UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD SANOFI-AVENTIS U.S. LLC, GENZYME CORP. AND

Transcription

1 UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD SANOFI-AVENTIS U.S. LLC, GENZYME CORP. AND REGENERON PHARMACEUTICALS, INC., PETITIONERS, V. IMMUNEX CORPORATION, PATENT OWNER. PATENT NO. 8,679,487 DECLARATION OF WILLIAM H. ROBINSON, PH.D., M.D.! 03/23/ DATE NAME

2 TABLE OF CONTENTS I. Education and Experience... 1 II. Compensation... 5 III. Legal Considerations... 6 A. Priority... 6 B. Written Description... 7 C. Enablement... 8 IV. Level of Ordinary Skill in the Art at the Time V. Task Summary V. Generating and Testing Human Antibodies A. Antibodies B. Generating Monoclonal Antibodies Using Transgenic Mice C. Competition Testing VI. The 487 Patent and Its Related Applications A. The 487 Priority Application (The 816 Application) B. The 487 Patent Claims C. Prosecution History of the 487 Patent and Related Patent Applications VII. No Application Filed Before the July 1, Application Sufficiently Describes The Claims of the 487 Patent or Enables One of Skill to Practice Their Full Scope Without Excessive Experimentation A. The Common Specification Does Not Specifically Identify Any Antibodies that Compete with the Reference Antibody B. The Six Antibodies Disclosed in the Common Specification Are Not Representative of the Claimed Antibody Genus C. One of Skill in the Art Could Not Make and Use the Full Scope of the Claims Based on the 816 Application Without Excessive Experimentation... 65

3 DECLARATION OF WILLIAM H. ROBINSON, PH.D., M.D. 1. I, William H. Robinson, Ph.D., M.D., declare as follows: 2. My name is Dr. William H. Robinson. I am a professor of Immunology and Rheumatology and a physician who is board certified in Rheumatology by the American Board of Internal Medicine. I am over the age of twenty-one (21) years, of sound mind, and capable of making the statements set forth in this Declaration. I am competent to testify about the matters set forth herein. All the facts and statements contained herein are within my personal knowledge and they are, in all things, true and correct. 3. I have been asked by Regeneron Pharmaceuticals, Inc. ( Regeneron ), and Sanofi-Aventis U.S. LLC and Genzyme Corp. ( Sanofi ) (collectively Petitioners ), to submit this declaration in support of their challenge to the validity of the claims of U.S. Patent No. 8,679,487 ( the 487 Patent ). I. Education and Experience 4. My curriculum vitae is attached as Exhibit I am currently an Associate Professor of Medicine (with tenure) in the Division of Immunology and Rheumatology and the Department of Medicine at Stanford University. I have held an appointment as an associate professor since I joined Stanford University as an assistant professor in

4 6. I received a Ph.D. in Immunology from Stanford University in I received an M.D. from Stanford University in I completed my internship and residency training (research pathway) in Internal Medicine at the University of California, San Francisco, from I completed my Rheumatology Fellowship training at Stanford University from I served as a Research Associate in the Department of Neurology and Neurological Sciences and Staff Physician in the Division of Immunology and Rheumatology at Stanford University from I am a Diplomat of the American Board of Internal Medicine in Rheumatology. 7. I have worked in the field of immunology, autoimmunity and antibodies since I co-founded the Human Immune Monitoring Center at Stanford University. I direct the VA Palo Alto Proteomics Core facility. I am the co-director of the National Institute of Health (NIH) T32 Training Program in Adult and Pediatric Rheumatology at Stanford University. I am the Principal Investigator of the Stanford NIH Accelerating Medicines Partnerships (AMP) Technology Center. I am the co-principal Investigator of the UCSF-Stanford Arthritis Foundation Center of Excellence. 8. During my career I have served on numerous committees and panels. I previously served on the editorial boards of Arthritis Research and Therapy and Clinical Immunology, and currently serve on the editorial board of Arthritis and - 2 -

