develop the molecule as a drug because without patent protection the available regulatory exclusiv-ities would not pass economic muster to sufficiently defray the large development costs (some of which prevent drugs neither safe nor effica-cious from being sold and thus provide their own justification)
There is one further pernicious outcome that can be predicted to arise from a ban on natural products patents (including patents on isolated DNA and genetic diagnostic methods based on such isolated DNA) Natural
xxii Foreword
products are almost by nature complex and an ldquoactive principlerdquo isolated from nature is beneficial because it is isolated Kodak ran an advertisement in the journal Nature in the 1970s showing a scientist in a lab coat holding a 250‐ml flask and standing next to several bushels of green peppers wherein the content of the flask was the purified ldquoessence of green pepperrdquo equivalent to that substance contained in all the peppers in all the bushels and bushels that the scientist was standing beside But this very complexity makes it possible for the ldquoactive principlerdquo (either as a chemical compound or as a diagnostic genetic sequence) to be ldquohidden in plain sightrdquo in ways that may be particularly refractory to reverse engineering
For example even using somewhat dated ldquogene chiprdquo technology genetically diagnostic markers could be encrypted onto a microchip comprising 10 000 unique sequences wherein a computer‐readable bar code would be used to identify the positions of diagnostically relevant sequences on the chip This form of encryption which can be random and confounded by the presence of positive and negative control sequences as well as variable numbers and lengths of sequences specific for the gene (or more likely genes) of interest would be very difficult if not impossible to reverse‐engineer Even if reverse engineering could be done it would be difficult and expensive to undertake and thus make it more likely that the innovator would be able to avoid com-petition (ie it would provide unlimited exclusivity to its purveyor not con-strained by patent term or burdened by the requirement that the invention be disclosed with the specificity required by the Patent Act) While the possi-bility that this type of chip could be made exists with or without patents the absence of patent protection could tip the scales in favor of the extra effort needed and risk entailed in nondisclosure if the reward of extended ldquomonopolyrdquo is great enough But particularly for genetic diagnostic inven-tions the benefits of developing a proprietary database for which a corpora-tion could provide the economic and marketing wherewithal to expeditiously produce would result in a ldquoworst of both worldsrdquo outcome unlimited exclu-sivity based on undisclosed proprietary information that not only is difficult to replicate but whose existence would inhibit competition After all if a company had such a database its outcome for any particular patientrsquos test would be more accurate (and might identify disease riskndashassociated genetic variants not available elsewhere) and this would provide little incentive for a physician to choose an alternative provider to perform the test (and even more malevolently could create a system where the wealthy could afford the best diagnostic testing while the less affluent would be restricted to the more
Foreword xxiii
limited assays offered by companies without access to the ldquoinnovatorrsquosrdquo proprietary database information)
The other aspect of foreclosing patents for certain substances or technology areas categorically is that it upsets a carefully crafted dynamic that has worked extremely well during the biotech era between ldquotruerdquo innovators (typically university professors or small start‐up biotechnology companies) and more established companies capable of commercializing innovation Pundits who worry that permitting patenting will harm innovation miss an important point innovation will happen particularly in universities research institutes and like places because human nature demands it and regardless of whether patent protection is available The intelligent ape in us wants to know and the disparity between how univer-sity professors and patent lawyers are paid should establish how powerful the need to know can be Patenting and the impetus for patenting provided for example by the BayhndashDole Act in the United States prevents the fruits of these inventive efforts from mere predation by commercial concerns The benefits that can be had from a system where private commercializa-tion is encouraged are tempered by the types of corporate shenanigans that raise cogent criticisms of the system But perhaps it is mere human nature that people (in the corporate as well as individual sense) will want to expro-priate technology rather than pay for it and patenting prohibits (or at least retards) this outcome (if not these tendencies) Thus paradoxically limiting patent rights does not free innovation but rather makes it more likely to be kept captive by the entities capable of using such innovation to make a commercial product that is not from the power of building a better mouse-trap but by being able to outcompete smaller innovators merely by their greater economic prowess and resources Conversely patents provide a way for the innovators to protect their innovations and compel corporations to license their inventions producing revenue that can be used to fund future research endeavors This useful cycle has resulted in the successes of the biotechnology era and is something that we abandon at our peril
Thus in my view patents are a useful tool for achieving these societally ben-eficial goals promoting innovation and commercialization and protecting and supporting individuals who use the patent system to protect the products of their labors from being expropriated by others David provides a cogent and honest counterpoint to these thoughts Enjoy reading them
Kevin E NoonanChicago Illinois 2014
Foreword xv
emotional plea to individuals afraid that corporate America was trying to ldquostealrdquo their genes which has proven very effective This process began with an Op‐Ed piece in The New York Times by Michael Crichton wherein he posited a scenario where a patent holder knocks on your door one day and demands payment for the use of ldquoherrdquo patented gene that resides in your liver (Not coincidentally Dr Crichton had just published a novel on the perils of genetic engineering and corporate ownership of human genes complete with an essay as an addendum containing his arguments against the practice And it should be noted that a constant theme in his novels was a mistrust of technology and particularly the ability of humans to use it without dire consequences) Academics like my friend Lori Andrews at Illinois Institute of Technology (IIT)‐Kent School of Law joined in this theme which was picked up eventually by most popular press outlets and became regrettably the canonical narrative on gene patenting culminating in the American Civil Liberties Unionrsquos (ACLUrsquos) ldquoKeep Your Hands Off My Genesrdquo slogan and logo I hope that this essay provides some antidote to this argument which is founded on the literal fear that someone can ldquoownrdquo you (David assures me that his title is allegorical and that he acknowledges that in all countries that have banned slavery no one can ldquoownrdquo another human being or a part of them See the 13th Amendment I assure you that the ACLU has no such illusions about the intended consequences of their ownership rhetoric)
My philosophy is that the principle we should follow is the greatest good to the greatest number while not infringing on individual rights without (at least) compensation As regards patent law this principle is translated into rules that foster the broadest disclosure of technology possible in return for exclusive patent rights and robust‐enough enforcement rights for patents that they provide sufficient certainty to promote investment so his technology is commercialized to benefit the greatest number In my role as a biotechnology patent attorney I have seen how risky investment in biotechnology can be (indeed the evidence is overwhelming that for all its successes biotechrsquos history is littered with the remains of companies that have failed) and how important it is to have a sound patent system of predictable rights go support that investment
The evidence in support of ldquogene patentingrdquo and more broadly natural products patenting is strong the biotechnology industry has promoted innovation in the form of new drugs and diagnostics assays for a genera-tion This may continue despite the recent restrictions on patent protection
xvi Foreword
for genes and natural products (including patent‐restricting decisions in Mayo Collaborative Labs v Prometheus Labs and Assoc of Molecular Pathologists v Myriad Genetics and recently promulgated US Patent and Trademark Office Guidances on Subject Matter Eligibility) In fact these very restrictions suggest that we would benefit from an appreciation of the facts surrounding the past thirty years of gene patenting to understand why these restrictions are not only wrongheaded but dangerous for future innovation
These include debunking several myths First the concern that patents on specific human genes in some way inhibit innovation in basic genetic research is entirely unfounded One reason is that the genetic information itself is not patented while isolated DNA is encompassed by gene patent claims and described in those claims by its sequence the sequence itself is unpatented information that can be used freely for any purpose (eg inter-rogating genetic databases from other species or even human DNA inter alia to find related genes in those databases) Indeed the innovative benefits to gene patenting are evident in at least two ways First scientific publication databases reveal that there have been more than 11 000 scientific papers published on the BRCA1 and BRCA2 genes since the patents claiming them were granted This outcome refutes the prediction that gene patenting would create a ldquotragedy of the anticommonsrdquo where scientific research would be stifled by patenting (see Heller amp Eisenberg 1998 ldquoCan Patents Deter Innovation The Anticommons in Biomedical Researchrdquo Science 280 698ndash701)) a conclusion supported by the overwhelming majority of studies done on this subject (see for example Walsh et al 2003 ldquoScience and the Law Working Through the Patent Problemrdquo Science 299 1020 Walsh et al 2005 ldquoScience and Law View from the Bench Patents and Material Transfersrdquo Science 309 2002ndash03)
In addition policies that the US Patent and Trademark Office adopted in 2001 required applicants to disclose a practical utility for the product of a gene claimed in a patent These requirements were imposed at a time when the standards for scientific journal publication were much less stringent so that identifying a gene by the extent of genetic similarity between the ldquonewrdquo gene and previously discovered genes was enough for publication But it was not enough for a patent which has been held to be ldquonot a hunting license It is not a reward for the search but compensation for its successful conclusionrdquo Thus genes encoding proteins having no known use or biological activity cannot be patented because to do so would allow the
Foreword xvii
gene to be within the exclusive patent right undeservedly the public would not have received its quid pro quo of a useful invention in return for patent exclusivity All such genes not having patent protection are in the public domain (from which they cannot be retrieved for future patenting) and for humans these constitute the vast majority of genes identified inter alia by the Human Genome Project
The role for patenting genes and the related genetic diagnostic methods using this genetic information in the successes of the biotechnology era are evident The industry has produced hundreds of biologic drugs (at an ever‐increasing rate) that have provided effective treatment for a variety of illnesses and decoding the human genome has enabled researchers to iden-tify genes like the BRCA1 and BRCA2 genes that can be used in predictive genetic diagnostic tests Even the much‐maligned Myriad Genetics has played a positive role in the development and prevalence of genetic diagnostic testing It must be remembered that in 1997 (when Myriadrsquos BRCA gene patents were granted) genetic testing was in its infancy and companies like Myriad were under the burden of convincing payers that the tests did the one thing that all insurers public or private require of such tests save them money in the long run by identifying patients with a high probability of becoming ill and costing the insurers much more for treatment than the costs of prophylaxis Moreover Myriad and like com-panies needed to convince doctors that the testing was worthwhile and to establish a network of genetic counselors who could explain to healthy women that they were at much greater risk of developing breast or ovarian cancer than normal under circumstances that resulted in empowerment from the information and not abject fear And in 1997 genetic sequencing technology was not as developed as it is now and the mechanisms and tech-niques needed to minimize or eliminate the occurrence of false positives or negatives had not been conclusively established All these burdens were ones borne by Myriad and these activities produced the world we have today
It is possible as some have argued that BRCA tests may have been devel-oped independently by individual researchers in the absence of patent pro-tection However it is almost certain that such researchers would have been located in medical centers in urban environments Under these circum-stances women living in or near cities such as New York Boston Philadelphia Cleveland Chicago Houston Denver Los Angeles San Francisco Portland and Seattle might have had access to these tests But what of women in
xviii Foreword
Appalachia or the Four Corners region in the Southwest or more generally in rural or other relatively remote locations Would Yale University for example have had any incentive to provide access to the BRCA tests to these women in these far‐off locations Or to provide genetic counseling where the women lived Or to lobby state Medicare administrators or private insurance commissioners to cover the test I think that unlikely Myriad Genetics did all of this as well as perform outreach to the obstetrics and gynecology doctors throughout the United States so that these primary care doctors were aware of the tests Myriad did not ace from altruism but as part of their business plan in order to expand the number of patients who received the test and thus maximize the companyrsquos revenue While it may be counterintuitive to some these circumstances may have been the most effective way not only to pro-mulgate the BRCA tests but also to facilitate acceptance of genetic diagnostic testing for other diseases showing that in this instance Adam Smith rather than Karl Marx provided the most practical solution to the problem of estab-lishing genetic diagnostic testing as a recognized component of a physicianrsquos diagnostic armamentarium
