SKGF_Presentation_The Role of Formulations in Biologics Patent Protection_08

transcript

Timothy J. Shea, Jr. � DirectorElizabeth Haanes - DirectorSterne, Kessler, Goldstein & Fox P.L.L.C.

IBC�s 8th Annual Conference on Formulation Strategies for Protein Therapeutics

Anaheim, CASeptember 24, 2008

The Role of Formulations in Biologics Patent Protection

Introduction

� Introduction of the concept of patent life cycle management

� Insights from the pharma industry

� Key patentability issues in patent life cycle management

� The role of formulations in biologics patent protection� Case Studies

� Erythropoietin

� Growth hormone

The Dilemma

� The cost to develop a drug or biologic and bring to market is hundreds of millions of $$$

� Patent protection for the basic NCE or protein is generally sought very early in the R&D process

� Due to the extensive regulatory review period, significant patent term has been lost by the time the product goes to market

Patent Life-Cycle Management

� Strategic use of patents to maintain product exclusivity and revenue stream over life of blockbuster drug or biologic

� Involves obtaining additional patents that extend protection beyond the original patents covering the NCE or biologic per se

Insights from the Pharma Industry

� Patent life-cycle management is a familiar concept for big pharma

� Hatch-Waxman Act

� Recognizes regulatory delay

� Allows innovator to extend patent term of single patent up to 5 years

� BUT, provides for generic entry immediatelyupon expiration of patent coverage

� Generics often seek to market upon expiration of original patent to NCE

Insights from Pharma Industry

� Pharma companies have countered generics by increasing the breadth and complexity of the patent �fence� around their crown jewels� �traditional� protection covered NCE, method of

making, method of using (treating), and a pharmaceutical formulation

� Today, patents are typically also filed on:� New indications

� Polymorphs

� Mechanisms of action

� Combination products/therapies

� Dosing regimens

� Dissolution/bio profiles

� NEW FORMULATIONS 0 very important

� Methods of stabilizing

Insights from Pharma Industry

� Novel formulations are extremely valuable to patent life cycle management

� Example: individual isomers are generally more potent than racemic mixtures

� Currently no formal legal/regulatory framework for approving generic biologics @ but it�s coming� pending legislation stalled pending election,

but demand for formal framework is great

Patentability Issues

� Term of a U.S. patent now extends 20 years from the earliest effective filing date

� Issue date is irrelevant

� To extend patent coverage on the drug or biologic, the second (improvement) patent must have a later filing date than the original patent to the product

� Thus, the original patent is often prior art to the later filed application

� To obtain an improvement patent, applicant must show claimed subject matter is novel, nonobvious, etc. over earlier patent to drug or biologic per se� Generally not difficult to show novelty

� But must be careful regarding inherent anticipation

� Focus is generally on obviousness

� KSR Int�l Co. v. Teleflex Inc., 550 U.S. ___(2007)� Supreme Court �clarified� obviousness

� Now easier for USPTO to establish prima facie case of obviousness and shift burden to applicant to prove otherwise

� KSR v. Teleflex

� Improvement must be more than predictable use of prior art elements

� Not limited to references dealing with precise problem addressed

� Any need or problem known in the field and addressed by patent can provide reason for combining elements

� �Obvious to try� could be enough in some instances

� In response to KSR case, USPTO established training guidelines for examiners

� Identified acceptable �rationales� to support prima facie case of obviousness:

A. Combining prior art elements according to known methods to yield predictable results

� USPTO �Rationales� for Obviousness� B. Simple substitution of one known, equivalent

element for another to obtain predictable results� E.g. one known excipient for another?

� C. Use of known technique to improve similar products in the same way

� Application of technique to similar product must be within ordinary skill in art

� D. Applying a known technique to a known product ready for improvement to yield predictable results

� E.g. lyophilization?

� E. �Obvious to try� � choosing from a finite number of predictable solutions

� Rebutting Obviousness Rejections� Submit technical evidence showing that subject

matter claimed in later (improvement) patent could not have been predicted to work

� Show that claimed subject matter (e.g. new formulation) has unexpected advantages (e.g., increased efficacy, stability, etc.)

� Clinical studies provide good opportunities for patenting improvements, since in vivo effect are difficult to predict

The Role of Formulations in Biologics

Patent Protection

� Although no formal legal/regulatory framework for approving generic biologics exists, biologic innovators are already applying patent life cycle management strategies to extend patent protection on blockbuster biologics

� As in the pharma industry, formulation patents are essential components of a patent life cycle management strategy for biologics

Case Study I � Erythropoietin (Amgen)

� U.S. Pat. No. 4,703,008� Effective filing date 12/13/83 (but 17-year term

from grant since pre-GATT)

� Claim 2: A purified and isolated DNA sequence consisting essentially of a DNA sequence

encoding human erythropoietin.