5 Rheumatology. I serve on the NIH s National Institute of Arthritis Musculoskeletal and Skin Diseases (NAIMS) ACTS Study Section. I previously served on the Board of Directors of the Federation of Societies of Clinical Immunology (FOCIS) and the American College of Rheumatology s Rheumatology Research Foundation (RRF), and currently serve on the Board of Directors of the American College of Rheumatology. I am an elected member of the Henry Kunkel Society and the American Society of Clinical Investigation (ASCI). 9. My Stanford University laboratory pioneered several technologies to characterize the specificity and functional properties of antibodies, including protein arrays, lipid arrays, and most recently large-scale sequencing approaches. My laboratory is applying these technologies to identify the targets of antibody responses, investigate mechanisms underlying disease, and to develop novel therapeutic approaches. My laboratory works primarily in the field of autoimmunity on rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis. We are also conducting studies on infectious diseases to characterize the antibody response to influenza vaccination, staphylococcal infection and rotavirus infection, as well as cancer to characterize the antibody response in cancer nonprogressors and in response to checkpoint inhibitors. I have over 165 peerreviewed publications. I am an inventor on over 20 patent applications, and - 3 -

6 technologies developed in my laboratory have been licensed to 9 companies in the biotechnology industry. 10. My Stanford University laboratory developed a cell-barcoding technology that enables the large-scale sequencing of antibody and T cell repertoires. This technology attaches a unique oligonucleotide cell barcode to all the cdna generated from each individual B cell, T cell or other cell. In contrast to other approaches to sequencing the antibody repertoire, this cell barcoding technology overcomes key challenges: First, it enables accurate pairing of the native heavy and light chain immunoglobulin genes expressed by individual B cells. Second, it determines full-length variable region sequences of the heavy and light chain, enabling generation of recombinant antibodies containing the complete native antibody binding domain (Fab). Third, it enables correction of sequence errors arising from PCR and high-throughput sequencing, thereby enabling one to distinguish bona fide somatic hypermutation arising from affinity maturation from process artifact. Together, these properties enable robust and high-fidelity analysis of antibody responses. My laboratory is using this cell-barcoding technology to identify the key antibodies mediating effective pathogenic immune responses in autoimmune diseases, and protective responses in cancer and infectious diseases. 11. The cell-barcoding technology my laboratory developed enables highfidelity analysis of the affinity maturation of B cells, and thereby the accurate - 4 -

7 identification of B cells expressing antibodies with single and multiple amino acid substitutions. We are using our antibody repertoire sequence datasets to bioinformatically and experimentally (via expression and testing of recombinant antibodies) determine the specific amino acids in antibody complementarity determining regions (CDRs) responsible for antigen binding and function. 12. Based on the cell-barcoding technology my Stanford laboratory developed, I co-founded Atreca, Inc. Atreca is a biotechnology company that performs analysis of antibody and T cell responses, and is developing therapeutic antibodies for cancer and other diseases. 13. Having the above knowledge and experience, I am well qualified to offer the opinions I express in this declaration. A detailed record of my professional qualifications, including a list of publications, awards, and professional activities, is set forth in my curriculum vitae. Ex II. Compensation 14. In consideration for my services, my work on this case is being billed to Regeneron and Sanofi at an hourly rate of $500 per hour, independent of the outcome of this proceeding. I am also being reimbursed for reasonable expenses I incur in relation to my services provided for this proceeding

8 III. Legal Considerations 15. I understand that the following standards govern the determination of whether a patent claim is entitled to an earlier priority date based on the filing of an earlier related application. I have applied these standards in my analysis of whether claims of the 487 Patent are entitled to any earlier priority date before the actual filing of U.S. Patent Application No. 12/829,231 (the 231 Application ), which issued as the ʼ487 Patent. A. Priority 16. I understand that a patent may be entitled to claim priority to the filing date of an earlier filed provisional or non-provisional patent application if certain conditions are satisfied. If those conditions are satisfied, the patent is said to have an earlier effective filing date. 17. I understand that a patent is entitled to an effective filing date of an earlier-filed non-provisional patent application if 1) the patent was filed prior to the issuance or abandonment of the earlier-filed non-provisional patent application, 2) the patent contains a specific reference to the earlier-filed non-provisional application, 3) the patent has at least one inventor in common with the named inventors of the earlier-filed non-provisional application and 4) the earlier-filed non-provisional application provides adequate written description and enablement support for the claims of the patent. I also understand that these priority claims can - 6 -

