Initial consultation draft only · (small, interfering RNA) and antisense RNA directed to H5N1...

Initial consultation draft only

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ANNEX

Patent Landscape for the H5 virus

Interim Report

November 17, 2007 Background: context of this report 1. This Annex provides an update on work currently under way by WIPO in cooperation with the WHO to develop a patent review and landscape to support policymakers in undertaking avian flu pandemic planning, and in assessing patents and patent applications relevant to the flu virus and flu vaccine production. This patent landscaping work aims to contribute factual background to the working paper on patent issues related to influenza viruses and their genes which was prepared by WIPO as described in the WHO Director-General's Report on "Patent issues related to influenza viruses and their genes" (Document A/PIP/IGM/3). As this work is still under way, this update is strictly provisional in character. 2. International health policy is acutely concerned with strategies and methodologies for developing, producing and circulating vaccines for variants of the H5N1 influenza virus, not least because one scenario for a flu pandemic is the mutation of the H5N1 subtype into a form readily and sustainably transmissible between humans. 3. Patent activity in this area is intensive, and is growing rapidly. Yet lack of clear, comprehensive, user-friendly information about the current patenting activity in this field has consistently been identified as a difficulty for policymakers, and a constraint on fully informed public policy decisions. This is a matter of considerable concern for policymakers at all levels, and in many public health fora. There is accordingly a strong need for accessible technical background information that is relevant to current policy questions, and provides an up to date factual basis for the analysis of policy options.

State of play 4. Work on patent search and analysis currently continues intensively, the review and analysis process needs to be taken with care and with suitable peer review. This means that no general assessments are made at this stage. However, some preliminary observations can be offered, based on preliminary analysis1:

(i) By a very broad measure of relevance, potentially relevant patent activity is intensive and increasing sharply, with many of the relevant patent documents having been published very recently.

1 This draws on working drafts under preparation for WIPO by an expert team coordinated by PIIPA (Public Interest Intellectual Property Advisors), with general guidance and technical background provided by officials of WHO and WIPO (the commissioning agency); the initial findings set out here are not definitive nor final, and will require further review and more extensive search and analysis, and do not represent the views of the experts concerned. Equally, the views expressed do not represent the views of WIPO or the WHO, their Secretariats or their Member States. A revised analysis is being developed to replace this initial extract.


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- This means that any preliminary judgment needs to be tentative, despite the strong need identified for a clearer information base for policymaking: much of the activity comprises applications in an early stage, and these may well be narrowed in scope before a patent is granted, if at all, on these applications; further work is also needed to ensure a more extensive and inclusive geographical scope of information, so that the practical implications for many countries, particularly developing countries, are better known.

(ii) The technologies covered by this patent activity are spaced out along the vaccine

and drug development pipeline, from ‘upstream’ technologies such as gene constructs and genetic products derived from flu virus genomes, to ‘downstream’ technologies for vaccine production, delivery and adjuvation (i.e. use of adjuvants that enhance immune response)

- in view of the policy context of this study, the initial focus of search and

analysis is on such ‘upstream’ technologies that seem to make most direct use of or directly refer to genes and gene products derived from flu viruses, particularly wild flu viruses of the H5N1 subtype. But the other technology areas may be of crucial significance in pandemic planning and further patent landscaping and analysis will also be required for those areas.2

(iii) The main clusters of such ‘upstream’ patenting activity reviewed in the initial survey are the following:

• Influenza HA and NA genes and gene products that specifically claim or may

encompass H5N1 sequences

• Vectors or cells containing influenza genes and vaccines containing influenza gene products

• siRNA (small, interfering RNA) and antisense RNA directed to H5N1, also

oligonucleotides having H5N1 sequences

(iv) As a preliminary observation, there appears to be little evidence of controlling patent claims or claims in patent applications over H5N1 viral gene sequences as such. Relatively few patent documents have claims reciting gene sequences of H5N1 isolates. While no firm conclusion can be drawn as to why this is the case, relevant factors may include non-patentability of bare sequences in many countries (e.g. as being non-inventive if undertaken through routine sequencing), greater commercial interest in products using the sequences or gene products they code for (e.g. in vaccine constructs) rather than the sequences themselves, and the publication or public release of sequence data before patent applications are filed (in effect, defensive publication that would pre-empting patent rights in most circumstances).

- Patents and applications directed to products designed for prevention or treatment of influenza are much more frequently encountered. Some claims

2 N.B. “Mapping of Intellectual Property Related to the Production of Pandemic Influenza Vaccines.” Prepared by IVR; 23 October 2007 at http://www.who.int/vaccine_research/diseases/influenza/Mapping_Intellectual_Property_Pandemic_Influenza_Vaccines.pdf


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are directed to viral sequences useful for diagnosis. Even if purely method or process patents are excluded from the survey, in the areas of prevention, treatment, and diagnosis, it has to be acknowledged that there may be no clear boundary in practice between claims on viral sequences and claims on elements for creation of vaccines.

- A highly active field of research & development – and patenting – is vaccine design. A variety of vaccine product designs include those already in use, such as virus like particles (VLPs) and “reverse genetics”, and others such as vaccines comprising viral HA, NA peptides, which are more conventional in design.

- Some claims refer to treatment of influenza using viral sequences using siRNA (small, interfering RNA) and antisense RNA directed to H5N1 technologies, as well as oligonucleotides with H5N1 sequences.

- Detection of influenza infections, especially of the H5N1 virus, is a high priority, with some relevant activity in this area.

(v) More work is required to assess the widely variable geographical scope of relevant

patenting activity, once the general methodology and the scope of the patent landscaping work have been settled at a general level, particularly in order to determine the extent of relevant activity in developing countries.

- In general, these preliminary observations are the result of an initial survey and

analysis only, and therefore inevitably have significant limitations, which mean that no authoritative judgment can be based on this initial work. In particular, it should be noted that these data are limited in terms of:

• The completeness of the survey of relevant patenting activity (i.e. more

relevant patent families may yet be located) • their geographical scope (i.e. more work needs to be done to look at

national level activity in more countries) • the capacity to analyse and report on the legal status (i.e. no assessment

is made as to the status of patents or patent applications, or likely outcomes of patent applications)

• certain languages of publication (i.e. greater attention is needed for certain countries where there is relevant patenting activity, where additional linguistic skills are needed.)

Further work is underway to overcome these limitations, and will in addition be guided by the current policy discussions. The necessary steps to broaden the search and make it more geographically inclusive will continue to be undertaken with the assistance and coordination of WIPO.