Fortunately the significance and impact of recent US court decisions (spe-cifically the Myriad case) is much less than it would have been ten to thirty years ago Due to patent term rules most patents (and applications) on iso-lated DNA filed in the heyday of the Human Genome Project (approxi-mately 1998ndash2001) are near the end of their actual or potential term indeed a recent study shows that the number of granted patents having at least one claim reciting an isolate DNA comprising a gene peaked in 1999 and has been dropping since 2005 (Graff et al 2013 ldquoNot quite a myriad of gene pat-entsrdquo Nature Biotechnology 31 404ndash410)) These recent decisions in the United States have not harmed the biotechnology industry because they retained patent eligibility for species of DNA that show evidence of the ldquohand of manrdquo and do not occur in nature These include enzymatically pro-duced copies (cDNA) of cellular messenger RNA and should also encom-pass the tools of the recombinant geneticist (eg including recombinant vectors for cloning and expressing genes in heterologous cells) Most impor-tantly the US Supreme Court did not overturn its Diamond v Chakrabarty decision wherein recombinant cells were determined to be patent eligible
Thus in many ways the question of patent eligibility for human genes is a philosophical one However that does not mean that how we think about patent eligibility for isolated DNA is irrelevant to important questions regarding the usefulness of patents for promoting progress and innovation
Foreword xix
Indeed the most pernicious effects of the current trend in the zeitgeist against patenting has been not that genes have become harder to patent but rather that the ability to patent other natural products has been called into question It is the extension of these recent decisions on isolated DNA to all natural products that poses the greatest threat to innovation This threat can be illustrated by a thought experiment for which of these substances should patent protection be withheld
bull A petrochemical with excellent lubrication qualities isolated in pure form and used as improved motor oil
bull Vitamin B12 isolated from beef muscle formulated into a medicament used to cure anemia in children
bull The drug penicillin isolated from a mixture of naturally produced chemicals made by a mold and formulated as a drug to cure syphilis (which is otherwise eventually fatal)
bull Human urinary erythropoietin formulated to treat anemia in kidney dialysis patients
bull The gene responsible for Gaucherrsquos disease a lipid storage disease wherein the gene is used to make the missing protein that is administered to children and that cures an otherwise incurable and fatal disease
The current answer is that none of them are patent‐eligible per se (although there may be ways to claim them that could pass eligibility muster that remains to be seen) Judge Sweet the US District Court judge who first ruled that isolated DNA was not patent‐eligible did so using language carefully crafted to avoid encompassing all natural products into his decision Specifically Judge Sweet distinguished isolated DNA as the ldquophysical embodiments of genetic informationrdquo a property limited to DNA and not shared by other natural products (While an enzymatic protein could be characterized as the physical embodiment of catalysis of a particular chemical reaction that formulation has much less appeal and inherent rationale than Judge Sweetrsquos regarding DNA) Instead of this careful formu-lation the broader language employed by the Supreme Court as well as the broader rationale the Court used in finding genomic DNA unpatentable has made it easier to employ that fractured logic to render patent‐ineligible naturally occurring molecules other than DNA
I would be remiss not to mention the rather comical (but persistent) efforts of former Acting Solicitor General Neal Katyal who included in the
xx Foreword
US Governmentrsquos amicus brief to the Federal Circuit the distinction engine he called a ldquomagic microscoperdquo embodying the concept that if you are able to visualize a natural product (like a genomic DNA molecule) using this mythical microscope then the natural product would not be patent‐eligible whereas if you could not (eg a cDNA molecule) then the natural product could be eligible for patenting Fortunately the disdain with which the Federal Circuit greeted this fantasy (particularly from Judge Moore) prompted its quick abandonment as are argumentative distinction as the case moved forward Nonetheless both the courts and the US Patent and Trademark Office have adopted this standard de facto even as it becomes the theory that dare not speak its name in legal circles
The philosophical point here is that these substances and natural products generally have been deemed patent‐ineligible categorically which while consistent with (and perhaps even mandated by) the deon-tological approach imposes a distinction that cannot be flexibly applied to the individual circumstances Without such flexibility the law is con-strained to use one criterion that the substance can be found in some form in nature to decide patent eligibility instead of making the deter-mination of whether permitting patenting exclusivity satisfies the cri-teria that the invention ldquopromotes progressrdquo as the US Constitution requires and has a benefit to the public that outweighs any categorical disabilities
The potential that using this standard for determining patent eligibility will result in negative practical outcomes that no one in this debate desires is illustrated by a 2012 Report from the National Institutes of Health Natural Product Branch regarding statistics relating to the number of FDA approvals (a total of 1355) for new drugs falling into the following categories
Drug typesource Number
Biological (B) 203Natural product (N) 55Natural product (botanical) (NB) 149Derived from a natural product (ND) 298Totally synthetic (S) 393Total synthesisnatural product (S) 176Vaccine (S) 81
Foreword xxi
These statistics illustrate the consequences of a general ban on patenting naturally derived products of the 1355 drugs approved between 1981 and 2010
bull Fifty percent of all small‐molecule drugs approved between 2000 and 2010 are natural products
bull About 75 of antibacterial drugs are natural products or derived from natural products
bull Almost 80 of small‐molecule anticancer drugs were natural products or derivatives
In addition only 15 of drugs approved during this time frame were so‐called biologic drugs which are also putatively patent‐ineligible This the problems caused by the current interpretation of the law excluding natural product drugs from patent eligibility will be exacerbated in view of reports from every study showing that the percentage of drugs that are biologic drugs has been growing and will be the predominant type of drug devel-oped in the 2011ndash2030 time period
Another ldquothought experimentrdquo illustrating the practical illogic (David can provide his philosophical justifications in the body of the text) of broad natural products patent ineligibility is as follows Suppose a researcher finds a molecule produced by the human body that causes blood pressure homeo-stasis that is lack of this molecule causes or contributes to the disease of high blood pressure The logical consequence of the current natural prod-uct patent ineligibility standards would be that the closer a drug molecule is to the structure of the molecule as it occurs in the body the less patent‐eli-gible it would be Practically speaking there would be no incentive to modify the molecule to confer patent eligibility on the altered molecule because of the unpredictability of such changes on the molecule such as its biological activity half‐life stability antigenicity or other biological prop-erties And there would be even less incentive to develop the molecule as a drug because without patent protection the available regulatory exclusiv-ities would not pass economic muster to sufficiently defray the large development costs (some of which prevent drugs neither safe nor effica-cious from being sold and thus provide their own justification)
There is one further pernicious outcome that can be predicted to arise from a ban on natural products patents (including patents on isolated DNA and genetic diagnostic methods based on such isolated DNA) Natural
xxii Foreword
products are almost by nature complex and an ldquoactive principlerdquo isolated from nature is beneficial because it is isolated Kodak ran an advertisement in the journal Nature in the 1970s showing a scientist in a lab coat holding a 250‐ml flask and standing next to several bushels of green peppers wherein the content of the flask was the purified ldquoessence of green pepperrdquo equivalent to that substance contained in all the peppers in all the bushels and bushels that the scientist was standing beside But this very complexity makes it possible for the ldquoactive principlerdquo (either as a chemical compound or as a diagnostic genetic sequence) to be ldquohidden in plain sightrdquo in ways that may be particularly refractory to reverse engineering
For example even using somewhat dated ldquogene chiprdquo technology genetically diagnostic markers could be encrypted onto a microchip comprising 10 000 unique sequences wherein a computer‐readable bar code would be used to identify the positions of diagnostically relevant sequences on the chip This form of encryption which can be random and confounded by the presence of positive and negative control sequences as well as variable numbers and lengths of sequences specific for the gene (or more likely genes) of interest would be very difficult if not impossible to reverse‐engineer Even if reverse engineering could be done it would be difficult and expensive to undertake and thus make it more likely that the innovator would be able to avoid com-petition (ie it would provide unlimited exclusivity to its purveyor not con-strained by patent term or burdened by the requirement that the invention be disclosed with the specificity required by the Patent Act) While the possi-bility that this type of chip could be made exists with or without patents the absence of patent protection could tip the scales in favor of the extra effort needed and risk entailed in nondisclosure if the reward of extended ldquomonopolyrdquo is great enough But particularly for genetic diagnostic inven-tions the benefits of developing a proprietary database for which a corpora-tion could provide the economic and marketing wherewithal to expeditiously produce would result in a ldquoworst of both worldsrdquo outcome unlimited exclu-sivity based on undisclosed proprietary information that not only is difficult to replicate but whose existence would inhibit competition After all if a company had such a database its outcome for any particular patientrsquos test would be more accurate (and might identify disease riskndashassociated genetic variants not available elsewhere) and this would provide little incentive for a physician to choose an alternative provider to perform the test (and even more malevolently could create a system where the wealthy could afford the best diagnostic testing while the less affluent would be restricted to the more
Foreword xxiii
limited assays offered by companies without access to the ldquoinnovatorrsquosrdquo proprietary database information)
The other aspect of foreclosing patents for certain substances or technology areas categorically is that it upsets a carefully crafted dynamic that has worked extremely well during the biotech era between ldquotruerdquo innovators (typically university professors or small start‐up biotechnology companies) and more established companies capable of commercializing innovation Pundits who worry that permitting patenting will harm innovation miss an important point innovation will happen particularly in universities research institutes and like places because human nature demands it and regardless of whether patent protection is available The intelligent ape in us wants to know and the disparity between how univer-sity professors and patent lawyers are paid should establish how powerful the need to know can be Patenting and the impetus for patenting provided for example by the BayhndashDole Act in the United States prevents the fruits of these inventive efforts from mere predation by commercial concerns The benefits that can be had from a system where private commercializa-tion is encouraged are tempered by the types of corporate shenanigans that raise cogent criticisms of the system But perhaps it is mere human nature that people (in the corporate as well as individual sense) will want to expro-priate technology rather than pay for it and patenting prohibits (or at least retards) this outcome (if not these tendencies) Thus paradoxically limiting patent rights does not free innovation but rather makes it more likely to be kept captive by the entities capable of using such innovation to make a commercial product that is not from the power of building a better mouse-trap but by being able to outcompete smaller innovators merely by their greater economic prowess and resources Conversely patents provide a way for the innovators to protect their innovations and compel corporations to license their inventions producing revenue that can be used to fund future research endeavors This useful cycle has resulted in the successes of the biotechnology era and is something that we abandon at our peril
Thus in my view patents are a useful tool for achieving these societally ben-eficial goals promoting innovation and commercialization and protecting and supporting individuals who use the patent system to protect the products of their labors from being expropriated by others David provides a cogent and honest counterpoint to these thoughts Enjoy reading them
Kevin E NoonanChicago Illinois 2014
xvi Foreword
for genes and natural products (including patent‐restricting decisions in Mayo Collaborative Labs v Prometheus Labs and Assoc of Molecular Pathologists v Myriad Genetics and recently promulgated US Patent and Trademark Office Guidances on Subject Matter Eligibility) In fact these very restrictions suggest that we would benefit from an appreciation of the facts surrounding the past thirty years of gene patenting to understand why these restrictions are not only wrongheaded but dangerous for future innovation