9 be chained together so that if patent A was filed prior to the issuance of patent B, and patent B was filed prior to the issuance of patent C, then patent A may be entitled to the filing date of patent C even if patent C had issued before patent A was filed. I further understand that in such a case, each earlier application in the chain must provide written description and enablement support for the claims of the patent. For example, for patent A to be entitled to the filing date of patent C, the applications for both patents B and C must provide written description and enablement support for the claims of patent A. B. Written Description 18. I further understand that, in the patent application process, the applicant may keep the originally filed claims, or change the claims (i.e., amend the claims) between the time the patent application is first filed and the time a patent is issued. An applicant may also add new claims, as long as the added subject matter is supported by the specification. These changes may narrow or broaden the scope of the claims. 19. I further understand that the inquiry to determine whether a claim satisfies the written description requirement is performed from the viewpoint of a person having ordinary skill in the field of technology of the patent as of the relevant filing date. The written description is sufficient if it reasonably conveys to - 7 -

10 those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date. 20. The written description requirement may be satisfied by any combination of the words, structures, figures, diagrams, formulas, etc., contained in the patent application. I understand that this requirement is satisfied if a person of ordinary skill in the art reading the patent would recognize that the patent application described the invention as claimed, even if the description does not use the exact words found in the claims. 21. I also understand, that when a patent claims a genus, such as a genus of antibodies, using functional language or otherwise, that the particular application must demonstrate that the patentee truly invented the genus by disclosing either a representative number of species falling within the scope of the genus or specifically identifying structural features common to the members of the genus so that one of skill in the art can visualize or recognize the members of the genus. C. Enablement 22. I understand that a patent claim is not enabled by an earlier application if that application does not describe the manner and process of making and using [the invention], in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly - 8 -

11 connected, to make and use the same. Conversely, I understand that a claim is enabled when a person having ordinary skill in the art, after reading the application, could practice the full scope of the claimed invention without undue experimentation. To be enabled, an application need not include minor details that are well known in the art to a person of ordinary skill; otherwise, the specification of the application would be of enormous and unnecessary length. Hence, a claim can be enabled based, in part, on the knowledge of minor details that are well known by one of ordinary skill. However, a claim is not enabled if the application does not describe the novel aspects of the invention, even if known by one of ordinary skill in the art. 23. I further understand that there are a number of factors that may be considered when determining whether experimentation is undue experimentation that precludes enablement: (1) the quantity of experimentation necessary; (2) the amount of direction or guidance presented; (3) the presence or absence of working examples; (4) the nature of the invention; (5) the state of the prior art; (6) the relative skill of those in the art; (7) the predictability or unpredictability of the art; and (8) the breadth of the claims. I understand that not all the factors need be reviewed when determining whether a disclosure is enabling; what is relevant depends on the particular facts

12 IV. Level of Ordinary Skill in the Art at the Time 24. I understand that a person having ordinary skill in the art may be defined by factors such as: (a) the levels of education and experience of the inventor and other persons actively involved in the field; (b) the types of problems encountered in the field; (c) prior art solutions to those problems; (d) rapidity with which innovations are made; and (e) the sophistication of the technology. 25. I understand that the relevant timeframe for assessing the priority of the claims of the 487 Patent for the purposes of this declaration is assumed to be May 1, 2001, the earliest claimed priority date of the application that led to the 487 Patent. Unless otherwise specifically noted, all of my opinions expressed herein regarding a person of ordinary skill in the art apply to a person of ordinary skill in the art as of May 1, However, my opinions would be the same if the relevant period were determined to be later, including any of the filing dates from the applications in the line of priority leading to the 487 Patent, i.e., December 19, 2002, October 27, 2006, or November 13, This is because I am unaware of any developments in that intervening time period that would have meaningfully altered how a person of ordinary skill, having knowledge of the relevant art, would have viewed the issues I address. 26. I understand that Dr. Zurawski has determined that: A person of ordinary skill in the art relevant to the 487 Patent and the earlier applications in its