Background: -Patenting activity in context 5. As noted in the covering study, this relevant patenting activity may be grouped in three general clusters, each of which may be of concern to public health policymakers concerned with virus sharing and surveillance, seasonal vaccine production and pandemic flu preparedness:


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• ‘Upstream’ patents may include patents on gene sequences or other derivatives such as peptide antigens and other gene products (proteins encoded by viral genes) derived from the virus, and research tools that are used in the isolation, identification and sequencing of viral material obtained from specimens. These technologies make the most direct use of or reference to genetic material, genetic products and genetic information derived from wild strains of the avian flu virus (but they do not necessarily entail direct physical access to a wild flu specimen).

• ‘Vaccine development’ patents may include patents on the techniques used to create a

vaccine, such as the seed viruses prepared for the production of seasonal flu vaccines. The ‘reverse genetics’ patent family is often discussed as highly relevant to production of seed viruses for vaccine production. These are significant technologies for the development of production capacity for a potential pandemic flu response.

• ‘Downstream’ patents may

include patents on general vaccine production technologies that may be relatively ‘neutral’ to the exact genetic make-up of the specific viruses the vaccines are produced for, but would nonetheless ‘use’ genetic material derived from a virus to produce a specfic vaccine against that virus. They may include technologies that are technically unrelated to access to and use of the flu virus as such, but may be vitally important in an effective response. For instance, adjuvants, by stimulating a stronger immune response from a given dose of vaccine, would greatly increase the number of available effective doses from the volume of vaccines produced, thus inoculating many more people from the same level of production.

Background: general trends in patenting activity 6. The rate of international applications in the PCT gives a rough indication of the trend in relevant patent activity, especially the activity with an international flavour (such as when an applicant especially wants to gain coverage in more than a small handful of countries and regions). The following chart gives an indication of all international (PCT) applications published that refer in some way to avian influenza or the H5N1 subtype (importantly, these do not necessarily claim viral genetic material even as partial subject matter of the patent; indeed, most do not). Nonetheless, the general trend is striking: of all relevant international applications since the first instance recorded in 1983, some 35% were published in the first 9 months of 2007. These publications therefore disclose relatively recent research and development activity, in the form of inventions that were first applied for between late 2005 and early 2006. There is considerable diversity in this activity, with publications from over 100 different actors representing a mix of private firms, individual inventors, public sector institutions and government agencies.

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PCT publications referring in some way to avian influenza or to H5N1 virus; publications up to 27.ix.07. Observations: patent statistics 7. There is a striking acceleration of patenting activity that is broadly relevant to the H5N1 virus; 85% of all such PCT activity has been published since 2000, and almost 35% in 2007 alone (to date). This is a very crude measure of basic activity – it gives no guidance on the legal scope or geographic reach of eventual patent rights, and omits applications filed outside the PCT system. Yet even this crude measure epitomizes both the promise and the challenges of the patent system – it reveals much more applied research and investment of resources on this public health concern – but it points to a complex field of potential patent rights, difficult to analyse and to assess freedom to operate – in relation to development and marketing of products that use upstream technologies.

Implications for public policy patent landscaping 8. This rapidly evolving and complex scene means that it is not a sufficient response to policymakers’ information needs simply to furnish large quantities of undifferentiated patent data, or basic statistics, without providing a clearer, objective analytical context. The development of useful and accessible patent landscapes that are also relevant and responsive to the needs of policymakers will inevitably be an interactive process, so that ideally, initial information products and analyses would be reviewed by health policymakers to assist in identifying and refining their information needs; this feedback would then go back into the development, focusing and updating of patent analysis. The process should be seen as a dialogue between patent analysts and the relevant policy communities, so that the available information resources are increasingly accessible and more directly supportive of public health policy debate and decision-making. 9. A key need is for clear and accessible overviews of patent trends and their implications that have as wide and inclusive a geographical scope as is possible, and make effective use of bioinformatics tools and real-time data on patenting activity and legal status, so as to provide the strongest possible empirical basis for policy discussions and public health policy decisions.


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10. Accordingly, the current phase of work entails one step in a nested approach that would deal with each of these areas with increasing feedback and support from international policymakers. The first step is to prepare a patent landscape on the first cluster of activity – the ‘upstream’ technologies discussed above- namely technologies making use of wild strains of virus and genetic extracts and gene products such as peptide antigens. This would be one element in an emerging matrix and set of bioinformatics tools that would lead to a more comprehensive, accessible and use-friendly landscape on the flu virus, flu vaccines and related technologies. 11. Two distinctive aspects of the landscaping methodology being undertaken are:

(i) an initial focus on international patent applications in the PCT system to provide an overview of the main clusters of patenting activity, to be subsequently supplemented with an analysis of selected national patent data; and

(ii) a focus on developing and sharing understanding about the methodologies and

search techniques used, including a peer review process, as the basis for a subsidiary report on methodological issues regarding public policy patent landscaping in the health sciences domain.

Ongoing landscaping activity 12. The ongoing patent landscaping work coordinated by WIPO in this area comprises the following steps:

(a) Reviewing existing published patent landscapes in the field of influenza;3

(b) Initially through searching international patent data, then supplemented by searches of national patent information, to identify patent families within the following technology clusters:

(i) patents that claim or otherwise refer to genetic material or gene products linked to the influenza virus (including sequences isolated from the virus); with a special focus on H5N1 strains; and

(ii) patents that claim or otherwise refer to specific vaccines for influenza and for H5N1 flu strains especially;

(iii) patents that claim or otherwise refer to pharmaceutical treatments for influenza, in particular Avian Flu and H5N1 variants;

(iv) patents that claim or otherwise refer to general vaccine production technologies relevant to influenza.

3 Useful recent work undertaken to date and referred to in the preparation of the current materials includes Edward Hammond, Sunshine Project, “Some Intellectual Property Issues Related to H5N1 Influenza Viruses, Research and Vaccines” commissioned by Third World Network, July 27, 2007; and very recently in relation to vaccine technologies for pandemic preparedness, “Mapping of Intellectual Property Related to the Production of Pandemic Influenza Vaccines.” Prepared by IVR; 23 October 2007 at http://www.who.int/vaccine_research/diseases/influenza/Mapping_Intellectual_Property_Pandemic_Influenza_Vaccines.pdf


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An initial analysis of patenting activity, commissioned by WIPO, is being undertaken under the initiative of Public Interest Intellectual Property Advisors, with technical guidance and framework provided by the WIPO Secretariat in collaboration with the WHO Secretariat. 13. In view of continuing policy debate over the nature of patenting activity making direct use of or reference to flu viruses, and in view of the rapidly changing patent environment, supplementary patent analysis is being planned to build the information base further. A pilot bioinformatics project undertaken with Cambia would map viral genetic material in patent claims against published gene sequence databases, so as to provide further insights into the degree to which influenza viruses are being used as the basis for patent claims, in view of continuing policy issues on this point. This pilot-level work would aim to combine with the current patent analysis to create a bioinformatics service that would directly recognize and map activity relevant to the viral genome, its gene products and variants to provide an up-to-date and accessible resource for policymakers, with as broad and inclusive a geographical reach and as timely information on legal status as is possible within existing systemic constraints. A key need is systematically to contrast the scope of patent applications as filed and patents as actually granted, as the difference can potentially be of practical significance.