These include debunking several myths First the concern that patents on specific human genes in some way inhibit innovation in basic genetic research is entirely unfounded One reason is that the genetic information itself is not patented while isolated DNA is encompassed by gene patent claims and described in those claims by its sequence the sequence itself is unpatented information that can be used freely for any purpose (eg inter-rogating genetic databases from other species or even human DNA inter alia to find related genes in those databases) Indeed the innovative benefits to gene patenting are evident in at least two ways First scientific publication databases reveal that there have been more than 11 000 scientific papers published on the BRCA1 and BRCA2 genes since the patents claiming them were granted This outcome refutes the prediction that gene patenting would create a ldquotragedy of the anticommonsrdquo where scientific research would be stifled by patenting (see Heller amp Eisenberg 1998 ldquoCan Patents Deter Innovation The Anticommons in Biomedical Researchrdquo Science 280 698ndash701)) a conclusion supported by the overwhelming majority of studies done on this subject (see for example Walsh et al 2003 ldquoScience and the Law Working Through the Patent Problemrdquo Science 299 1020 Walsh et al 2005 ldquoScience and Law View from the Bench Patents and Material Transfersrdquo Science 309 2002ndash03)
In addition policies that the US Patent and Trademark Office adopted in 2001 required applicants to disclose a practical utility for the product of a gene claimed in a patent These requirements were imposed at a time when the standards for scientific journal publication were much less stringent so that identifying a gene by the extent of genetic similarity between the ldquonewrdquo gene and previously discovered genes was enough for publication But it was not enough for a patent which has been held to be ldquonot a hunting license It is not a reward for the search but compensation for its successful conclusionrdquo Thus genes encoding proteins having no known use or biological activity cannot be patented because to do so would allow the
Foreword xvii
gene to be within the exclusive patent right undeservedly the public would not have received its quid pro quo of a useful invention in return for patent exclusivity All such genes not having patent protection are in the public domain (from which they cannot be retrieved for future patenting) and for humans these constitute the vast majority of genes identified inter alia by the Human Genome Project
The role for patenting genes and the related genetic diagnostic methods using this genetic information in the successes of the biotechnology era are evident The industry has produced hundreds of biologic drugs (at an ever‐increasing rate) that have provided effective treatment for a variety of illnesses and decoding the human genome has enabled researchers to iden-tify genes like the BRCA1 and BRCA2 genes that can be used in predictive genetic diagnostic tests Even the much‐maligned Myriad Genetics has played a positive role in the development and prevalence of genetic diagnostic testing It must be remembered that in 1997 (when Myriadrsquos BRCA gene patents were granted) genetic testing was in its infancy and companies like Myriad were under the burden of convincing payers that the tests did the one thing that all insurers public or private require of such tests save them money in the long run by identifying patients with a high probability of becoming ill and costing the insurers much more for treatment than the costs of prophylaxis Moreover Myriad and like com-panies needed to convince doctors that the testing was worthwhile and to establish a network of genetic counselors who could explain to healthy women that they were at much greater risk of developing breast or ovarian cancer than normal under circumstances that resulted in empowerment from the information and not abject fear And in 1997 genetic sequencing technology was not as developed as it is now and the mechanisms and tech-niques needed to minimize or eliminate the occurrence of false positives or negatives had not been conclusively established All these burdens were ones borne by Myriad and these activities produced the world we have today
It is possible as some have argued that BRCA tests may have been devel-oped independently by individual researchers in the absence of patent pro-tection However it is almost certain that such researchers would have been located in medical centers in urban environments Under these circum-stances women living in or near cities such as New York Boston Philadelphia Cleveland Chicago Houston Denver Los Angeles San Francisco Portland and Seattle might have had access to these tests But what of women in
xviii Foreword
Appalachia or the Four Corners region in the Southwest or more generally in rural or other relatively remote locations Would Yale University for example have had any incentive to provide access to the BRCA tests to these women in these far‐off locations Or to provide genetic counseling where the women lived Or to lobby state Medicare administrators or private insurance commissioners to cover the test I think that unlikely Myriad Genetics did all of this as well as perform outreach to the obstetrics and gynecology doctors throughout the United States so that these primary care doctors were aware of the tests Myriad did not ace from altruism but as part of their business plan in order to expand the number of patients who received the test and thus maximize the companyrsquos revenue While it may be counterintuitive to some these circumstances may have been the most effective way not only to pro-mulgate the BRCA tests but also to facilitate acceptance of genetic diagnostic testing for other diseases showing that in this instance Adam Smith rather than Karl Marx provided the most practical solution to the problem of estab-lishing genetic diagnostic testing as a recognized component of a physicianrsquos diagnostic armamentarium
Fortunately the significance and impact of recent US court decisions (spe-cifically the Myriad case) is much less than it would have been ten to thirty years ago Due to patent term rules most patents (and applications) on iso-lated DNA filed in the heyday of the Human Genome Project (approxi-mately 1998ndash2001) are near the end of their actual or potential term indeed a recent study shows that the number of granted patents having at least one claim reciting an isolate DNA comprising a gene peaked in 1999 and has been dropping since 2005 (Graff et al 2013 ldquoNot quite a myriad of gene pat-entsrdquo Nature Biotechnology 31 404ndash410)) These recent decisions in the United States have not harmed the biotechnology industry because they retained patent eligibility for species of DNA that show evidence of the ldquohand of manrdquo and do not occur in nature These include enzymatically pro-duced copies (cDNA) of cellular messenger RNA and should also encom-pass the tools of the recombinant geneticist (eg including recombinant vectors for cloning and expressing genes in heterologous cells) Most impor-tantly the US Supreme Court did not overturn its Diamond v Chakrabarty decision wherein recombinant cells were determined to be patent eligible
Thus in many ways the question of patent eligibility for human genes is a philosophical one However that does not mean that how we think about patent eligibility for isolated DNA is irrelevant to important questions regarding the usefulness of patents for promoting progress and innovation
Foreword xix
Indeed the most pernicious effects of the current trend in the zeitgeist against patenting has been not that genes have become harder to patent but rather that the ability to patent other natural products has been called into question It is the extension of these recent decisions on isolated DNA to all natural products that poses the greatest threat to innovation This threat can be illustrated by a thought experiment for which of these substances should patent protection be withheld
bull A petrochemical with excellent lubrication qualities isolated in pure form and used as improved motor oil
bull Vitamin B12 isolated from beef muscle formulated into a medicament used to cure anemia in children
bull The drug penicillin isolated from a mixture of naturally produced chemicals made by a mold and formulated as a drug to cure syphilis (which is otherwise eventually fatal)
bull Human urinary erythropoietin formulated to treat anemia in kidney dialysis patients
bull The gene responsible for Gaucherrsquos disease a lipid storage disease wherein the gene is used to make the missing protein that is administered to children and that cures an otherwise incurable and fatal disease
The current answer is that none of them are patent‐eligible per se (although there may be ways to claim them that could pass eligibility muster that remains to be seen) Judge Sweet the US District Court judge who first ruled that isolated DNA was not patent‐eligible did so using language carefully crafted to avoid encompassing all natural products into his decision Specifically Judge Sweet distinguished isolated DNA as the ldquophysical embodiments of genetic informationrdquo a property limited to DNA and not shared by other natural products (While an enzymatic protein could be characterized as the physical embodiment of catalysis of a particular chemical reaction that formulation has much less appeal and inherent rationale than Judge Sweetrsquos regarding DNA) Instead of this careful formu-lation the broader language employed by the Supreme Court as well as the broader rationale the Court used in finding genomic DNA unpatentable has made it easier to employ that fractured logic to render patent‐ineligible naturally occurring molecules other than DNA
I would be remiss not to mention the rather comical (but persistent) efforts of former Acting Solicitor General Neal Katyal who included in the
xx Foreword
US Governmentrsquos amicus brief to the Federal Circuit the distinction engine he called a ldquomagic microscoperdquo embodying the concept that if you are able to visualize a natural product (like a genomic DNA molecule) using this mythical microscope then the natural product would not be patent‐eligible whereas if you could not (eg a cDNA molecule) then the natural product could be eligible for patenting Fortunately the disdain with which the Federal Circuit greeted this fantasy (particularly from Judge Moore) prompted its quick abandonment as are argumentative distinction as the case moved forward Nonetheless both the courts and the US Patent and Trademark Office have adopted this standard de facto even as it becomes the theory that dare not speak its name in legal circles
The philosophical point here is that these substances and natural products generally have been deemed patent‐ineligible categorically which while consistent with (and perhaps even mandated by) the deon-tological approach imposes a distinction that cannot be flexibly applied to the individual circumstances Without such flexibility the law is con-strained to use one criterion that the substance can be found in some form in nature to decide patent eligibility instead of making the deter-mination of whether permitting patenting exclusivity satisfies the cri-teria that the invention ldquopromotes progressrdquo as the US Constitution requires and has a benefit to the public that outweighs any categorical disabilities
The potential that using this standard for determining patent eligibility will result in negative practical outcomes that no one in this debate desires is illustrated by a 2012 Report from the National Institutes of Health Natural Product Branch regarding statistics relating to the number of FDA approvals (a total of 1355) for new drugs falling into the following categories
Drug typesource Number
Biological (B) 203Natural product (N) 55Natural product (botanical) (NB) 149Derived from a natural product (ND) 298Totally synthetic (S) 393Total synthesisnatural product (S) 176Vaccine (S) 81
Foreword xxi
These statistics illustrate the consequences of a general ban on patenting naturally derived products of the 1355 drugs approved between 1981 and 2010
bull Fifty percent of all small‐molecule drugs approved between 2000 and 2010 are natural products
bull About 75 of antibacterial drugs are natural products or derived from natural products
bull Almost 80 of small‐molecule anticancer drugs were natural products or derivatives
In addition only 15 of drugs approved during this time frame were so‐called biologic drugs which are also putatively patent‐ineligible This the problems caused by the current interpretation of the law excluding natural product drugs from patent eligibility will be exacerbated in view of reports from every study showing that the percentage of drugs that are biologic drugs has been growing and will be the predominant type of drug devel-oped in the 2011ndash2030 time period
Another ldquothought experimentrdquo illustrating the practical illogic (David can provide his philosophical justifications in the body of the text) of broad natural products patent ineligibility is as follows Suppose a researcher finds a molecule produced by the human body that causes blood pressure homeo-stasis that is lack of this molecule causes or contributes to the disease of high blood pressure The logical consequence of the current natural prod-uct patent ineligibility standards would be that the closer a drug molecule is to the structure of the molecule as it occurs in the body the less patent‐eli-gible it would be Practically speaking there would be no incentive to modify the molecule to confer patent eligibility on the altered molecule because of the unpredictability of such changes on the molecule such as its biological activity half‐life stability antigenicity or other biological prop-erties And there would be even less incentive to develop the molecule as a drug because without patent protection the available regulatory exclusiv-ities would not pass economic muster to sufficiently defray the large development costs (some of which prevent drugs neither safe nor effica-cious from being sold and thus provide their own justification)
There is one further pernicious outcome that can be predicted to arise from a ban on natural products patents (including patents on isolated DNA and genetic diagnostic methods based on such isolated DNA) Natural
xxii Foreword
products are almost by nature complex and an ldquoactive principlerdquo isolated from nature is beneficial because it is isolated Kodak ran an advertisement in the journal Nature in the 1970s showing a scientist in a lab coat holding a 250‐ml flask and standing next to several bushels of green peppers wherein the content of the flask was the purified ldquoessence of green pepperrdquo equivalent to that substance contained in all the peppers in all the bushels and bushels that the scientist was standing beside But this very complexity makes it possible for the ldquoactive principlerdquo (either as a chemical compound or as a diagnostic genetic sequence) to be ldquohidden in plain sightrdquo in ways that may be particularly refractory to reverse engineering