13 family would have had at least a Ph.D. or an M.D., with research experience in immunology, biochemistry, cell biology, molecular biology, or a related field or at least 2-3 years of professional experience in one or more of those fields. Furthermore, a person of ordinary skill in the art would have had an understanding of how one generates antibodies to a chosen antigen from animals (e.g., mice), and how one isolates human antibodies by generating human antibodies directly from transgenic animals or transforming animal antibodies into human antibodies. I agree with Dr. Zurawski regarding the level of ordinary skill in the art with respect to the 487 Patent and its family of earlier applications, and have applied this understanding in my analysis and opinions set forth herein. In addition, it is my opinion that the level of ordinary skill in the art would not appreciably change if the date for making this determination was on May 1, 2001, or later, including December 19, 2002, October 27, 2006, or November 13, V. Task Summary 27. I have been asked to review the 487 Patent and the applications that the ʼ487 Patent claims priority to. I have also been asked to provide my opinion from the perspective of a person of ordinary skill in the art, having knowledge of the relevant art as of May 1, 2001, whether the claims of the 487 Patent find priority support in certain of the related patent applications which precede the filing of the application that led to the 487 Patent. As I understand this inquiry, it

14 requires that I assess whether one of skill in the art at the time reading a particular priority application would understand that the inventors had in fact invented the subject matter claimed in the claims of the later-issued ʼ487 Patent. It further requires that one of skill in the art could make and use the full scope of the claims of the ʼ487 Patent based on the disclosure included in the priority application without undue experimentation. The qualifications and abilities of such a person are described in paragraphs above. I have also been asked to consider whether any of my opinions would change if the date were later including December 19, 2002, October 27, 2006, or November 13, 2008, instead of May 1, The considerations on which my opinions are based would not have materially changed if this date were as late as November 13, 2008 as explained in this declaration. 28. In preparing this declaration, I have considered the 487 Patent in its entirety, the related applications to which it claims priority, the prosecution history of the 487 Patent and portions of the prosecution histories of its related applications, and the general knowledge of persons of ordinary skill in the art, as of May 1, 2001, December 19, 2002, October 27, 2006, and November 13, In addition, I have reviewed certain references cited herein in my declaration that support my opinions, including the references and documents listed below:

15 Exhibit Description 1001 U.S. Patent No. 8,679,487 ( 487 Patent ) 1002 Excerpts from the File History of U.S. Patent No. 8,679,487 (U.S. Patent Application No. 12/829,231 ( 231 Application )) 1003 Excerpts from the File History of U.S. Patent Application No. Application No. 14/175,943 ( 943 Application ), which is a continuation of U.S. Patent No. 8,679, U.S. Patent Publication No. 2008/ ( Stevens or 035 Publication ) 1008 U.S. Patent Application No. 09/847,816 ( ʼ816 Application ) 1017 Harlow & Lane, Antibodies, A Laboratory Manual (1988) 1021 Borrebaeck, Antibody Engineering, Second Ed. (1995) 1022 Kussie et al., A single engineered amino acid substitution changes antibody fine specificity, J Immunol 1994, 152: Winkler et al., Changing the Antigen Binding Specificity by Single Point Mutations of an Anti-p24 (HIV-1) Antibody, J Immunol 2000, 165: Vasudevan et al., A single amino acid change in the binding pocket alters specificity of an anti-integrin antibody AP7.4 as revealed by its crystal structure, Blood Cells, Molecules, and Diseases 32, 2004, Zola, Monoclonal Antibodies A Manual of Techniques, CRC Press, Perez et al., Epitope Mapping of 10 monoclonal antibodies against the pig analogue of human membrane cofactor protein (MCP), Immunology 1999, 96: Alberts B. et al., Molecular Biology of the Cell, 4th ed. 2002, Garland Science, New York

16 Exhibit Description 1028 U.S. Patent Application No. 10/324,493 ( 493 Application ) 1029 U.S. Patent No. 7,186,809 ( 809 Patent ) 1030 U.S. Patent Application No. 11/588,696 ( 696 Application ) 1031 U.S. Patent No. 7,465,450 ( 450 Patent ) 1032 U.S. Patent Application No. 12/291,702 ( 702 Application ) 1033 Cooper et al., Role of heavy chain constant domains in antibodyantigen interaction. Apparent specificity differences among streptococcal IgG antibodies expressing identical variable domains, J Immunol 1993, 150: McLean et al., Isotype Can Affect the Fine Specificity of an Antibody for a Polysaccharide Antigen, J Immunol 2002, 169: Walter et al., Analysis of human antibody sequences in Antibody Engineering, A Practical Approach (1996) 1036 Berman & Alt, Human heavy chain variable region gene diversity, organization and expression, International Review Immunology 1990, 5: Alberts B. et al., Molecular Biology of the Cell, 3d ed. 1994, Garland Science, New York 1038 U.S. Patent No. 5,599,905 ( 905 Patent ) 1039 U.S. Patent No. 9,587,026 ( 026 Patent ) 1040 Brüggemann et al., Human Atibody Production in Transgenic Animals, Arch. Immunol. Ther. Exp. 2015, 63: Nicholson et al., Antibody Repertoires of Four- and Five-Feature Translocus Mice Carrying Human Immunoglobulin Heavy Chain and ϰ and λ Light Chain Yeast Artificial Chromosomes, J Immunol 1999, 163:

17 Exhibit Description 1042 King, D., Applications and Engineering of Monoclonal Antibodies, Chapter 1, (1998) 1043 Minton et al., Microbiota: A natural vaccine adjuvant. Nature Reviews Immunology, 2014; 14: Lee et al., Complete humanization of the mouse immunoglobulin loci enables efficient therapeutic antibody discovery, Nature Biotechnology 2016; 32: Lefranc, Nomenclature of the Human Immunoglobulin Heavy (IGH) Genes, Exp Clin Immunogenet 2001;18: Lefranc, Nomenclature of the Human Immunoglobulin Kappa (IGK) Genes, Exp Clin Immunogenet 2001;18: Lefranc, Nomenclature of the Human Immunoglobulin Lambda (IGL) Genes, Exp Clin Immunogenet 2001;18: V. Generating and Testing Human Antibodies A. Antibodies 29. Antibodies are a type of protein. They are generally characterized by their Y structure and highly specific binding affinity to a particular target (e.g., a molecule, receptor, virus, etc.). Although not an absolute rule, highly specific usually means that a particular antibody binds to just one target. The target of an antibody is referred to as the antigen. 30. Like all proteins, antibodies are made of a string of amino acids. There are twenty known amino acids which are combined together in different arrangements or sequences to form antibodies. The twenty available amino acids

18 provide a wide variety of chemical properties and nearly all chemical diversity of proteins in the body arises from stringing the twenty amino acids together in varying sequences and lengths. The twenty amino acids are listed and described in the table below: Ex [Harlow & Lane, Antibodies, A Laboratory Manual (1988)] at 660 (Appendix II). 31. Antibodies are generally made up of four strings of amino acids: two identical light chains and two identical heavy chains. Each light chain is bonded to a heavy chain by a disulfide bond (a bond between two sulfur atoms). The heavy chains are also bonded together by disulfide bonds. Thus, the four bonded chains form one antibody. As the names imply, light chains are composed

19 of fewer amino acid residues (e.g., around 220 residues per light chain) than heavy chains (e.g., around 440 residues per heavy chain). Accordingly, an entire antibody is comprised of around 1,320 amino acid residues. 32. As shown below, antibodies are graphically represented as Y shaped molecules (left), which is a fair approximation of their actual shape (right). Ex [Borrebaeck. Antibody Engineering, Second Ed. (1995)] at Each heavy and light chain is subdivided into a constant region ( C H and C L above) and variable region ( V H and V L above). While there is some amino acid sequence diversity in the constant region, nearly all sequence diversity in antibodies is found in the variable region. Accordingly, the variable region is predominantly responsible for an antibody s binding properties. 34. Each variable region contains three relatively short complementarity determining regions ( CDRs ). The CDRs are the portions of an antibody that actually bind to an antigen. Accordingly, they are often grouped and termed the

20 antigen binding site and/or the hypervariable region. In the illustration below, the CDRs are depicted as dark strips. Ex [Harlow and Lane] at As shown above, each antibody contains two antigen binding sites, one on each arm of the Y. Each antigen binding site is made of six CDRs (three light chain and three heavy chain CDRs). 36. The part of an antigen to which an antibody binds is called the epitope. An antibody s binding properties, such as its specificity for a particular epitope on an antigen and its affinity for that epitope, are dependent on the antibody s amino acid sequence, often referred to as its primary structure. An antibody s primary structure determines its three-dimensional structure, which ultimately determines the antibody s antigen-binding characteristics. In fact, there are numerous reported instances in the scientific literature where single amino acid changes to an antibody sequence have altered the antibody s binding characteristics. Ex [Kussie, et al. J Immunol 1994; 152: ] at Title,