What needs for policymakers? 14. It is of course for health policymakers to set their own needs and priorities for the information required to make sound policy decisions; it is not for patent analysts or bioinformatics initiatives to define or prejudge the need. The initial survey and analysis that are under development are therefore intended above all to illustrate the kind of work that can be undertaken, the broad trends that can be currently discerned, the kind of information product that may be further developed and refined under the guidance of health policymakers, and the current constraints and limitations. The first draft of the present survey would not offered in the expectation that it would be sufficiently broad or comprehensive in scope, or definitive in its analysis, for concrete decisions to be taken on the strength of this information. Rather, it is hoped that further policy discussion will help further to define and focus information needs so that future products are increasingly relevant and practically useful. Accordingly, input and commentary from health policymakers would be most welcome to help guide further elaboration of this work.

Limitations of the initial patent review 15. The present work products are very much interim and initial in character, and are subject to significant limitations and caveats. These include:

• Any analysis is for general information only, and should not be considered as legal advice nor an assessment of policy options.

• The geographical reach of data consulted is limited to that which was readily available

for an initial search; this may give the data an apparent skew towards certain regions or countries which is not intended and which will be addressed in future enhancements of this work, including through more extensive use of the PatentScope patent database and other patent information services.


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• Considerable further analysis is required to assess the emerging differences between the scope of relevant patent claims as filed, and the scope of claims as actually granted by patent authorities.

Categorizing patenting activity 16. A large number of patents and patent applications relate directly or indirectly to influenza virus and an increasing number refer in some way to the H5N1 subtype of the virus. Ongoing analysis will progress from ‘upstream’ patents addressing the genome level, to patents claiming such ‘downstream’ technologies as adjuvants, methods of vaccine manufacture and other important aspects of the vaccine production and delivery. This process of analysis will need to consider how patent activity can be grouped and classified and what aspects of these patents are most important from the point of view of ongoing policy discussions. 17. The initial criteria for patent searching were to include any patents and patent applications with any:

• claims to compositions of genes and gene products; or • claims to vaccines comprising specific gene and gene product sequences

that encompass H5N1;

but to exclude patents and patent applications if they only comprised: • claims to methods for diagnostics; or • methods of making vaccines.

18. A number of relevant patent documents are reviewed under the following three sections, according to their subject matter (the one patent document may fit into more than one section, but in that case would only be listed under one section):

1. Influenza HA and NA genes and gene products that specifically claim or may encompass H5N1 sequences;

2. Vectors or cells containing influenza genes and vaccines containing influenza gene products;

3. siRNA and antisense directed to H5N1, also oligonucleotides having H5N1 sequences.


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LISTING AND INITIAL DISCUSSION OF PATENTS DISCLOSED

19. The following discussion is provided for background only. It represents work in progress and should not be taken as a definitive or firm assessment as to the state of play. It should be stressed that work is still actively under way to advance this search and analysis, and further patent families and further family members are likely to be disclosed and added to the list. In addition, the analysis is incomplete in each case and will need to be further refined and developed..

Table. Distribution of patent families identified thus far (subject to revision).

CATEGORY NO. OF PATENT FAMILIES

Influenza HA and NA genes and gene products that specifically claim or may encompass H5N1 sequences

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Vectors or cells containing influenza genes and vaccines containing influenza gene products

18

siRNA and antisense directed to H5N1, also oligonucleotides having H5N1 sequences

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SECTION 1: INFLUENZA HA AND NA GENES AND GENE PRODUCTS THAT SPECIFICALLY CLAIM OR MAY ENCOMPASS H5N1 SEQUENCES Further searching and review of initial search results are still in progress. Some initial observations, subject to review and elaboration, may be offered concerning these patents:

• Few patent applications in this section directly claim native DNA or protein sequences; some claim N1 sequences from viruses other than the H5N1 subtype.

• One patent family is directed to codon optimization of sequences encoding hemagglutinin and neuraminidase polypeptides. Although the disclosure is mostly directed to codon-optimization of H1 and H3 subtypes, the H5 subtype is briefly mentioned. Many more codon-optimized sequences are constructed and claimed in an application by the U.S. Government. While many different influenza viruses are subjected to codon-optimization, many H5N1 sequences are mutagenized.

• Other applications in this section are directed to fragments or non-native sequences derived from the H5N1 virus. Very short peptides constitute the subject matter of an application by ProImmune Ltd. (UK). This application claims a series of very short peptides derived from a hemagglutinin of a specific H5N1 virus; the hallmark of the peptides is that each binds to an MHC class I protein. Two other patent


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applications in this section disclose and claim mutants of viral genes, mostly of hemagglutinin. The NIH application discloses and claims HA variants in which the polybasic cleavage site is deleted; St Jude’s has made a number of point mutants and focuses on altering Ser223, especially Ser223 to Asp (asparagine) changes.

• All of the references in this section are only patent applications; no issued patent was found from the patent searches. Because they aren’t granted patents, the published claims represent what the applicants are requesting. The patent claims that ultimately are granted (if granted at all) may have a different scope. Nearly always, the scope of a granted claim will be narrower than a request.

SECTION 2: VECTORS OR CELLS CONTAINING INFLUENZA GENES AND VACCINES CONTAINING INFLUENZA GENE PRODUCTS This section encompasses Group 2 patents to vectors or cells containing H5N1-related influenza genes, and vaccines containing influenza gene products. Some scientific information and patenting aspects are discussed. Within this section, patent documents are identified within two groups that claim:

1. constructs and components useful for production of vaccines; and 2. vaccines.

These two groups do overlap, making assignment to a particular category a value judgment. The assignment is primarily based on the claims as published; certainly patent documents that claim constructs and components for vaccine production also disclose the use of a resulting vaccine. Similarly, patent claims directed to specific vaccines disclose and teach constructs and components necessary to manufacture a vaccine. In addition, related applications may be directed to claims of the other category or directed to claims of both categories (in jurisdictions that allow such claim groupings). That said, from the information presented herein it appears that protection for vaccines is more often sought by applicants. The reason(s) for this are not yet clear. An initial review highlighted the following preliminary observations, still subject to elaboration and revision:

− Within category 1 – constructs and components for production of vaccine – the applicants are nearly all public organizations. The licensees, if any, of this technology are currently unknown. The patent and applications in this category are drawn primarily to vectors that could be used for production of vaccines of any RNA type virus.