For example even using somewhat dated ldquogene chiprdquo technology genetically diagnostic markers could be encrypted onto a microchip comprising 10 000 unique sequences wherein a computer‐readable bar code would be used to identify the positions of diagnostically relevant sequences on the chip This form of encryption which can be random and confounded by the presence of positive and negative control sequences as well as variable numbers and lengths of sequences specific for the gene (or more likely genes) of interest would be very difficult if not impossible to reverse‐engineer Even if reverse engineering could be done it would be difficult and expensive to undertake and thus make it more likely that the innovator would be able to avoid com-petition (ie it would provide unlimited exclusivity to its purveyor not con-strained by patent term or burdened by the requirement that the invention be disclosed with the specificity required by the Patent Act) While the possi-bility that this type of chip could be made exists with or without patents the absence of patent protection could tip the scales in favor of the extra effort needed and risk entailed in nondisclosure if the reward of extended ldquomonopolyrdquo is great enough But particularly for genetic diagnostic inven-tions the benefits of developing a proprietary database for which a corpora-tion could provide the economic and marketing wherewithal to expeditiously produce would result in a ldquoworst of both worldsrdquo outcome unlimited exclu-sivity based on undisclosed proprietary information that not only is difficult to replicate but whose existence would inhibit competition After all if a company had such a database its outcome for any particular patientrsquos test would be more accurate (and might identify disease riskndashassociated genetic variants not available elsewhere) and this would provide little incentive for a physician to choose an alternative provider to perform the test (and even more malevolently could create a system where the wealthy could afford the best diagnostic testing while the less affluent would be restricted to the more
Foreword xxiii
limited assays offered by companies without access to the ldquoinnovatorrsquosrdquo proprietary database information)
The other aspect of foreclosing patents for certain substances or technology areas categorically is that it upsets a carefully crafted dynamic that has worked extremely well during the biotech era between ldquotruerdquo innovators (typically university professors or small start‐up biotechnology companies) and more established companies capable of commercializing innovation Pundits who worry that permitting patenting will harm innovation miss an important point innovation will happen particularly in universities research institutes and like places because human nature demands it and regardless of whether patent protection is available The intelligent ape in us wants to know and the disparity between how univer-sity professors and patent lawyers are paid should establish how powerful the need to know can be Patenting and the impetus for patenting provided for example by the BayhndashDole Act in the United States prevents the fruits of these inventive efforts from mere predation by commercial concerns The benefits that can be had from a system where private commercializa-tion is encouraged are tempered by the types of corporate shenanigans that raise cogent criticisms of the system But perhaps it is mere human nature that people (in the corporate as well as individual sense) will want to expro-priate technology rather than pay for it and patenting prohibits (or at least retards) this outcome (if not these tendencies) Thus paradoxically limiting patent rights does not free innovation but rather makes it more likely to be kept captive by the entities capable of using such innovation to make a commercial product that is not from the power of building a better mouse-trap but by being able to outcompete smaller innovators merely by their greater economic prowess and resources Conversely patents provide a way for the innovators to protect their innovations and compel corporations to license their inventions producing revenue that can be used to fund future research endeavors This useful cycle has resulted in the successes of the biotechnology era and is something that we abandon at our peril
Thus in my view patents are a useful tool for achieving these societally ben-eficial goals promoting innovation and commercialization and protecting and supporting individuals who use the patent system to protect the products of their labors from being expropriated by others David provides a cogent and honest counterpoint to these thoughts Enjoy reading them
Kevin E NoonanChicago Illinois 2014
Foreword xvii
gene to be within the exclusive patent right undeservedly the public would not have received its quid pro quo of a useful invention in return for patent exclusivity All such genes not having patent protection are in the public domain (from which they cannot be retrieved for future patenting) and for humans these constitute the vast majority of genes identified inter alia by the Human Genome Project
The role for patenting genes and the related genetic diagnostic methods using this genetic information in the successes of the biotechnology era are evident The industry has produced hundreds of biologic drugs (at an ever‐increasing rate) that have provided effective treatment for a variety of illnesses and decoding the human genome has enabled researchers to iden-tify genes like the BRCA1 and BRCA2 genes that can be used in predictive genetic diagnostic tests Even the much‐maligned Myriad Genetics has played a positive role in the development and prevalence of genetic diagnostic testing It must be remembered that in 1997 (when Myriadrsquos BRCA gene patents were granted) genetic testing was in its infancy and companies like Myriad were under the burden of convincing payers that the tests did the one thing that all insurers public or private require of such tests save them money in the long run by identifying patients with a high probability of becoming ill and costing the insurers much more for treatment than the costs of prophylaxis Moreover Myriad and like com-panies needed to convince doctors that the testing was worthwhile and to establish a network of genetic counselors who could explain to healthy women that they were at much greater risk of developing breast or ovarian cancer than normal under circumstances that resulted in empowerment from the information and not abject fear And in 1997 genetic sequencing technology was not as developed as it is now and the mechanisms and tech-niques needed to minimize or eliminate the occurrence of false positives or negatives had not been conclusively established All these burdens were ones borne by Myriad and these activities produced the world we have today
It is possible as some have argued that BRCA tests may have been devel-oped independently by individual researchers in the absence of patent pro-tection However it is almost certain that such researchers would have been located in medical centers in urban environments Under these circum-stances women living in or near cities such as New York Boston Philadelphia Cleveland Chicago Houston Denver Los Angeles San Francisco Portland and Seattle might have had access to these tests But what of women in
xviii Foreword
Appalachia or the Four Corners region in the Southwest or more generally in rural or other relatively remote locations Would Yale University for example have had any incentive to provide access to the BRCA tests to these women in these far‐off locations Or to provide genetic counseling where the women lived Or to lobby state Medicare administrators or private insurance commissioners to cover the test I think that unlikely Myriad Genetics did all of this as well as perform outreach to the obstetrics and gynecology doctors throughout the United States so that these primary care doctors were aware of the tests Myriad did not ace from altruism but as part of their business plan in order to expand the number of patients who received the test and thus maximize the companyrsquos revenue While it may be counterintuitive to some these circumstances may have been the most effective way not only to pro-mulgate the BRCA tests but also to facilitate acceptance of genetic diagnostic testing for other diseases showing that in this instance Adam Smith rather than Karl Marx provided the most practical solution to the problem of estab-lishing genetic diagnostic testing as a recognized component of a physicianrsquos diagnostic armamentarium
Fortunately the significance and impact of recent US court decisions (spe-cifically the Myriad case) is much less than it would have been ten to thirty years ago Due to patent term rules most patents (and applications) on iso-lated DNA filed in the heyday of the Human Genome Project (approxi-mately 1998ndash2001) are near the end of their actual or potential term indeed a recent study shows that the number of granted patents having at least one claim reciting an isolate DNA comprising a gene peaked in 1999 and has been dropping since 2005 (Graff et al 2013 ldquoNot quite a myriad of gene pat-entsrdquo Nature Biotechnology 31 404ndash410)) These recent decisions in the United States have not harmed the biotechnology industry because they retained patent eligibility for species of DNA that show evidence of the ldquohand of manrdquo and do not occur in nature These include enzymatically pro-duced copies (cDNA) of cellular messenger RNA and should also encom-pass the tools of the recombinant geneticist (eg including recombinant vectors for cloning and expressing genes in heterologous cells) Most impor-tantly the US Supreme Court did not overturn its Diamond v Chakrabarty decision wherein recombinant cells were determined to be patent eligible
Thus in many ways the question of patent eligibility for human genes is a philosophical one However that does not mean that how we think about patent eligibility for isolated DNA is irrelevant to important questions regarding the usefulness of patents for promoting progress and innovation
Foreword xix
Indeed the most pernicious effects of the current trend in the zeitgeist against patenting has been not that genes have become harder to patent but rather that the ability to patent other natural products has been called into question It is the extension of these recent decisions on isolated DNA to all natural products that poses the greatest threat to innovation This threat can be illustrated by a thought experiment for which of these substances should patent protection be withheld
bull A petrochemical with excellent lubrication qualities isolated in pure form and used as improved motor oil
bull Vitamin B12 isolated from beef muscle formulated into a medicament used to cure anemia in children
bull The drug penicillin isolated from a mixture of naturally produced chemicals made by a mold and formulated as a drug to cure syphilis (which is otherwise eventually fatal)
bull Human urinary erythropoietin formulated to treat anemia in kidney dialysis patients
bull The gene responsible for Gaucherrsquos disease a lipid storage disease wherein the gene is used to make the missing protein that is administered to children and that cures an otherwise incurable and fatal disease
The current answer is that none of them are patent‐eligible per se (although there may be ways to claim them that could pass eligibility muster that remains to be seen) Judge Sweet the US District Court judge who first ruled that isolated DNA was not patent‐eligible did so using language carefully crafted to avoid encompassing all natural products into his decision Specifically Judge Sweet distinguished isolated DNA as the ldquophysical embodiments of genetic informationrdquo a property limited to DNA and not shared by other natural products (While an enzymatic protein could be characterized as the physical embodiment of catalysis of a particular chemical reaction that formulation has much less appeal and inherent rationale than Judge Sweetrsquos regarding DNA) Instead of this careful formu-lation the broader language employed by the Supreme Court as well as the broader rationale the Court used in finding genomic DNA unpatentable has made it easier to employ that fractured logic to render patent‐ineligible naturally occurring molecules other than DNA
I would be remiss not to mention the rather comical (but persistent) efforts of former Acting Solicitor General Neal Katyal who included in the
xx Foreword
US Governmentrsquos amicus brief to the Federal Circuit the distinction engine he called a ldquomagic microscoperdquo embodying the concept that if you are able to visualize a natural product (like a genomic DNA molecule) using this mythical microscope then the natural product would not be patent‐eligible whereas if you could not (eg a cDNA molecule) then the natural product could be eligible for patenting Fortunately the disdain with which the Federal Circuit greeted this fantasy (particularly from Judge Moore) prompted its quick abandonment as are argumentative distinction as the case moved forward Nonetheless both the courts and the US Patent and Trademark Office have adopted this standard de facto even as it becomes the theory that dare not speak its name in legal circles
The philosophical point here is that these substances and natural products generally have been deemed patent‐ineligible categorically which while consistent with (and perhaps even mandated by) the deon-tological approach imposes a distinction that cannot be flexibly applied to the individual circumstances Without such flexibility the law is con-strained to use one criterion that the substance can be found in some form in nature to decide patent eligibility instead of making the deter-mination of whether permitting patenting exclusivity satisfies the cri-teria that the invention ldquopromotes progressrdquo as the US Constitution requires and has a benefit to the public that outweighs any categorical disabilities
The potential that using this standard for determining patent eligibility will result in negative practical outcomes that no one in this debate desires is illustrated by a 2012 Report from the National Institutes of Health Natural Product Branch regarding statistics relating to the number of FDA approvals (a total of 1355) for new drugs falling into the following categories
Drug typesource Number
Biological (B) 203Natural product (N) 55Natural product (botanical) (NB) 149Derived from a natural product (ND) 298Totally synthetic (S) 393Total synthesisnatural product (S) 176Vaccine (S) 81
Foreword xxi
These statistics illustrate the consequences of a general ban on patenting naturally derived products of the 1355 drugs approved between 1981 and 2010
bull Fifty percent of all small‐molecule drugs approved between 2000 and 2010 are natural products
bull About 75 of antibacterial drugs are natural products or derived from natural products
bull Almost 80 of small‐molecule anticancer drugs were natural products or derivatives
In addition only 15 of drugs approved during this time frame were so‐called biologic drugs which are also putatively patent‐ineligible This the problems caused by the current interpretation of the law excluding natural product drugs from patent eligibility will be exacerbated in view of reports from every study showing that the percentage of drugs that are biologic drugs has been growing and will be the predominant type of drug devel-oped in the 2011ndash2030 time period