21 Abstract, 146, 148, 151 ( A single engineered amino acid substitution changes antibody fine specificity ); Ex [Winkler, et al. J Immunol 2000; 165: ] at 4505, ( Changing the Antigen Binding Specificity by Single Point Mutations of an Anti-p24 (HIV-1) Antibody ); Ex [Vasudevan et al., Blood Cells, Molecules, and Diseases 32 (2004) ] at ( A single amino acid change in the binding pocket alters specificity of an anti-integrin antibody AP7.4 as revealed by its crystal structure. ). In addition to an antibody s primary structure, non-covalent interactions can also contribute to the antibodyantigen binding interaction, including van der Waals forces, hydrophobic forces, electrostatic forces, and hydrogen bonds. 37. Light and heavy chains are sorted into various classes based on the sequence of amino acids in the constant region. Heavy chains are sorted into five classes: IgA, IgD, IgE, IgG, and IgM and light chains are sorted into two classes: Kappa ( κ ) and Lambda ( λ ). These different antibody classes are shown below in Table 2.1 from Harlow and Lane

22 Ex [Harlow and Lane] at 10. The variation in heavy chain polypeptides allows each immunoglobulin class to function in a different type of immune response or during a different stage of the body s defense. For example, the IgG class of antibodies provides the majority of antibody-based immunity against invading pathogens. It is also the only antibody capable of crossing the placenta to give passive immunity to the fetus. 38. In addition to every light and heavy chain being a member of a particular class, light and heavy chains are also divided into families based on the amino acid sequence in the variable region. Ex [Walter et al. Analysis of human antibody sequences in Antibody Engineering, A Practical Approach. (1996)] at In general, there are eighteen light chain families and seven

23 heavy chain families. Human kappa light chains are generally organized into seven different families (V κ 1 to V κ 7) with the first four families (V κ 1 to V κ 4) generally predominating. Ex [Lefranc. Nomenclature of the Human Immunoglobulin Kappa (IGK) Genes. Exp Clin Immunogenet 2001;18: ] at 163. Similarly human lambda chains are organized into 11 families (V λ 1 to V λ 11) with the first three (V λ 1 to V λ 3) being the most predominant. Ex [Lefranc. Nomenclature of the Human Immunoglobulin Lambda (IGL) Genes. Exp Clin Immunogenet 2001;18: ] at 243. Human V H domains generally fall into seven separate families V H 1 to V H 7. Ex [Lefranc. Nomenclature of the Human Immunoglobulin Heavy (IGH) Genes. Exp Clin Immunogenet 2001;18: ] at B. Generating Monoclonal Antibodies Using Transgenic Mice 39. Monoclonal antibodies are antibodies that are generated by clones of the same immune cell. Monoclonal antibodies produced by these cell clones share the same amino acid sequence and bind to the same epitope of an antigen. 40. One way that was developed in the 1970s by Milstein and Köhler for generating monoclonal antibodies was the use of rodents, such as wild-type mice, and hybridoma technology. Ex [King, D., Applications and Engineering of Monoclonal Antibodies, Chapter 1, (1998)] at Using this technique, B cells able to make antibodies to a particular antigen are obtained from a rodent and

24 fused together with myeloma cells to generate hybrid cells called a hybridoma. Ex [King] at These hybridomas which generate particular monoclonal antibodies can be separated and grown in culture to generate a large quantity of specific monoclonal antibodies. Ex [King] at While the use of this method was suitable to generate a large quantity of monoclonal antibodies specific to a particular antigen, unfortunately, the use of monoclonal antibodies generated by other species like rodents, were not found to be suitable for use in humans due to the immune response that they elicit. Ex [King] at 18. As a result, scientists sought to develop other ways to generate human monoclonal antibodies that would be tolerated by a human immune system. 42. One method that was developed to generate human monoclonal antibodies in the 1990s was the use of mice that had been genetically engineered to express human antibodies instead of mouse antibodies i.e., human antibody transgenic mice. Ex [King] at Human antibody transgenic mice are mice that have had DNA encoding human antibody genes inserted into their genome for the generation and production of human antibodies. Transgenic mice are created by inserting DNA into embryonic stem cells which are then injected into an embryo. Ex [King] at 21. This technique is used to add DNA encoding human antibody genes into the mouse s genome and also to inject DNA for disrupting or knocking out a target gene in a mouse. This latter approach is