− The St. Jude’s and WARF technologies are directed to dual promoter systems, specifically a pol I – pol II dual promoter system, for high level expression of viral RNAs. The MedImmune patent application also contains claims to bi-directional expression vectors but appears to mainly disclose a method of producing a recombinant virus vaccine, including influenza virus vaccine, in low-temperature growth conditions. The U.S. Government and University of Pittsburgh’s patent applications teach adenoviral vectors as a backbone for expression of genes from avian or pandemic influenza viruses. The patent application submitted from Yangzhou University is directed to a series of constructs for producing a recombinant reassorted virus – that is a virus that is composed of genes derived from two or more viruses. Sometimes called “reverse genetics” the method and


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constructs shortcuts the conventional method for constructing reassorted viruses. The resulting reassorted virus of Yangzhou’s technology has the H5 and N1 proteins from an H5N1 virus and the other gene products from an H9N2 virus. An additional application appears to claim constructs for producing a reassorted virus.

− The second category – vaccines – contains applications disclosing and claiming a diverse set of vaccine strategies. These strategies fall into a few basic patterns: vaccines comprising recombinant viruses, cells expression one or more viral antigen, and combinations of viral gene products or peptides from viral gene products.

− Recombinant viruses are the subject of recently filed patent applications by Novavax, Mount Sinai Medical Center, Rutgers State and Texas Universities, Kanazawa University in Japan and an unknown Chinese entity. The types of recombinant viruses include VLPs (virus-like particles) comprising influenza virus M1 protein, H5 hemagglutinin protein, and N1 neuraminidase protein, chimeric influenza viruses displaying a fusion protein of a protein ectodomain from an infectious agent (e.g., H5 or N1) fused to a transmembrane / cytoplasmic domains of neuraminidase or hemagglutinin from a different influenza virus, influenza viruses that have mutated NS1 proteins that result in attenuated virus or have a mutated H5 hemagglutinin.

− A single patent application submitted from Creatogen Labs is directed to a bacterial cell that expresses at least one influenza virus antigen on its cell surface.

− A larger group of patent applications is directed to vaccines that are made up of combinations of genes, proteins or peptides derived from influenza viruses. Cure Labs discloses a vaccine containing nucleic acids encoding three influenza proteins – NP, M1 and NS-1, which are either native or modified sequences. The vaccines of Protelix and Biotempt contain peptides from HA or from both HA and NA. Yeda discloses vaccines comprising fusion proteins, in which the fusion is of a matrix protein or fragment and an hemagglutinin fragment. A Chinese patent application is directed to a vaccine comprising H5N1 viral proteins obtained from a baculovirus or prokaryotic expression system.

Section 3: siRNA and antisense directed to H5N1, also oligonucleotides having H5N1 sequences This section will review patents and patent applications of relating to oligonucleotides, antisense molecules, and small interfering RNA (siRNA) having H5N1 sequences. Oligonucleotides, sometimes referred to as oligos, are short nucleic acid molecules which typically comprises about 20 or fewer bases. Oligonucleotides are often used as probes to detect complementary nucleic acid molecules. Oligonucleotides are also used as primers in order to amplify a target sequence. Antisense molecules are nucleic acid molecules which interact with complementary nucleic acid molecules and thereby modify the expression of genes. Small interfering RNA (siRNA) are sometimes referred to as short interfering RNA or silencing RNA. An siRNA is a double-stranded ribonucleic acid molecule about 20-25 base pairs in length. RNA interference (RNAi) is a mechanism wherein siRNA inhibits the expression of genes having complementary sequences.


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Since antisense molecules and siRNAs can modulate the expression of a given gene, antisense molecules and siRNAs have the potential to be used as therapeutic agents, for preventing or treating influenza virus infections.

ILLUSTRATIVE PATENT FAMILIES DISCLOSED

NB: these listings are illustrative only at this stage; further families, and further details and other national patents or applications within these families may be added in future.

SECTION 1: INFLUENZA HA AND NA GENES AND GENE PRODUCTS THAT SPECIFICALLY CLAIM OR MAY ENCOMPASS H5N1 SEQUENCES

Title: Influenza Hemagglutinin and Neuraminidase Variants Publication No.: US 2006/252132 and US 2005/042229 Assignee: MedImmune, Inc. Priority Date: 2004-05-25 Family members: Canada (CA 2529647); Europe (EP 1 633 312); WIPO (WO 2005/018539

and WO 2006/098901) Description: Polypeptides, polynucleotides, methods, compositions, and vaccines comprising

(avian pandemic) influenza hemagglutinin and neuraminidase variants are provided.

MedImmune, Inc. is the assignee of several patent applications directed to influenza oligonucleotide sequences. One of the U.S. applications and WO ‘539 claim the benefit of U.S. Provisional Application Serial No. 60/479,078, filed 16 June 2003. The ‘246 application claims the benefit of the ‘690 application and U.S. Provisional Application Serial Nos. 60/659,832, filed 8 March 2005, and 60/479,078, filed 16 June 2003. WO ‘901 claims the benefit of U.S. Provisional Application Serial No. 60/659,832, filed 8 March 2005. As of mid-November 2007, the two U.S. applications have been undergoing prosecution on the merits. The claims of these applications as published are broadly directed to polypeptides, polynucleotides, methods, compositions, and vaccines comprising influenza hemagglutinin and neuraminidase variants. Generally, the published claims are limited to specific sequences.

Title: Influenza nucleic acids, polypeptides, and uses thereof Publication no.: US 2006/00217338 Assignee: Univ Massachusetts Priority Date: 2005-02-24 Family members: Europe (EP 1851238); WIPO (WO 2006/104615) Description: Codon−optimized nucleic acids encoding influenza polypeptides and uses of the

nucleic acids and polypeptides for inducing immune responses are provided herein.

The U.S. and PCT applications disclose codon-optimized nucleic acids encoding influenza polypeptides and uses of the nucleic acids and polypeptides. To increase expression, the codons


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have been altered to those preferentially used in humans or to codons that reduce secondary structure of RNA. The broadest claim as published is directed to:

An isolated nucleic acid molecule comprising: a sequence encoding an influenza type hemagglutinin (HA) polypeptide or antigenic fragment thereof, or an influenza neuraminidase (NA) polypeptide or antigenic fragment thereof, wherein the sequence has been codon-optimized for expression in a human cell

As of mid-November 2007, the 617 application has been undergoing prosecution on the merits. European Patent application EP1851238 is included in the patent family of WO ‘615.

Title: Antiviral agents and vaccines Publication no.: WO 2007/100584 A Assignee: U.S. Government Priority Date: Description: These vaccines target H5N1, H1, H3 and other subtypes of influenza and are designed

to elicit neutralizing antibodies, as well as cellular immunity. The DNA vaccines express hemagglutinin (HA) or nucleoprotein (NP) proteins from influenza which are codon optimized and/or contain modifications to protease cleavage sites of HA which affect the normal function of the protein. Adenoviral constructs expressing the same inserts have been engineered for prime boost strategies. Protein−based vaccines based on protein production from insect or mammalian cells using fold on trimerization stabilization domains with or without cleavage sites to assist in purification of such proteins have been developed. Another embodiment of this invention is the work with HA pseudotyped lentiviral vectors which would be used to screen for neutralizing antibodies in patients and to screen for diagnostic and therapeutic antivirals such as monoclonal antibodies.