Another ldquothought experimentrdquo illustrating the practical illogic (David can provide his philosophical justifications in the body of the text) of broad natural products patent ineligibility is as follows Suppose a researcher finds a molecule produced by the human body that causes blood pressure homeo-stasis that is lack of this molecule causes or contributes to the disease of high blood pressure The logical consequence of the current natural prod-uct patent ineligibility standards would be that the closer a drug molecule is to the structure of the molecule as it occurs in the body the less patent‐eli-gible it would be Practically speaking there would be no incentive to modify the molecule to confer patent eligibility on the altered molecule because of the unpredictability of such changes on the molecule such as its biological activity half‐life stability antigenicity or other biological prop-erties And there would be even less incentive to develop the molecule as a drug because without patent protection the available regulatory exclusiv-ities would not pass economic muster to sufficiently defray the large development costs (some of which prevent drugs neither safe nor effica-cious from being sold and thus provide their own justification)
There is one further pernicious outcome that can be predicted to arise from a ban on natural products patents (including patents on isolated DNA and genetic diagnostic methods based on such isolated DNA) Natural
xxii Foreword
products are almost by nature complex and an ldquoactive principlerdquo isolated from nature is beneficial because it is isolated Kodak ran an advertisement in the journal Nature in the 1970s showing a scientist in a lab coat holding a 250‐ml flask and standing next to several bushels of green peppers wherein the content of the flask was the purified ldquoessence of green pepperrdquo equivalent to that substance contained in all the peppers in all the bushels and bushels that the scientist was standing beside But this very complexity makes it possible for the ldquoactive principlerdquo (either as a chemical compound or as a diagnostic genetic sequence) to be ldquohidden in plain sightrdquo in ways that may be particularly refractory to reverse engineering
For example even using somewhat dated ldquogene chiprdquo technology genetically diagnostic markers could be encrypted onto a microchip comprising 10 000 unique sequences wherein a computer‐readable bar code would be used to identify the positions of diagnostically relevant sequences on the chip This form of encryption which can be random and confounded by the presence of positive and negative control sequences as well as variable numbers and lengths of sequences specific for the gene (or more likely genes) of interest would be very difficult if not impossible to reverse‐engineer Even if reverse engineering could be done it would be difficult and expensive to undertake and thus make it more likely that the innovator would be able to avoid com-petition (ie it would provide unlimited exclusivity to its purveyor not con-strained by patent term or burdened by the requirement that the invention be disclosed with the specificity required by the Patent Act) While the possi-bility that this type of chip could be made exists with or without patents the absence of patent protection could tip the scales in favor of the extra effort needed and risk entailed in nondisclosure if the reward of extended ldquomonopolyrdquo is great enough But particularly for genetic diagnostic inven-tions the benefits of developing a proprietary database for which a corpora-tion could provide the economic and marketing wherewithal to expeditiously produce would result in a ldquoworst of both worldsrdquo outcome unlimited exclu-sivity based on undisclosed proprietary information that not only is difficult to replicate but whose existence would inhibit competition After all if a company had such a database its outcome for any particular patientrsquos test would be more accurate (and might identify disease riskndashassociated genetic variants not available elsewhere) and this would provide little incentive for a physician to choose an alternative provider to perform the test (and even more malevolently could create a system where the wealthy could afford the best diagnostic testing while the less affluent would be restricted to the more
Foreword xxiii
limited assays offered by companies without access to the ldquoinnovatorrsquosrdquo proprietary database information)
The other aspect of foreclosing patents for certain substances or technology areas categorically is that it upsets a carefully crafted dynamic that has worked extremely well during the biotech era between ldquotruerdquo innovators (typically university professors or small start‐up biotechnology companies) and more established companies capable of commercializing innovation Pundits who worry that permitting patenting will harm innovation miss an important point innovation will happen particularly in universities research institutes and like places because human nature demands it and regardless of whether patent protection is available The intelligent ape in us wants to know and the disparity between how univer-sity professors and patent lawyers are paid should establish how powerful the need to know can be Patenting and the impetus for patenting provided for example by the BayhndashDole Act in the United States prevents the fruits of these inventive efforts from mere predation by commercial concerns The benefits that can be had from a system where private commercializa-tion is encouraged are tempered by the types of corporate shenanigans that raise cogent criticisms of the system But perhaps it is mere human nature that people (in the corporate as well as individual sense) will want to expro-priate technology rather than pay for it and patenting prohibits (or at least retards) this outcome (if not these tendencies) Thus paradoxically limiting patent rights does not free innovation but rather makes it more likely to be kept captive by the entities capable of using such innovation to make a commercial product that is not from the power of building a better mouse-trap but by being able to outcompete smaller innovators merely by their greater economic prowess and resources Conversely patents provide a way for the innovators to protect their innovations and compel corporations to license their inventions producing revenue that can be used to fund future research endeavors This useful cycle has resulted in the successes of the biotechnology era and is something that we abandon at our peril
Thus in my view patents are a useful tool for achieving these societally ben-eficial goals promoting innovation and commercialization and protecting and supporting individuals who use the patent system to protect the products of their labors from being expropriated by others David provides a cogent and honest counterpoint to these thoughts Enjoy reading them
Kevin E NoonanChicago Illinois 2014
xviii Foreword
Appalachia or the Four Corners region in the Southwest or more generally in rural or other relatively remote locations Would Yale University for example have had any incentive to provide access to the BRCA tests to these women in these far‐off locations Or to provide genetic counseling where the women lived Or to lobby state Medicare administrators or private insurance commissioners to cover the test I think that unlikely Myriad Genetics did all of this as well as perform outreach to the obstetrics and gynecology doctors throughout the United States so that these primary care doctors were aware of the tests Myriad did not ace from altruism but as part of their business plan in order to expand the number of patients who received the test and thus maximize the companyrsquos revenue While it may be counterintuitive to some these circumstances may have been the most effective way not only to pro-mulgate the BRCA tests but also to facilitate acceptance of genetic diagnostic testing for other diseases showing that in this instance Adam Smith rather than Karl Marx provided the most practical solution to the problem of estab-lishing genetic diagnostic testing as a recognized component of a physicianrsquos diagnostic armamentarium
Fortunately the significance and impact of recent US court decisions (spe-cifically the Myriad case) is much less than it would have been ten to thirty years ago Due to patent term rules most patents (and applications) on iso-lated DNA filed in the heyday of the Human Genome Project (approxi-mately 1998ndash2001) are near the end of their actual or potential term indeed a recent study shows that the number of granted patents having at least one claim reciting an isolate DNA comprising a gene peaked in 1999 and has been dropping since 2005 (Graff et al 2013 ldquoNot quite a myriad of gene pat-entsrdquo Nature Biotechnology 31 404ndash410)) These recent decisions in the United States have not harmed the biotechnology industry because they retained patent eligibility for species of DNA that show evidence of the ldquohand of manrdquo and do not occur in nature These include enzymatically pro-duced copies (cDNA) of cellular messenger RNA and should also encom-pass the tools of the recombinant geneticist (eg including recombinant vectors for cloning and expressing genes in heterologous cells) Most impor-tantly the US Supreme Court did not overturn its Diamond v Chakrabarty decision wherein recombinant cells were determined to be patent eligible
Thus in many ways the question of patent eligibility for human genes is a philosophical one However that does not mean that how we think about patent eligibility for isolated DNA is irrelevant to important questions regarding the usefulness of patents for promoting progress and innovation
Foreword xix
Indeed the most pernicious effects of the current trend in the zeitgeist against patenting has been not that genes have become harder to patent but rather that the ability to patent other natural products has been called into question It is the extension of these recent decisions on isolated DNA to all natural products that poses the greatest threat to innovation This threat can be illustrated by a thought experiment for which of these substances should patent protection be withheld
bull A petrochemical with excellent lubrication qualities isolated in pure form and used as improved motor oil
bull Vitamin B12 isolated from beef muscle formulated into a medicament used to cure anemia in children
bull The drug penicillin isolated from a mixture of naturally produced chemicals made by a mold and formulated as a drug to cure syphilis (which is otherwise eventually fatal)
bull Human urinary erythropoietin formulated to treat anemia in kidney dialysis patients
bull The gene responsible for Gaucherrsquos disease a lipid storage disease wherein the gene is used to make the missing protein that is administered to children and that cures an otherwise incurable and fatal disease
The current answer is that none of them are patent‐eligible per se (although there may be ways to claim them that could pass eligibility muster that remains to be seen) Judge Sweet the US District Court judge who first ruled that isolated DNA was not patent‐eligible did so using language carefully crafted to avoid encompassing all natural products into his decision Specifically Judge Sweet distinguished isolated DNA as the ldquophysical embodiments of genetic informationrdquo a property limited to DNA and not shared by other natural products (While an enzymatic protein could be characterized as the physical embodiment of catalysis of a particular chemical reaction that formulation has much less appeal and inherent rationale than Judge Sweetrsquos regarding DNA) Instead of this careful formu-lation the broader language employed by the Supreme Court as well as the broader rationale the Court used in finding genomic DNA unpatentable has made it easier to employ that fractured logic to render patent‐ineligible naturally occurring molecules other than DNA
I would be remiss not to mention the rather comical (but persistent) efforts of former Acting Solicitor General Neal Katyal who included in the
xx Foreword
US Governmentrsquos amicus brief to the Federal Circuit the distinction engine he called a ldquomagic microscoperdquo embodying the concept that if you are able to visualize a natural product (like a genomic DNA molecule) using this mythical microscope then the natural product would not be patent‐eligible whereas if you could not (eg a cDNA molecule) then the natural product could be eligible for patenting Fortunately the disdain with which the Federal Circuit greeted this fantasy (particularly from Judge Moore) prompted its quick abandonment as are argumentative distinction as the case moved forward Nonetheless both the courts and the US Patent and Trademark Office have adopted this standard de facto even as it becomes the theory that dare not speak its name in legal circles
The philosophical point here is that these substances and natural products generally have been deemed patent‐ineligible categorically which while consistent with (and perhaps even mandated by) the deon-tological approach imposes a distinction that cannot be flexibly applied to the individual circumstances Without such flexibility the law is con-strained to use one criterion that the substance can be found in some form in nature to decide patent eligibility instead of making the deter-mination of whether permitting patenting exclusivity satisfies the cri-teria that the invention ldquopromotes progressrdquo as the US Constitution requires and has a benefit to the public that outweighs any categorical disabilities
The potential that using this standard for determining patent eligibility will result in negative practical outcomes that no one in this debate desires is illustrated by a 2012 Report from the National Institutes of Health Natural Product Branch regarding statistics relating to the number of FDA approvals (a total of 1355) for new drugs falling into the following categories
Drug typesource Number
Biological (B) 203Natural product (N) 55Natural product (botanical) (NB) 149Derived from a natural product (ND) 298Totally synthetic (S) 393Total synthesisnatural product (S) 176Vaccine (S) 81
Foreword xxi
These statistics illustrate the consequences of a general ban on patenting naturally derived products of the 1355 drugs approved between 1981 and 2010
bull Fifty percent of all small‐molecule drugs approved between 2000 and 2010 are natural products
bull About 75 of antibacterial drugs are natural products or derived from natural products
bull Almost 80 of small‐molecule anticancer drugs were natural products or derivatives
In addition only 15 of drugs approved during this time frame were so‐called biologic drugs which are also putatively patent‐ineligible This the problems caused by the current interpretation of the law excluding natural product drugs from patent eligibility will be exacerbated in view of reports from every study showing that the percentage of drugs that are biologic drugs has been growing and will be the predominant type of drug devel-oped in the 2011ndash2030 time period