� U.S. Pat. No. 5,547,933� Effective filing date = 12/13/83 (17 year term)

� Claim 3. A non-naturally occurring erythropoietin glycoprotein product . . . having glycosylation

which differs from that of human urinary

erythropoietin.

� U.S. Pat. No. 5,597,562 � Effective filing date = 6/3/91 (17-year

� Claim 1: An oral dosage form

comprising the components:

(a) GCSF or erythropoietin;

(b) Surfactant(s)

(c) Fatty acid(s); and

(d) Enteric material,

wherein said components (a), (b) and (c) are mixed in liquid phase and lyophilized prior to combination with component (d).

Case Study I: Erythropoietin (Amgen)

� U.S. Pat. No. 5,856,298� Effective filing date = 10/13/89 (17-year

� Claim 1: An isolated biologically active

erythropoietin isoform having a single isoelectric point and having a specific number of sialic acids per molecule, said number selected from the group consisting of 1-14 . . . .

� U.S. Pat. No. 7,217,689� Effective filing date = 10/13/89 (17 year

� Claim 1: An analog of human

erythropoietin . . . comprising an amino acid sequence which differs from the amino acid sequence of human erythropoietin . . . by having one or more

additional glycosylation site(s) as compared to human erythropoietin.

� U.S. Pat. No. 5,661,125� Effective filing date = 08/06/92 (almost 9

years after first patent) (17-year term)

� Claim 1: A stable pharmaceutical

composition comprising a solution of a therapeutically effective amount of erythropoietin and a preservative selected from the group consisting of benzyl alcohol, a paraben and phenol or a mixture thereof.

� U.S. Pat. Pub. No. 2006/0264377� Effective filing date = 4/7/00 � If issues will expire 4/7/2020� Claim 1: A pharmaceutical composition

comprising:(a) A substantially homogenous preparation of mono-

PEGylated NESP, said mono-PEGylated NESP consisting of a polyethylene glycol moiety connected to a NESP moiety solely at the N-terminus thereof;

(b) Fewer than 5% non-pegylated NESP molecules; and

(c) A pharmaceutically acceptable diluent, adjuvant or carrier.

(NESP is a hyperglycosylated EPO analog having five changes in the amino acid sequence of rHuEPO which provide for two additional carbohydrate chains)

Case Study II: Growth Hormone (Novo)

� U.S. Pat. No. 5,633,352� Effective filing date = 12/9/83 (17-year term)

� Claim 1: Biosynthetic ripe human growth

hormone from pituitary derived human growth hormone.

� U.S. Pat. No. 5,547,696� Effective filing date = 10/13/94 (17-year term)

� Claim 1: A pharmaceutical formulation comprising

a growth hormone in the amount of about 0.1 mg/ml to about 40 mg/ml and valine at a concentration up to about 100 mM.

� U.S. Pat. No. 5,552,385� Effective filing date = 6/5/95

� Claim 1: A pharmaceutical formulation comprising a growth hormone and Lys-

Gly-Asp-Ser (SEQ ID No: 1).

� Claim 1: Divalent cation crystals of human

growth hormone (hGH) or derivatives thereof.

� Claim 1: A pharmaceutical composition in the form of a lyophilized powder comprising a growth hormone or a derivative thereof and histidine or histidine derivative . . . .

� Claim 1: A pharmaceutical formulation comprising a human growth hormone pretreated with zinc salt

for at least one hour before addition of other components to the formulation and optionally containing lysine or calcium ion.

� U.S. Pat. No. 6,566,329� Effective filing date = 06/28/99� Claim 1: A method for preparing a soluble freeze-

dried solid preparation of hGH . . . .

� U.S. Pat. Pub. No. 2006/0257479� Effective filing date = 10/8/04� If issues, patent will expire in 2024

� Claim 1: A sustained release formulationcomprising a protein modified so as to provide a reduced clearance, wherein said protein does not comprise a methionine in which the side chain sulphur has been modified.

� Claim 2: The formulation according to claim 1, wherein said protein is a growth hormone compound.

Conclusions

� Patent life-cycle management is the strategic use of patents to maintain product exclusivity and revenue stream over the life of a commercially valuable drug or biologic

� Successful companies will have fully integrated patent life-cycle and product life cycle programs

� Companies should consider strategic patenting both before and after marketing approval

� Formulation patents are particularly effective at extending exclusivity

� Effective patent life-cycle management requires careful attention to the timing of filings and the content of the application

The Role of Formulations in Biologics Patent Protection

Thank You

Timothy J. Shea, Jr.

Elizabeth Haanes

Sterne, Kessler, Goldstein & Fox, P.L.L.C.

(202) 772-8679

SKGF_Presentation_The Role of Formulations in Biologics Patent Protection_08

Technology