Title: MHC binding peptides and their uses Publication no.: EP 1820511 A1 (also US 2007/197446) Assignee: ProImmune Ltd. Priority Date: Family members: Europe; United States Description: The present invention is concerned with MHC binding peptides derived from the

avian influenza virus H5N1 and in particular MHC class I restricted binding peptides from the Hemagglutinin 5 (H5) protein from this virus and their uses.

Title: Influenza Hemagglutinin and Neuraminidase Variants Publication no.: US 2006/0008473 Assignee: U.S. Government(National Institutes of Health) Priority Date: 2004-05-25 Family members: Australia; Canada; Europe; WIPO Description: Polypeptides, polynucleotides, methods, compositions, and vaccines comprising (avian

pandemic) influenza hemagglutinin and neuraminidase variants are provided.


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Title: Modified Influenza Virus for Monitoring and Improving Vaccine Efficiency Publication no.: US 2007/0031453 Assignee: St Jude Children’s Research Hospital Priority Date: 2005-08-04 Family members: WIPO (conversion date 2008-02-04) Description: The immunogenicity of the influenza virus hemagglutinin (HA) molecule may be

increased by substitutions of amino acids in the HA sequence. The substitution of specific HA residues, such as asparagine at position 223 of H5 HA, increase the sensitivity of the hemagglutinin inhibition (HI) assay by altering receptor specificity and/or antibody−antigen binding. HA molecules containing such substitutions will be useful in the development of diagnostic reference viruses and improved influenza vaccines.

SECTION 2: VECTORS OR CELLS CONTAINING INFLUENZA GENES AND VACCINES CONTAINING INFLUENZA GENE PRODUCTS 1. Constructs and components for production of vaccine

Title: DNA transfection system for the generation of infectious influenza virus Publication No.: US 6951754 Assignee: St. Jude Children's Research Hospital (Memphis, TN, US) Priority Date: 2000-04-28 Family Members: AU 5921101A, AU 2006228054A1, BR 0110607A, CA 2406100A1, CN 1856575A,

EA 6311B1, EP 1317559A2, HU 0303036A2, JP 2004/500842T, KR 2007/0086094A, MX PA02010642A, NO 2002/5171A, NZ 521840A, NZ 536260A, PL 366064A1, US 2002/164770A1, US 2005/186563A1, WO 0183794A2, WO 0183794A3, ZA 2002/08065A

Description: The invention is based on the development of a RNA pol I−pol II dual promoter

system for the efficient intracellular synthesis of viral RNA. The resulting plasmid −based system may be used to synthesize any RNA virus, including those such as H5N1 having a negative single stranded RNA genome. The viral product is produced when the plasmids are introduced into a suitable host cell. The system can be used for production of attenuated, reassortant influenza viruses for use as antigens in vaccines. The reassortant viruses generated by cotransfection of plasmids comprise genes encoding the surface glycoproteins hemagglutinin and neuraminidase from an influenza virus currently infecting the population and the internal genes from an attenuated influenza virus. According to the disclosure the system can be quickly and easily adapted to synthesize an attenuated version of any RNA virus, and the resulting attenuated or inactivated RNA viruses administered to a patient.

The claims include compositions for generating infectious flu viruses from cloned viral cDNA, host cells containing these compositions, and methods of using the compositions. 19 DNA sequences are listed in the disclosure, but none of these appear


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in the issued claims. Title: Recombinant Influenza Vectors with Tandem Transcription Units Publication No.: US 2006/166321 Assignee: Wisconsin Alumni research Foundation (WARF) Priority Date: 2004-11-19 Family Members: AU 2005337178A1, CA 2587510A1, EP 1814990A2, KR 20070086344A, WO

2007044024A2, WO 2007044024A3 Description: This application claims a composition useful to prepare influenza viruses in the

absence of helper virus, using vectors which include tandem transcription cassettes containing PolI and PolII promoters. The broadest claim is drawn to tandem cassettes containing H and N cDNAs, respectively.

Title: Multi plasmid system for the production of influenza virus Publication No.: US2004/029251A Assignee: MedImmune Vaccines Inc. Priority Date: 2002-04-26 Family Members: Description: Vectors and methods for the production of influenza viruses suitable as recombinant

influenza vaccines in cell culture are provided. Bi-directional expression vectors for use in a multi-plasmid influenza virus expression system are provided.

Title: Vaccine Against Pandemic Strains of Influenza Viruses Publication No.: WO 2006/113214 A2 Assignee: U.S. Government Priority Date: 2005-04-11 Family Members: WO 2006113214A2, A3* Description: The invention is directed to compositions and methods for eliciting an immune

response against avian or pandemic influenza. The compositions include adenovirus vectors with avian influenza antigens, recombinant adenovirus and immunogenic compositions comprising such recombinant vectors and adenovirus. Methods for eliciting an immune response against avian or pandemic influenza involving administering such adenovirus vectors or recombinant adenovirus are also provided.

The broadest embodiment of the invention is a recombinant adenovirus vector comprising a polynucleotide sequence that encodes at least one antigen of an avian influenza strain. Although cell lines and methods comprising adenoviruses directed to influenza are also claimed.

Title: Vaccines For the Rapid response to Pandemic Avian Influenza Publication No.: US 2007/000357 A1 Assignee: University of Pittsburgh Priority Date: 2004-12-09 Family Members: EP 1819357A2, WO 2006063101A2, WO 2006063101A3 Description: This application claims adenovirus-based vaccines against avian influenza viruses

with pandemic potential. Replication-defective adenoviral vectors, each having a


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nucleic acid encoding an influenza A polypeptide, are administered to subjects to induce the production of antibodies that bind to influenza.

Title: Gene Recombinant Fowl Influenza Virus D3/F-R2?6 and its Construction

Method Publication No.: CN1313605C Assignee: Yangzhou University Priority Date: Unknown Description: The invention provides an avian influenza virus D3/F−R2/6ss reassortment and

construction method which is related to the field of reverse genetic technology. The invention comprises reassorting the six internal genes of the MPAIV chicken embryonic highly adaptive strain A/Chicken/Shanghai/F/98(H9N2) PB2, PB1, PA, NP, M, NS and the NA gene and attenuate HA gene of the HPAIV epidemigenic strain A/Duck/Huadong/D3/00 (H5N1), thus constructing an avian influenza virus D3/F−R2/6ss reassortment, which can be used for manufacturing vaccine for treating avian influenza.