Another ldquothought experimentrdquo illustrating the practical illogic (David can provide his philosophical justifications in the body of the text) of broad natural products patent ineligibility is as follows Suppose a researcher finds a molecule produced by the human body that causes blood pressure homeo-stasis that is lack of this molecule causes or contributes to the disease of high blood pressure The logical consequence of the current natural prod-uct patent ineligibility standards would be that the closer a drug molecule is to the structure of the molecule as it occurs in the body the less patent‐eli-gible it would be Practically speaking there would be no incentive to modify the molecule to confer patent eligibility on the altered molecule because of the unpredictability of such changes on the molecule such as its biological activity half‐life stability antigenicity or other biological prop-erties And there would be even less incentive to develop the molecule as a drug because without patent protection the available regulatory exclusiv-ities would not pass economic muster to sufficiently defray the large development costs (some of which prevent drugs neither safe nor effica-cious from being sold and thus provide their own justification)
There is one further pernicious outcome that can be predicted to arise from a ban on natural products patents (including patents on isolated DNA and genetic diagnostic methods based on such isolated DNA) Natural
xxii Foreword
products are almost by nature complex and an ldquoactive principlerdquo isolated from nature is beneficial because it is isolated Kodak ran an advertisement in the journal Nature in the 1970s showing a scientist in a lab coat holding a 250‐ml flask and standing next to several bushels of green peppers wherein the content of the flask was the purified ldquoessence of green pepperrdquo equivalent to that substance contained in all the peppers in all the bushels and bushels that the scientist was standing beside But this very complexity makes it possible for the ldquoactive principlerdquo (either as a chemical compound or as a diagnostic genetic sequence) to be ldquohidden in plain sightrdquo in ways that may be particularly refractory to reverse engineering
For example even using somewhat dated ldquogene chiprdquo technology genetically diagnostic markers could be encrypted onto a microchip comprising 10 000 unique sequences wherein a computer‐readable bar code would be used to identify the positions of diagnostically relevant sequences on the chip This form of encryption which can be random and confounded by the presence of positive and negative control sequences as well as variable numbers and lengths of sequences specific for the gene (or more likely genes) of interest would be very difficult if not impossible to reverse‐engineer Even if reverse engineering could be done it would be difficult and expensive to undertake and thus make it more likely that the innovator would be able to avoid com-petition (ie it would provide unlimited exclusivity to its purveyor not con-strained by patent term or burdened by the requirement that the invention be disclosed with the specificity required by the Patent Act) While the possi-bility that this type of chip could be made exists with or without patents the absence of patent protection could tip the scales in favor of the extra effort needed and risk entailed in nondisclosure if the reward of extended ldquomonopolyrdquo is great enough But particularly for genetic diagnostic inven-tions the benefits of developing a proprietary database for which a corpora-tion could provide the economic and marketing wherewithal to expeditiously produce would result in a ldquoworst of both worldsrdquo outcome unlimited exclu-sivity based on undisclosed proprietary information that not only is difficult to replicate but whose existence would inhibit competition After all if a company had such a database its outcome for any particular patientrsquos test would be more accurate (and might identify disease riskndashassociated genetic variants not available elsewhere) and this would provide little incentive for a physician to choose an alternative provider to perform the test (and even more malevolently could create a system where the wealthy could afford the best diagnostic testing while the less affluent would be restricted to the more
Foreword xxiii
limited assays offered by companies without access to the ldquoinnovatorrsquosrdquo proprietary database information)
The other aspect of foreclosing patents for certain substances or technology areas categorically is that it upsets a carefully crafted dynamic that has worked extremely well during the biotech era between ldquotruerdquo innovators (typically university professors or small start‐up biotechnology companies) and more established companies capable of commercializing innovation Pundits who worry that permitting patenting will harm innovation miss an important point innovation will happen particularly in universities research institutes and like places because human nature demands it and regardless of whether patent protection is available The intelligent ape in us wants to know and the disparity between how univer-sity professors and patent lawyers are paid should establish how powerful the need to know can be Patenting and the impetus for patenting provided for example by the BayhndashDole Act in the United States prevents the fruits of these inventive efforts from mere predation by commercial concerns The benefits that can be had from a system where private commercializa-tion is encouraged are tempered by the types of corporate shenanigans that raise cogent criticisms of the system But perhaps it is mere human nature that people (in the corporate as well as individual sense) will want to expro-priate technology rather than pay for it and patenting prohibits (or at least retards) this outcome (if not these tendencies) Thus paradoxically limiting patent rights does not free innovation but rather makes it more likely to be kept captive by the entities capable of using such innovation to make a commercial product that is not from the power of building a better mouse-trap but by being able to outcompete smaller innovators merely by their greater economic prowess and resources Conversely patents provide a way for the innovators to protect their innovations and compel corporations to license their inventions producing revenue that can be used to fund future research endeavors This useful cycle has resulted in the successes of the biotechnology era and is something that we abandon at our peril
Thus in my view patents are a useful tool for achieving these societally ben-eficial goals promoting innovation and commercialization and protecting and supporting individuals who use the patent system to protect the products of their labors from being expropriated by others David provides a cogent and honest counterpoint to these thoughts Enjoy reading them
Kevin E NoonanChicago Illinois 2014
Foreword xix
Indeed the most pernicious effects of the current trend in the zeitgeist against patenting has been not that genes have become harder to patent but rather that the ability to patent other natural products has been called into question It is the extension of these recent decisions on isolated DNA to all natural products that poses the greatest threat to innovation This threat can be illustrated by a thought experiment for which of these substances should patent protection be withheld
bull A petrochemical with excellent lubrication qualities isolated in pure form and used as improved motor oil
bull Vitamin B12 isolated from beef muscle formulated into a medicament used to cure anemia in children
bull The drug penicillin isolated from a mixture of naturally produced chemicals made by a mold and formulated as a drug to cure syphilis (which is otherwise eventually fatal)
bull Human urinary erythropoietin formulated to treat anemia in kidney dialysis patients
bull The gene responsible for Gaucherrsquos disease a lipid storage disease wherein the gene is used to make the missing protein that is administered to children and that cures an otherwise incurable and fatal disease
The current answer is that none of them are patent‐eligible per se (although there may be ways to claim them that could pass eligibility muster that remains to be seen) Judge Sweet the US District Court judge who first ruled that isolated DNA was not patent‐eligible did so using language carefully crafted to avoid encompassing all natural products into his decision Specifically Judge Sweet distinguished isolated DNA as the ldquophysical embodiments of genetic informationrdquo a property limited to DNA and not shared by other natural products (While an enzymatic protein could be characterized as the physical embodiment of catalysis of a particular chemical reaction that formulation has much less appeal and inherent rationale than Judge Sweetrsquos regarding DNA) Instead of this careful formu-lation the broader language employed by the Supreme Court as well as the broader rationale the Court used in finding genomic DNA unpatentable has made it easier to employ that fractured logic to render patent‐ineligible naturally occurring molecules other than DNA
I would be remiss not to mention the rather comical (but persistent) efforts of former Acting Solicitor General Neal Katyal who included in the
xx Foreword
US Governmentrsquos amicus brief to the Federal Circuit the distinction engine he called a ldquomagic microscoperdquo embodying the concept that if you are able to visualize a natural product (like a genomic DNA molecule) using this mythical microscope then the natural product would not be patent‐eligible whereas if you could not (eg a cDNA molecule) then the natural product could be eligible for patenting Fortunately the disdain with which the Federal Circuit greeted this fantasy (particularly from Judge Moore) prompted its quick abandonment as are argumentative distinction as the case moved forward Nonetheless both the courts and the US Patent and Trademark Office have adopted this standard de facto even as it becomes the theory that dare not speak its name in legal circles
The philosophical point here is that these substances and natural products generally have been deemed patent‐ineligible categorically which while consistent with (and perhaps even mandated by) the deon-tological approach imposes a distinction that cannot be flexibly applied to the individual circumstances Without such flexibility the law is con-strained to use one criterion that the substance can be found in some form in nature to decide patent eligibility instead of making the deter-mination of whether permitting patenting exclusivity satisfies the cri-teria that the invention ldquopromotes progressrdquo as the US Constitution requires and has a benefit to the public that outweighs any categorical disabilities
The potential that using this standard for determining patent eligibility will result in negative practical outcomes that no one in this debate desires is illustrated by a 2012 Report from the National Institutes of Health Natural Product Branch regarding statistics relating to the number of FDA approvals (a total of 1355) for new drugs falling into the following categories
Drug typesource Number
Biological (B) 203Natural product (N) 55Natural product (botanical) (NB) 149Derived from a natural product (ND) 298Totally synthetic (S) 393Total synthesisnatural product (S) 176Vaccine (S) 81
Foreword xxi
These statistics illustrate the consequences of a general ban on patenting naturally derived products of the 1355 drugs approved between 1981 and 2010
bull Fifty percent of all small‐molecule drugs approved between 2000 and 2010 are natural products
bull About 75 of antibacterial drugs are natural products or derived from natural products
bull Almost 80 of small‐molecule anticancer drugs were natural products or derivatives
In addition only 15 of drugs approved during this time frame were so‐called biologic drugs which are also putatively patent‐ineligible This the problems caused by the current interpretation of the law excluding natural product drugs from patent eligibility will be exacerbated in view of reports from every study showing that the percentage of drugs that are biologic drugs has been growing and will be the predominant type of drug devel-oped in the 2011ndash2030 time period
Another ldquothought experimentrdquo illustrating the practical illogic (David can provide his philosophical justifications in the body of the text) of broad natural products patent ineligibility is as follows Suppose a researcher finds a molecule produced by the human body that causes blood pressure homeo-stasis that is lack of this molecule causes or contributes to the disease of high blood pressure The logical consequence of the current natural prod-uct patent ineligibility standards would be that the closer a drug molecule is to the structure of the molecule as it occurs in the body the less patent‐eli-gible it would be Practically speaking there would be no incentive to modify the molecule to confer patent eligibility on the altered molecule because of the unpredictability of such changes on the molecule such as its biological activity half‐life stability antigenicity or other biological prop-erties And there would be even less incentive to develop the molecule as a drug because without patent protection the available regulatory exclusiv-ities would not pass economic muster to sufficiently defray the large development costs (some of which prevent drugs neither safe nor effica-cious from being sold and thus provide their own justification)
There is one further pernicious outcome that can be predicted to arise from a ban on natural products patents (including patents on isolated DNA and genetic diagnostic methods based on such isolated DNA) Natural
xxii Foreword
products are almost by nature complex and an ldquoactive principlerdquo isolated from nature is beneficial because it is isolated Kodak ran an advertisement in the journal Nature in the 1970s showing a scientist in a lab coat holding a 250‐ml flask and standing next to several bushels of green peppers wherein the content of the flask was the purified ldquoessence of green pepperrdquo equivalent to that substance contained in all the peppers in all the bushels and bushels that the scientist was standing beside But this very complexity makes it possible for the ldquoactive principlerdquo (either as a chemical compound or as a diagnostic genetic sequence) to be ldquohidden in plain sightrdquo in ways that may be particularly refractory to reverse engineering