25 used to create mice that are unable to make mouse antibodies. When these socalled mouse antibody knockout mice are bred with mice capable of making human antibodies, human antibody transgenic mice result. These so-called human antibody transgenic mice are mice capable of making only human antibodies. 43. The method used to make antibodies to a specific antigen using human antibody transgenic mice is generally the same as that which has been used for over two decades prior to 2001 with wild-type mice and hybridomas. This procedure is described in detail in Harlow and Lane (1988) (Ex. 1017). Mice are first injected with an antigen and once a good humoral response is exhibited, a screening methodology is developed and tested. Ex [Harlow and Lane] at p After an appropriate screening procedure is developed, the next step is production of hybridomas capable of generating monoclonal antibodies to the antigen. Ex [Harlow and Lane] at p For this procedure, the mice may be boosted with the antigen and then sacrificed. Antibody secreting B cells are isolated from the appropriate tissue, such as the spleen, and mixed with myeloma cells, which are subsequently fused in polyethylene glycol. Ex [Harlow and Lane] at 196. After fusion, the fused cells are diluted in selective medium (called HAT medium) which select for hybridomas, and plated in a multiwell tissue culture dish. Ex [Harlow and Lane] at 196, 204. After about a week of culturing, samples of the tissue culture supernatants are removed from wells and

26 screened for the production of the appropriate antibodies. Ex [Harlow and Lane] at 196. This screening procedure identifies the hybridomas that produce the antibodies of interest. As shown in Figure 6.3 from Harlow and Lane, this process can take between 3 months to 14 months to accomplish: Ex [Harlow and Lane] at p

27 44. An antibody s heavy chain is generally arranged in variable (V), diversity (D), joining (J) and constant gene segments, while its light chain is generally arranged in V, J and constant gene segments. The rearrangement of these gene segments to produce a diverse repertoire of antibodies is generally called somatic recombination V(D)J recombination for heavy chains and VJ recombination for light chains. The human antibody transgenic mice utilized in Examples 3, 4, 8 and 9 in the 487 Patent, when compared to the complete human antibody gene locus possess reduced numbers of human heavy chain and light chain V genes, reduced numbers of human heavy and light chain J genes, only possess heavy chain IgM and IgG1 constant regions (missing IgD, IgG2, IgG3, IgG4, IgA and IgE), and only possess one kappa light chain constant region (missing the lambda light chain constant region). Ex [ 487 Patent] at 38:18-39:20 (referencing U.S. Pat. No. 5,770,429 and Fishwild et al., High-avidity human IgG kappa monoclonal antibodies from a novel strain of minilocus transgenic mice. Nature Biotechnology, 1996; 14: ). Due to the limited set of heavy and light chain V, D (only for heavy chain), J and constant region genes possessed by the transgenic mice described in the ʼ487 Patent, immunization of such mice with an antigen does not provide a full antibody repertoire against the antigen. Ex [Bruggemann et al, Human antibody production in transgenic animals. Arch. Immunol. Ther. Exp (Warsz), 2015; 63: ] at Next-generation

28 human antibody transgenic mice that contain the full set of human heavy and light chain V, D (only for heavy chain), and J region genes produce broader and more diverse antibody responses following immunization with an antigen. Ex [Nicholson et al, Antibody repertoires of four- and five-feature translocus mice carrying human immunoglobulin heavy chain and kappa and lambda light chain yeast artificial chromosomes. J. Immunology, 1999; 163: ] at ; Ex [Lee et al. Complete humanization of the mouse immunoglobulin loci enables efficient therapeutic antibody discovery. Nature Biotechnology 2016; 32: ] at 356, It is well established that beyond the repertoire of the human heavy and light chain V, D, and J genes in a particular human antibody transgenic mouse, multiple additional factors influence the diversity and specificity of the monoclonal antibodies ( mabs ) generated following immunization. The immunization regimen, adjuvant utilized, form of antigen used as an immunogen, and the methods used to generate hybridomas and mabs all can significantly influence the diversity and specificity of the mabs generated. Ex [Harlow and Lane] at ; Ex [Zola, Monoclonal Antibodies A Manual of Techniques, CRC Press, 1987] at The genetic background and major histocompatibility complex (MHC) alleles possessed by the human antibody transgenic mice are also anticipated to have a significant impact on the antibody repertoire following