Title: Artificial Recombined Influenza Virus and its Application Publication No.: CN 1261564C Assignees: Priority Date: Description: A molecular modification attenuated artificially recombinant H5−subtype influenza

virus (CCTCC−V200312) used to prepare the vaccine for preventing fowl's influenza is disclosed, which has the hemagglutinin (HA) gene of A/goose/Guangdong/1196(H5N1), the neuraminidase (NA) gene of A/Hongkong/486/97 (H5N1) and the 6 internal genes PB2, PB1, PA, NP, A and NS of A/PR/8/34(N1N1).

2. Vaccines

Title: Functional Influenza-like Particles (VLPs) Publication No.: WO 2007/047831 Assignee: Novavax, Inc. Priority Date: 2005-10-18 Family Members: AU 2004268510A1, BR PI0412519A, CA 2532335A1, CN 1849134A, EP

1644037A2, KR 20060052804A, MX PA06000469A, RU 2006104113A, US 2005009008A1, US 2006263804A1, US 2007184526A1, WO 2005020889A2, WO 2005020889A3, WO 2007047831A2, WO 2007047831A3

Description: Recombinant influenza virus proteins including influenza capsomers, subviral particles, virus-like particles (VLP), and VLP complexes are described as a vaccine for influenza viruses. The invention is based on the combination of two vaccine technologies: (1) recombinant vaccine technology, and (2) highly immunogenic, self-assembled protein macromolecules embedded in plasma membranes containing multiple copies of influenza virus structural proteins exhibiting neutralizing epitopes in native


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conformations. The invention includes vector constructs comprising viral proteins, cells containing these constructs, and VLP formulations and vaccines. Also claimed are methods of making and administrating VLPs and methods of inducing immunity to either seasonal or avian influenza.

Title: Chimeric viruses presenting non-native surface proteins and uses thereof Publication No.: WO 2007/064802 A1 Assignee: Mount Sinai Medical Center of New York University Priority Date: 2005-12-02 Family Members: WO 2007064802A1* Description: This application discloses chimeric negative-strand RNA viruses that provide

immunization against two infectious agents by using a single chimeric virus. Chimeric influenza viruses are engineered to express and incorporate a fusion protein comprising an ectodomain of a protein of an infectious agent and the transmembrane and cytoplasmic domain of an influenza virus protein. Such chimeric viruses induce an immune response against influenza virus and the infectious agent. The broadest claim is drawn to an engineered chimeric influenza virus.

Title: Novel compositions and vaccines against influenza A and influenza B

infections Publication No.: WO 2007/061969 A2 Assignee: Rutgers State Univ; Univ Texas Priority Date: 2005-11-18 Family Members: WO 2007/061969A2*, WO 2007/061969 A3 Description: Novel models of interactions of the Nonstructural Protein of influenza A and

influenza B viruses (NSlA and NSlB, respectively) with dsRNA are presented. On the basis of the models, novel recombinant viruses and vaccines against influenza A and influenza B viruses are provided.

Claims are most broadly drawn to an attenuated influenza A or B virus vaccine comprising eight viral RNA segments having a mutation which causes a substitution of an amino acid corresponding to an amino acid chosen from defined sequences, and where the mutation decreases the double-stranded RNA (dsRNA) binding ability of the Nonstructural Protein of influenza A or B.

Title: Recombinant Influenza Virus and Vaccine Using the Same Publication No.: JP 2005-245302 A2 Assignee: Kanazawa University, Japan Priority Date: Unknown Description: In order to provide an effective vaccine against H5N1 type influenza, a virus strain

having low pathogenesis and high immunogenicity is prepared by modifying a hemagglutinin gene in order to reduce the number of basic amino acids existing in rows on the cleavage site of a hemagglutinin protein of H5N1 type influenza. The vaccine is prepared by using the virus strain.


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2Title: Influenza vaccine Publication No.: WO 2007/082734 A2 Assignee: Creatogen Laboratories GMBH Priority Date: 2006-01-17 Family Members: WO 2007/082734 A2*, WO 2007/082734 A3 Description: The disclosure is to a live-attenuated bacterial cell comprising a heterologous

nucleotide sequence encoding at least one influenza virus antigen linked to an expression system. However, the claims are diverse, and include live-attenuated cells, nucleotide vectors, virus epitope, pharmaceutical compositions, and other categories.

3Title: Influenza vaccine compositions and methods of use thereof Publication No.: US 2007/116717 Assignee: Cure Lab, Inc. Priority Date: 2005-08-01 Family Members: US 2007116717A1, US 2007122430A1*, WO 2007016598A2, WO 2007016598A3 Description: This application includes compositions of ant-influenza vaccine containing nucleic

acids encoding influenza proteins NP, Ml and NS−I and methods of inducing a protective immune response using these compositions. Also included is the enhancement of antigenic presentation or increasing immunogenicity of an influenza NP, Ml and/or NS−I polypeptide by modifying the three dimensional structure of the polypeptide. The broadest claim is to anti-influenza vaccines containing an influenza nucleoprotein, a second nucleic acid sequence encoding an influenza M1 protein, and a third nucleic acid sequence encoding an influenza NS-1 protein.

Title: Influenza combinatorial antigen vaccine Publication No.: WO 2007/051036 A2 Assignee: Protelix, Inc. Priority Date: 2005-10-26 Family Members: WO 2007/051036A2* Description: This application describes a combinatorial influenza vaccine composition for use in

providing prophylactic protection against influenza viruses, and a method of producing the vaccine. The broadest claim is directed to an influenza vaccine composition containing a subset of 5-50 peptide antigens defined within 13 peptide sequences derived from the major influenza surface antigens hemagglutinin (HA) and neuraminidase (NA).

Title: Pharmaceutical compositions for the treatment of influenza infections Publication no.: WO 2007/097624 Assignee: BIOTEMPT B.V. (The Netherlands) Priority Date: 2006-02-21 Description: The invention relates to the field of the production of a pharmaceutical composition

for the treatment of a subject suffering or believed to be suffering from an acute


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influenza virus infection. Provided is the use of a peptide consisting of 3 to 6 amino acids for the production of a pharmaceutical composition for the treatment of a subject, preferably a human subject, suffering or believed to be suffering from an influenza infection. Also provided is a pharmaceutical composition comprising at least one antiviral peptide consisting of 3 to 6 amino acids in combination with an additional antiviral agent.

Title: Improved influenza vaccine Publication No.: WO 2007/066334 A1 Assignee: Yeda Res and Dev Co., Ltd., Israel Priority Date: 2005-12-06 Family Members: WO 2007/066334 A1* Description: This disclosure is drawn to influenza vaccines where the vaccine is able to confer long

term and cross-strain protection. The vaccine comprises at least two influenza virus epitopes expressed as a chimeric polypeptide having at least one epitope from influenza A virus matrix protein and a second epitope from a hemagglutinin peptide. As claimed, the invention includes peptide epitopes derived from a series of peptides defined in the application. Claims are limited to various embodiments of the vaccine, and a method of use.