For example even using somewhat dated ldquogene chiprdquo technology genetically diagnostic markers could be encrypted onto a microchip comprising 10 000 unique sequences wherein a computer‐readable bar code would be used to identify the positions of diagnostically relevant sequences on the chip This form of encryption which can be random and confounded by the presence of positive and negative control sequences as well as variable numbers and lengths of sequences specific for the gene (or more likely genes) of interest would be very difficult if not impossible to reverse‐engineer Even if reverse engineering could be done it would be difficult and expensive to undertake and thus make it more likely that the innovator would be able to avoid com-petition (ie it would provide unlimited exclusivity to its purveyor not con-strained by patent term or burdened by the requirement that the invention be disclosed with the specificity required by the Patent Act) While the possi-bility that this type of chip could be made exists with or without patents the absence of patent protection could tip the scales in favor of the extra effort needed and risk entailed in nondisclosure if the reward of extended ldquomonopolyrdquo is great enough But particularly for genetic diagnostic inven-tions the benefits of developing a proprietary database for which a corpora-tion could provide the economic and marketing wherewithal to expeditiously produce would result in a ldquoworst of both worldsrdquo outcome unlimited exclu-sivity based on undisclosed proprietary information that not only is difficult to replicate but whose existence would inhibit competition After all if a company had such a database its outcome for any particular patientrsquos test would be more accurate (and might identify disease riskndashassociated genetic variants not available elsewhere) and this would provide little incentive for a physician to choose an alternative provider to perform the test (and even more malevolently could create a system where the wealthy could afford the best diagnostic testing while the less affluent would be restricted to the more
Foreword xxiii
limited assays offered by companies without access to the ldquoinnovatorrsquosrdquo proprietary database information)
The other aspect of foreclosing patents for certain substances or technology areas categorically is that it upsets a carefully crafted dynamic that has worked extremely well during the biotech era between ldquotruerdquo innovators (typically university professors or small start‐up biotechnology companies) and more established companies capable of commercializing innovation Pundits who worry that permitting patenting will harm innovation miss an important point innovation will happen particularly in universities research institutes and like places because human nature demands it and regardless of whether patent protection is available The intelligent ape in us wants to know and the disparity between how univer-sity professors and patent lawyers are paid should establish how powerful the need to know can be Patenting and the impetus for patenting provided for example by the BayhndashDole Act in the United States prevents the fruits of these inventive efforts from mere predation by commercial concerns The benefits that can be had from a system where private commercializa-tion is encouraged are tempered by the types of corporate shenanigans that raise cogent criticisms of the system But perhaps it is mere human nature that people (in the corporate as well as individual sense) will want to expro-priate technology rather than pay for it and patenting prohibits (or at least retards) this outcome (if not these tendencies) Thus paradoxically limiting patent rights does not free innovation but rather makes it more likely to be kept captive by the entities capable of using such innovation to make a commercial product that is not from the power of building a better mouse-trap but by being able to outcompete smaller innovators merely by their greater economic prowess and resources Conversely patents provide a way for the innovators to protect their innovations and compel corporations to license their inventions producing revenue that can be used to fund future research endeavors This useful cycle has resulted in the successes of the biotechnology era and is something that we abandon at our peril
Thus in my view patents are a useful tool for achieving these societally ben-eficial goals promoting innovation and commercialization and protecting and supporting individuals who use the patent system to protect the products of their labors from being expropriated by others David provides a cogent and honest counterpoint to these thoughts Enjoy reading them
Kevin E NoonanChicago Illinois 2014
xx Foreword
US Governmentrsquos amicus brief to the Federal Circuit the distinction engine he called a ldquomagic microscoperdquo embodying the concept that if you are able to visualize a natural product (like a genomic DNA molecule) using this mythical microscope then the natural product would not be patent‐eligible whereas if you could not (eg a cDNA molecule) then the natural product could be eligible for patenting Fortunately the disdain with which the Federal Circuit greeted this fantasy (particularly from Judge Moore) prompted its quick abandonment as are argumentative distinction as the case moved forward Nonetheless both the courts and the US Patent and Trademark Office have adopted this standard de facto even as it becomes the theory that dare not speak its name in legal circles
The philosophical point here is that these substances and natural products generally have been deemed patent‐ineligible categorically which while consistent with (and perhaps even mandated by) the deon-tological approach imposes a distinction that cannot be flexibly applied to the individual circumstances Without such flexibility the law is con-strained to use one criterion that the substance can be found in some form in nature to decide patent eligibility instead of making the deter-mination of whether permitting patenting exclusivity satisfies the cri-teria that the invention ldquopromotes progressrdquo as the US Constitution requires and has a benefit to the public that outweighs any categorical disabilities
The potential that using this standard for determining patent eligibility will result in negative practical outcomes that no one in this debate desires is illustrated by a 2012 Report from the National Institutes of Health Natural Product Branch regarding statistics relating to the number of FDA approvals (a total of 1355) for new drugs falling into the following categories
Drug typesource Number
Biological (B) 203Natural product (N) 55Natural product (botanical) (NB) 149Derived from a natural product (ND) 298Totally synthetic (S) 393Total synthesisnatural product (S) 176Vaccine (S) 81
Foreword xxi
These statistics illustrate the consequences of a general ban on patenting naturally derived products of the 1355 drugs approved between 1981 and 2010
bull Fifty percent of all small‐molecule drugs approved between 2000 and 2010 are natural products
bull About 75 of antibacterial drugs are natural products or derived from natural products
bull Almost 80 of small‐molecule anticancer drugs were natural products or derivatives
In addition only 15 of drugs approved during this time frame were so‐called biologic drugs which are also putatively patent‐ineligible This the problems caused by the current interpretation of the law excluding natural product drugs from patent eligibility will be exacerbated in view of reports from every study showing that the percentage of drugs that are biologic drugs has been growing and will be the predominant type of drug devel-oped in the 2011ndash2030 time period
Another ldquothought experimentrdquo illustrating the practical illogic (David can provide his philosophical justifications in the body of the text) of broad natural products patent ineligibility is as follows Suppose a researcher finds a molecule produced by the human body that causes blood pressure homeo-stasis that is lack of this molecule causes or contributes to the disease of high blood pressure The logical consequence of the current natural prod-uct patent ineligibility standards would be that the closer a drug molecule is to the structure of the molecule as it occurs in the body the less patent‐eli-gible it would be Practically speaking there would be no incentive to modify the molecule to confer patent eligibility on the altered molecule because of the unpredictability of such changes on the molecule such as its biological activity half‐life stability antigenicity or other biological prop-erties And there would be even less incentive to develop the molecule as a drug because without patent protection the available regulatory exclusiv-ities would not pass economic muster to sufficiently defray the large development costs (some of which prevent drugs neither safe nor effica-cious from being sold and thus provide their own justification)
There is one further pernicious outcome that can be predicted to arise from a ban on natural products patents (including patents on isolated DNA and genetic diagnostic methods based on such isolated DNA) Natural
xxii Foreword
products are almost by nature complex and an ldquoactive principlerdquo isolated from nature is beneficial because it is isolated Kodak ran an advertisement in the journal Nature in the 1970s showing a scientist in a lab coat holding a 250‐ml flask and standing next to several bushels of green peppers wherein the content of the flask was the purified ldquoessence of green pepperrdquo equivalent to that substance contained in all the peppers in all the bushels and bushels that the scientist was standing beside But this very complexity makes it possible for the ldquoactive principlerdquo (either as a chemical compound or as a diagnostic genetic sequence) to be ldquohidden in plain sightrdquo in ways that may be particularly refractory to reverse engineering
For example even using somewhat dated ldquogene chiprdquo technology genetically diagnostic markers could be encrypted onto a microchip comprising 10 000 unique sequences wherein a computer‐readable bar code would be used to identify the positions of diagnostically relevant sequences on the chip This form of encryption which can be random and confounded by the presence of positive and negative control sequences as well as variable numbers and lengths of sequences specific for the gene (or more likely genes) of interest would be very difficult if not impossible to reverse‐engineer Even if reverse engineering could be done it would be difficult and expensive to undertake and thus make it more likely that the innovator would be able to avoid com-petition (ie it would provide unlimited exclusivity to its purveyor not con-strained by patent term or burdened by the requirement that the invention be disclosed with the specificity required by the Patent Act) While the possi-bility that this type of chip could be made exists with or without patents the absence of patent protection could tip the scales in favor of the extra effort needed and risk entailed in nondisclosure if the reward of extended ldquomonopolyrdquo is great enough But particularly for genetic diagnostic inven-tions the benefits of developing a proprietary database for which a corpora-tion could provide the economic and marketing wherewithal to expeditiously produce would result in a ldquoworst of both worldsrdquo outcome unlimited exclu-sivity based on undisclosed proprietary information that not only is difficult to replicate but whose existence would inhibit competition After all if a company had such a database its outcome for any particular patientrsquos test would be more accurate (and might identify disease riskndashassociated genetic variants not available elsewhere) and this would provide little incentive for a physician to choose an alternative provider to perform the test (and even more malevolently could create a system where the wealthy could afford the best diagnostic testing while the less affluent would be restricted to the more
Foreword xxiii
limited assays offered by companies without access to the ldquoinnovatorrsquosrdquo proprietary database information)
The other aspect of foreclosing patents for certain substances or technology areas categorically is that it upsets a carefully crafted dynamic that has worked extremely well during the biotech era between ldquotruerdquo innovators (typically university professors or small start‐up biotechnology companies) and more established companies capable of commercializing innovation Pundits who worry that permitting patenting will harm innovation miss an important point innovation will happen particularly in universities research institutes and like places because human nature demands it and regardless of whether patent protection is available The intelligent ape in us wants to know and the disparity between how univer-sity professors and patent lawyers are paid should establish how powerful the need to know can be Patenting and the impetus for patenting provided for example by the BayhndashDole Act in the United States prevents the fruits of these inventive efforts from mere predation by commercial concerns The benefits that can be had from a system where private commercializa-tion is encouraged are tempered by the types of corporate shenanigans that raise cogent criticisms of the system But perhaps it is mere human nature that people (in the corporate as well as individual sense) will want to expro-priate technology rather than pay for it and patenting prohibits (or at least retards) this outcome (if not these tendencies) Thus paradoxically limiting patent rights does not free innovation but rather makes it more likely to be kept captive by the entities capable of using such innovation to make a commercial product that is not from the power of building a better mouse-trap but by being able to outcompete smaller innovators merely by their greater economic prowess and resources Conversely patents provide a way for the innovators to protect their innovations and compel corporations to license their inventions producing revenue that can be used to fund future research endeavors This useful cycle has resulted in the successes of the biotechnology era and is something that we abandon at our peril
Thus in my view patents are a useful tool for achieving these societally ben-eficial goals promoting innovation and commercialization and protecting and supporting individuals who use the patent system to protect the products of their labors from being expropriated by others David provides a cogent and honest counterpoint to these thoughts Enjoy reading them
Kevin E NoonanChicago Illinois 2014
Foreword xxi
These statistics illustrate the consequences of a general ban on patenting naturally derived products of the 1355 drugs approved between 1981 and 2010
bull Fifty percent of all small‐molecule drugs approved between 2000 and 2010 are natural products
bull About 75 of antibacterial drugs are natural products or derived from natural products
bull Almost 80 of small‐molecule anticancer drugs were natural products or derivatives
In addition only 15 of drugs approved during this time frame were so‐called biologic drugs which are also putatively patent‐ineligible This the problems caused by the current interpretation of the law excluding natural product drugs from patent eligibility will be exacerbated in view of reports from every study showing that the percentage of drugs that are biologic drugs has been growing and will be the predominant type of drug devel-oped in the 2011ndash2030 time period
Another ldquothought experimentrdquo illustrating the practical illogic (David can provide his philosophical justifications in the body of the text) of broad natural products patent ineligibility is as follows Suppose a researcher finds a molecule produced by the human body that causes blood pressure homeo-stasis that is lack of this molecule causes or contributes to the disease of high blood pressure The logical consequence of the current natural prod-uct patent ineligibility standards would be that the closer a drug molecule is to the structure of the molecule as it occurs in the body the less patent‐eli-gible it would be Practically speaking there would be no incentive to modify the molecule to confer patent eligibility on the altered molecule because of the unpredictability of such changes on the molecule such as its biological activity half‐life stability antigenicity or other biological prop-erties And there would be even less incentive to develop the molecule as a drug because without patent protection the available regulatory exclusiv-ities would not pass economic muster to sufficiently defray the large development costs (some of which prevent drugs neither safe nor effica-cious from being sold and thus provide their own justification)
There is one further pernicious outcome that can be predicted to arise from a ban on natural products patents (including patents on isolated DNA and genetic diagnostic methods based on such isolated DNA) Natural
xxii Foreword
products are almost by nature complex and an ldquoactive principlerdquo isolated from nature is beneficial because it is isolated Kodak ran an advertisement in the journal Nature in the 1970s showing a scientist in a lab coat holding a 250‐ml flask and standing next to several bushels of green peppers wherein the content of the flask was the purified ldquoessence of green pepperrdquo equivalent to that substance contained in all the peppers in all the bushels and bushels that the scientist was standing beside But this very complexity makes it possible for the ldquoactive principlerdquo (either as a chemical compound or as a diagnostic genetic sequence) to be ldquohidden in plain sightrdquo in ways that may be particularly refractory to reverse engineering
For example even using somewhat dated ldquogene chiprdquo technology genetically diagnostic markers could be encrypted onto a microchip comprising 10 000 unique sequences wherein a computer‐readable bar code would be used to identify the positions of diagnostically relevant sequences on the chip This form of encryption which can be random and confounded by the presence of positive and negative control sequences as well as variable numbers and lengths of sequences specific for the gene (or more likely genes) of interest would be very difficult if not impossible to reverse‐engineer Even if reverse engineering could be done it would be difficult and expensive to undertake and thus make it more likely that the innovator would be able to avoid com-petition (ie it would provide unlimited exclusivity to its purveyor not con-strained by patent term or burdened by the requirement that the invention be disclosed with the specificity required by the Patent Act) While the possi-bility that this type of chip could be made exists with or without patents the absence of patent protection could tip the scales in favor of the extra effort needed and risk entailed in nondisclosure if the reward of extended ldquomonopolyrdquo is great enough But particularly for genetic diagnostic inven-tions the benefits of developing a proprietary database for which a corpora-tion could provide the economic and marketing wherewithal to expeditiously produce would result in a ldquoworst of both worldsrdquo outcome unlimited exclu-sivity based on undisclosed proprietary information that not only is difficult to replicate but whose existence would inhibit competition After all if a company had such a database its outcome for any particular patientrsquos test would be more accurate (and might identify disease riskndashassociated genetic variants not available elsewhere) and this would provide little incentive for a physician to choose an alternative provider to perform the test (and even more malevolently could create a system where the wealthy could afford the best diagnostic testing while the less affluent would be restricted to the more
Foreword xxiii
limited assays offered by companies without access to the ldquoinnovatorrsquosrdquo proprietary database information)
The other aspect of foreclosing patents for certain substances or technology areas categorically is that it upsets a carefully crafted dynamic that has worked extremely well during the biotech era between ldquotruerdquo innovators (typically university professors or small start‐up biotechnology companies) and more established companies capable of commercializing innovation Pundits who worry that permitting patenting will harm innovation miss an important point innovation will happen particularly in universities research institutes and like places because human nature demands it and regardless of whether patent protection is available The intelligent ape in us wants to know and the disparity between how univer-sity professors and patent lawyers are paid should establish how powerful the need to know can be Patenting and the impetus for patenting provided for example by the BayhndashDole Act in the United States prevents the fruits of these inventive efforts from mere predation by commercial concerns The benefits that can be had from a system where private commercializa-tion is encouraged are tempered by the types of corporate shenanigans that raise cogent criticisms of the system But perhaps it is mere human nature that people (in the corporate as well as individual sense) will want to expro-priate technology rather than pay for it and patenting prohibits (or at least retards) this outcome (if not these tendencies) Thus paradoxically limiting patent rights does not free innovation but rather makes it more likely to be kept captive by the entities capable of using such innovation to make a commercial product that is not from the power of building a better mouse-trap but by being able to outcompete smaller innovators merely by their greater economic prowess and resources Conversely patents provide a way for the innovators to protect their innovations and compel corporations to license their inventions producing revenue that can be used to fund future research endeavors This useful cycle has resulted in the successes of the biotechnology era and is something that we abandon at our peril
Thus in my view patents are a useful tool for achieving these societally ben-eficial goals promoting innovation and commercialization and protecting and supporting individuals who use the patent system to protect the products of their labors from being expropriated by others David provides a cogent and honest counterpoint to these thoughts Enjoy reading them
Kevin E NoonanChicago Illinois 2014
xxii Foreword
products are almost by nature complex and an ldquoactive principlerdquo isolated from nature is beneficial because it is isolated Kodak ran an advertisement in the journal Nature in the 1970s showing a scientist in a lab coat holding a 250‐ml flask and standing next to several bushels of green peppers wherein the content of the flask was the purified ldquoessence of green pepperrdquo equivalent to that substance contained in all the peppers in all the bushels and bushels that the scientist was standing beside But this very complexity makes it possible for the ldquoactive principlerdquo (either as a chemical compound or as a diagnostic genetic sequence) to be ldquohidden in plain sightrdquo in ways that may be particularly refractory to reverse engineering
For example even using somewhat dated ldquogene chiprdquo technology genetically diagnostic markers could be encrypted onto a microchip comprising 10 000 unique sequences wherein a computer‐readable bar code would be used to identify the positions of diagnostically relevant sequences on the chip This form of encryption which can be random and confounded by the presence of positive and negative control sequences as well as variable numbers and lengths of sequences specific for the gene (or more likely genes) of interest would be very difficult if not impossible to reverse‐engineer Even if reverse engineering could be done it would be difficult and expensive to undertake and thus make it more likely that the innovator would be able to avoid com-petition (ie it would provide unlimited exclusivity to its purveyor not con-strained by patent term or burdened by the requirement that the invention be disclosed with the specificity required by the Patent Act) While the possi-bility that this type of chip could be made exists with or without patents the absence of patent protection could tip the scales in favor of the extra effort needed and risk entailed in nondisclosure if the reward of extended ldquomonopolyrdquo is great enough But particularly for genetic diagnostic inven-tions the benefits of developing a proprietary database for which a corpora-tion could provide the economic and marketing wherewithal to expeditiously produce would result in a ldquoworst of both worldsrdquo outcome unlimited exclu-sivity based on undisclosed proprietary information that not only is difficult to replicate but whose existence would inhibit competition After all if a company had such a database its outcome for any particular patientrsquos test would be more accurate (and might identify disease riskndashassociated genetic variants not available elsewhere) and this would provide little incentive for a physician to choose an alternative provider to perform the test (and even more malevolently could create a system where the wealthy could afford the best diagnostic testing while the less affluent would be restricted to the more
Foreword xxiii
limited assays offered by companies without access to the ldquoinnovatorrsquosrdquo proprietary database information)
The other aspect of foreclosing patents for certain substances or technology areas categorically is that it upsets a carefully crafted dynamic that has worked extremely well during the biotech era between ldquotruerdquo innovators (typically university professors or small start‐up biotechnology companies) and more established companies capable of commercializing innovation Pundits who worry that permitting patenting will harm innovation miss an important point innovation will happen particularly in universities research institutes and like places because human nature demands it and regardless of whether patent protection is available The intelligent ape in us wants to know and the disparity between how univer-sity professors and patent lawyers are paid should establish how powerful the need to know can be Patenting and the impetus for patenting provided for example by the BayhndashDole Act in the United States prevents the fruits of these inventive efforts from mere predation by commercial concerns The benefits that can be had from a system where private commercializa-tion is encouraged are tempered by the types of corporate shenanigans that raise cogent criticisms of the system But perhaps it is mere human nature that people (in the corporate as well as individual sense) will want to expro-priate technology rather than pay for it and patenting prohibits (or at least retards) this outcome (if not these tendencies) Thus paradoxically limiting patent rights does not free innovation but rather makes it more likely to be kept captive by the entities capable of using such innovation to make a commercial product that is not from the power of building a better mouse-trap but by being able to outcompete smaller innovators merely by their greater economic prowess and resources Conversely patents provide a way for the innovators to protect their innovations and compel corporations to license their inventions producing revenue that can be used to fund future research endeavors This useful cycle has resulted in the successes of the biotechnology era and is something that we abandon at our peril
Thus in my view patents are a useful tool for achieving these societally ben-eficial goals promoting innovation and commercialization and protecting and supporting individuals who use the patent system to protect the products of their labors from being expropriated by others David provides a cogent and honest counterpoint to these thoughts Enjoy reading them
Kevin E NoonanChicago Illinois 2014
Foreword xxiii
limited assays offered by companies without access to the ldquoinnovatorrsquosrdquo proprietary database information)
The other aspect of foreclosing patents for certain substances or technology areas categorically is that it upsets a carefully crafted dynamic that has worked extremely well during the biotech era between ldquotruerdquo innovators (typically university professors or small start‐up biotechnology companies) and more established companies capable of commercializing innovation Pundits who worry that permitting patenting will harm innovation miss an important point innovation will happen particularly in universities research institutes and like places because human nature demands it and regardless of whether patent protection is available The intelligent ape in us wants to know and the disparity between how univer-sity professors and patent lawyers are paid should establish how powerful the need to know can be Patenting and the impetus for patenting provided for example by the BayhndashDole Act in the United States prevents the fruits of these inventive efforts from mere predation by commercial concerns The benefits that can be had from a system where private commercializa-tion is encouraged are tempered by the types of corporate shenanigans that raise cogent criticisms of the system But perhaps it is mere human nature that people (in the corporate as well as individual sense) will want to expro-priate technology rather than pay for it and patenting prohibits (or at least retards) this outcome (if not these tendencies) Thus paradoxically limiting patent rights does not free innovation but rather makes it more likely to be kept captive by the entities capable of using such innovation to make a commercial product that is not from the power of building a better mouse-trap but by being able to outcompete smaller innovators merely by their greater economic prowess and resources Conversely patents provide a way for the innovators to protect their innovations and compel corporations to license their inventions producing revenue that can be used to fund future research endeavors This useful cycle has resulted in the successes of the biotechnology era and is something that we abandon at our peril
Thus in my view patents are a useful tool for achieving these societally ben-eficial goals promoting innovation and commercialization and protecting and supporting individuals who use the patent system to protect the products of their labors from being expropriated by others David provides a cogent and honest counterpoint to these thoughts Enjoy reading them
Kevin E NoonanChicago Illinois 2014