Title: Subunit Vaccine of H5N1 subtype Bird Flu Virus Gene Engineering and its

Preparing Method Publication No.: CN 1781553 Assignees: Unknown Priority Date: Unknown Description: The invention discloses a H5N1 influenza virus subunit vaccine and its preparation

process. The vaccine consists of protein obtained through expression of a specified gene sequence in an insect/baculovirus or prokaryotic expression system, and an adjuvant. Immunization of chicken with the vaccine can elicits a protective immune response, no gene recombination, and no apparent toxicity. The application claims that immunized and naturally infected subjects can be distinguished, and that this aids epidemiological investigation and eliminates environmental and ecological safety problems.

Section 3: siRNA and antisense directed to H5N1, also oligonucleotides having H5N1 sequences 1. Oligonucleotide Patents and Applications

Title: Compositions For Use in Identification of Influenza Viruses Publication no.: US 2007/087336 Assignee: Isis Pharmaceuticals, Inc.


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Priority Date: 2005-10-17 Family members: PCT (WPO 2007/047778); US -------- Description: The present invention provides oligonucleotide primers, compositions, and kits

containing the same for rapid identification of viruses which are members of the influenza virus family by amplification of a segment of viral nucleic acid followed by molecular mass analysis.

As of mid-November 2007, the U.S. applications are undergoing prosecution on the merits. The claims of the applications as published are broadly directed to oligonucleotide primer pairs of 20 to 35 nucleotides in length and at least 70% sequence identity to a given sequence. The applications as published also have claims to methods of making and using and claims to kits.

Title: Diagnostic Primers and Method For detecting Avian Influenza Virus Subtype

H5 and H5N1 Publication no.: WO 2005/121367 Assignee: Agency for Science Technology and Research (Singapore) Priority Date: 2004-06-10 Family members: Europe (EP 1 761 645), Canada (CA 2567793), PCT (WO 2006/132601) Description: The present invention provides primers directed to conserved regions of the HA and

NA genes of avian influenza virus subtypes H5 and H5N1, and provides a method for detecting avian influenza subtype H5 or H5N1.

The PCT application discloses primers directed to conserved regions of the HA and NA genes of avian influenza virus subtypes H5 or H5N1, and methods for detecting avian influenza subtype H5 or H5N1. The claims are limited to specific sequences. The related PCT application appears to be directed to a preferred sequence, SEQ ID NO:118.

Title: Influenza A Virus Detection Method and Kit Therefor Publication no.: WO 2007/058629 Assignees: Agency for Science Technology and Research (Singapore) Priority Date: 2005-11-16 Description: The invention provides oligonucleotides for a simple, specific and/or sensitive test for

the presence of Influenza A. In particular, the present invention provides a primer(s), probe(s) and/or test(s) for Influenza A Subtype H5N1. The application also discloses kits comprising probe(s) and/or primer(s) useful in the test. The claims of the PCT application are limited to specific sequences.

Title: Process For Detecting H5N1 Hypotype Avian Influenza Virus and Special-

purpose Reagent Kit Publication no.: CN 1274851C (granted patent) Assignees: China Agricultural University Priority Date: 2004-11-01 Description: The invention disclosed a detection method for H5N1 subtype avian influenza virus

and special purpose reagent case thereof. The reagent case comprises avian influenza A virus general primer NPF and NPL, specificity primer H5F and H5L of H5 subtype avian influenza virus hemagglutinin and specificity primer N1F and N1L of N1


21

subtype avian influenza virus neuraminidase; said NPF processes nucleotide sequence 1, said NPL processes nucleotide sequence 2, said H5F processes nucleotide sequence 3, said H5L processes nucleotide sequence 4, said N1F processes nucleotide sequence 5 and 6. The invention can be used not only for laboratory diagnosis and scientific research, but also for large−scale epidemiology survey.

The claims and specification are in Chinese, but based on the English abstract, CN ‘851 is directed to detection methods for H5N1 subtype avian influenza virus and kits comprising avian influenza A virus general primer NPF and NPL, specificity primer H5F and H5L of H5 subtype avian influenza virus hemagglutinin and specificity primer N1F and N1L of N1 subtype avian influenza virus neuraminidase which can be used for laboratory diagnosis, scientific research, and large-scale epidemiology surveys.

Title: Method of the cDNA identification of the strains of the high-pathogenic virus

of bird’s influenza H5 type by the gene specific site amplification Publication no.: UA18727U (Ukraine) Assignees: Instex and Clinical Veterinary Medicine Priority Date: 2006-05-29

Description: Based on the English abstract, UA ‘727 is directed to methods of identifying strains of a high-pathogenic virus of bird's influenza H5 type using polymerase chain reaction (PCR) and specific primers.

2. Antisense and siRNA Patents and Applications

Title: Potent inhibition of influenza virus by specifically designed short interfering

RNA Publication no.: US 7199109 (US 2006/275265 A) Assignee: Cal Poly Pomona Foundation (USA) Priority Date: 2005-06-03 Family members: PCT/US0711741 Description: This patent application discloses siRNA sequences against the constant region of the

influenza virus nucleoprotein gene comprising specified sequences which inhibit influenza virus. The invention includes these siRNA sequences as an aqueous suspension for nasal inhalation. In addition, the invention includes one or more of these siRNA sequences in the form of plasmids expressing intracellularly. The invention also includes administration of these siRNAs in a therapeutically effective amount.

One of the US applications contains claims directed to a siRNA sequence against the constant region of the influenza virus nucleoprotein gene as well as methods which comprise administering the siRNA sequence to a subject. Another of the US applications contains claims directed to a siRNA sequence against the constant region of the influenza virus nucleoprotein gene and methods which comprise administering the siRNA sequence to a subject. Although one of the applications is not yet published, based on the original claims filed in the ‘573 application, it is likely that it contains claims directed to a siRNA sequence


22

against the constant region of the influenza virus nucleoprotein gene methods which comprise administering the siRNA sequence to a subject.

Although the challenge experiments disclosed in these applications used strains of murine flu virus, the specifications disclose that:

The NP gene regions of avian flu were also compared with the siRNA sequences of this invention. Among the 50 isolates of H5N1 studied, all 50 showed 100% homology with the NP regions corresponding to the siRNA of this invention, suggesting they would be effective against avian flu.

It is noted that the claims of two of the applications are limited to the specifically recited sequences; however, the method claims are not limited to treating or preventing infection by a particular influenza strain.

Title: Antisense Antiviral Compound and Method for Treating Influenza Viral Infection

Publication no.: US 2007/0004661 Assignees: MIT and AVI Biopharma, Inc. Priority Date: 2004-10-26 Family members US 11/433,213; PCT (PCT/US2005/38780 and PCT/US2007/11435);

AU2005299306, CA2584599, EP1814898, and WO2006047683 Description: The invention provides antisense antiviral compounds and methods of their use and

production in inhibition of growth of viruses of the Orthomyxoviridae family and in the treatment of a viral infection. The compounds are particularly useful in the treatment of influenza virus infection in a mammal. The antisense antiviral compounds are substantially uncharged morpholino oligonucleotides having 1) a nuclease resistant backbone, 2) 12−40 nucleotide bases, and 3) a targeting sequence of at least 12 bases in length that hybridizes to a target region selected from the following: a) the 5' or 3' terminal 25 bases of the negative sense viral RNA segment of Influenza virus A, Influenza virus B and Influenza virus C; b) the terminal 25 bases of the 3' terminus of the positive sense cRNA and; and c) the 50 bases surrounding the AUG start codon of an influenza viral mRNA.

As of mid-November 2007, the two US applications have been undergoing prosecution on the merits. The broadest claim of the ‘first application as published is directed to:

An antiviral compound comprising an oligonucleotide analog having a) a nuclease-resistant backbone, b) 12-40 nucleotide bases, and c) a targeting sequence of at least 12 bases in length that hybridizes to a target region selected from the following: i) the 5' or 3' terminal 25 bases of a negative sense viral RNA segment of Influenzavirus A, Influenzavirus B and Influenzavirus C, ii) the terminal 25 bases of the 3' terminus of a positive sense cRNA of Influenzavirus A, Influenzavirus B and Influenzavirus C, and iii) the 50 bases surrounding the AUG start codon of an influenza viral mRNA.

The broadest claim of the other application as published is further limiting by including the following wherein clause as follows:

wherein said oligonucleotide analog further has: a) the capability of being actively taken up by mammalian host cells, and b) the ability to form a heteroduplex structure with the viral target region, wherein said heteroduplex structure is: i) composed of the positive or


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negative sense strand of the virus and the oligonucleotide compound, and ii) characterized by a Tm of dissociation of at least 45 °C.

Some, but not all, of the claims of the applications as published are limited to specific sequences. Title: RNAi inhibition of influenza virus replication Publication no.: US 2007/197460 A Assignee: Alnylam Pharmaceuticals, Inc. Priority Date: 2005-11-01 Family members: PCT (WO 2007/053696) Description: The invention relates to compositions and methods for modulating the expression of influenza viral genes, and more particularly to the down regulation of influenza viral genes by chemically modified oligonucleotides. As of mid-November 2007, the U.S. application has been undergoing prosecution on the merits. The claims of the application as published are directed to iRNA agents comprising a sense strand and/or antisense strand of at least 15 contiguous nucleotides with no more than a few bases different from specific sequences. Methods of using the iRNAs are also claimed.

Title: siRNA silencing of influenza virus gene expression Publication no.: US 2007/218122 A Assignee: Protiva Biotherapeutics, Inc. Priority Date: 205-11-18 Description: The present invention provides siRNA molecules that target influenza virus gene expression and methods of using such siRNA molecules to silence influenza virus gene expression. The present invention also provides nucleic acid−lipid particles that target influenza virus gene expression comprising an siRNA that silences influenza virus gene expression, a cationic lipid, and a non−cationic lipid. As of mid-November 2007, prosecution of the US application had yet to begin. The published claims are directed to siRNA molecules comprising a double-stranded region of about 15 to about 60 nucleotides in length, wherein said siRNA molecule silences expression of an influenza virus gene selected from the group consisting of PA, PB1, PB2, NP, M1, M2, NS1, and NS2 and methods of making and using thereof.

Title: Compositions For Treating Viral Infections and Their Use Publication no.: WO 2006/121464 Assignee: Intradigm Corp. Priority Date: 2004-11-05

Description: The broadest composition claim is directed to: An isolated polynucleotide whose length is 200 or fewer nucleotides, the polynucleotide comprising a first nucleotide sequence wherein the first nucleotide sequence targets the genome of a respiratory syncytial virus or an influenza A virus, wherein any T (thymidine) or any U (uridine) may optionally be substituted by the other and wherein the first nucleotide


24

sequence consists of a) a sequence whose length is any number of nucleotides from 15 to 30, or b) a complement of a sequence given in a).

Title: Influenza therapeutic Publication no.: US 2004/242518A Assignee: MIT Priority Date: Description: The present invention provides methods and compositions for inhibiting influenza

infection and/or replication based on the phenomenon of RNA interference (RNAi) well as systems for identifying effective siRNAs and shRNAs for inhibiting influenza virus and systems for studying influenza virus infective mechanisms. The invention also provides methods and compositions for inhibiting infection, pathogenicity and/or replication of other infectious agents, particularly those that infect cells that are directly accessible from outside the body, e.g., skin cells or mucosal cells. In addition, the invention provides compositions comprising an RNAi−inducing entity, e.g., an siRNA, shRNA, or RNAi−inducing vector targeted to an influenza virus transcript and any of a variety of delivery agents. The invention further includes methods of use of the compositions for treatment of influenza.

Title: Anti H5N1 Highly Pathogenic Avian Influenza Virus Antisense Oligonucleotide Structure and its Use

Publication no.: CN 1936007A Assignee: Radio and Radiation Medicine Inst. Priority Date: Description: The invention relates to a structure of antisense oligonucleotide medicine to restrain

replicating H5N1 type HPAIV and the application. It has good specificity and could restrain the virus replicating in MDCK cell. In the model of rats, the lung sickness caused by virus would be relieved through nasal drip and intravenous injection to improve livability. The invention could be made into a new type biology engineer medicine.

The claims and specification are in Chinese, but based on the English abstract, CN ‘007 is directed to antisense oligonucleotides that prevent H5N1 type HPAIV replication and methods of using to treat influenza.

Title: Diagnostic Primers and Method For detecting Avian Influenza Virus Subtype

H5 and H5N1 Publication no.: EP 1761645 Title: Process For Detecting H5N1 Hypotype Avian Influenza Virus and Special-

purpose Reagent Kit Publication no.: CN 1274851C Assignees: Priority Date: Description: The invention disclosed a detection method for H5N1 subtype avian influenza virus


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and special purpose reagent case thereof. The reagent case comprises avian influenza A virus general primer NPF and NPL, specificity primer H5F and H5L of H5 subtype avian influenza virus hemagglutinin and specificity primer N1F and N1L of N1 subtype avian influenza virus neuraminidase; said NPF processes nucleotide sequence 1, said NPL processes nucleotide sequence 2, said H5F processes nucleotide sequence 3, said H5L processes nucleotide sequence 4, said N1F processes nucleotide sequence 5 and 6. The invention can be used not only for laboratory diagnosis and scientific research, but also for large−scale epidemiology survey.

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