29 immunization. Finally, environmental factors and the microbiome of the mice are also known to influence immune and antibody responses following immunization. Ex [Minton et al. Microbiota: A natural vaccine adjuvant. Nature Reviews Immunology, 2014; 14: ]. Thus, to comprehensively define the repertoire of antibodies to a particular antigen target or immunogen, a spectrum of different immunization regimens, adjuvants, mab generation approaches, genetic backgrounds, and microbiomes would need to be examined. C. Competition Testing 46. Once antibodies are isolated from transgenic mice, researchers need to conduct tests to characterize the antibodies they have generated and identified. One type of test that can be performed is called a competition assay. Antibody competition assays generally assess the capability of two antibodies to bind to the same or proximate epitope on an antigen. Antibodies that bind to the same or a proximate epitope will compete with one another for binding to the same antigen as one antibody will interfere with the binding of the other antibody and vice versa. Antibodies need not bind to the same epitope on an antigen in order to compete with one another for binding. Because antibodies are large molecules (between 146 for IgG1 to 970 kda for IgGM), they can also sterically inhibit other antibodies from binding to the same antigen and hence exhibit antibody-antibody competition. In addition, even if antibodies don t bind to the same or a proximate

30 epitope on an antigen or sterically interfere with the binding of another antibody, the binding of a first antibody to an antigen can cause conformational changes that may hide the binding site of the second antibody and prevent that antibody from binding. This is another instance that would result in antibody-antibody competition. 47. As of May 1, 2001, several different assays were known in the art for assessing antibody-antibody competition with respect to a particular antigen like human IL-4R. These include, for example, a competitive flow cytometry assay and competition tests using surface plasmon resonance (SPR). Each of these is described below. 48. An example of a competitive flow cytometry assay is described in Ex [Perez, et al. 1999], Epitope Mapping of 10 monoclonal antibodies against the pig analogue of human membrane cofactor protein (MCP), Immunology 1999, 96: In that assay, porcine peripheral blood mononuclear cells (PMBC) were incubated with an excess of unlabeled anti-mcp (membrane cofactor protein) mabs (first mab) at 4 o C for 15 min. Ex [Perez] at 664. Next, cells were incubated with a biotin-labelled mab (second mab), at a previously identified submaximal concentration at 4 o C for 30 min. Id. Following the second incubation step, the cells were washed and incubated with streptavidin-phycoerythrin at 4 o C for 15 min. Id. Fluorescence was measured using flow cytometry. In addition, an

31 irrelevant mab having an IgG1 isotype was used as a negative control. Id. The results were expressed as a ratio between the fluorescence intensity (mean channel) of the cells preincubated with the unlabeled mab and the fluorescence intensity obtained for the second biotinylated mab alone. Id. Perez then calculated the percentage of inhibition (PI) using the following formula: Ex [Perez] at The results of the Perez competition experiment are shown below in Table 2 from Perez showing percent inhibition of the second labelled mab by the first unlabeled mab: Ex [Perez] at Antibody-antibody competition can also be performed using a Surface Plasmon Resonance (SPR) instrument such as BIAcore. This technique is also described, for example, in Ex [Perez 1999]. Therein, Perez describes an

32 antibody-antibody competition assay using a sandwich assay configuration whereby rabbit anti-mouse immunoglobulin was immobilized on a BiaCore CM5 chip. Ex [Perez] at 665. Next, a first mab (referred to as the capture MAb ) was injected through a flow cell at 50 μg/ml for 4 min during which time SPR measurements were recorded (expressed as resonance units ( RU ). Ex [Perez] at 665. Unoccupied binding sites were then blocked by injecting 20 μl of mouse IgG (100 μg/ml) until no further SPR response was observed. Ex [Perez] at 665. The antigen, purified pig MCP, was then injected at 25 μg/ml for 4 min. Ex [Perez] at 665. The second mab (referred to as the detection mab ) was then introduced at 50 μg/ml for 4 min. and tested for binding to the antigen. Ex [Perez] at 665. All measurements were performed at 25 o C using a flow rate of 5 μl/min with HEPES-buffered saline as the running buffer and all mabs were tested in both directions as the first and second mab. Ex [Perez] at 665. In addition, the BIACore chip was regenerated by injection of 20 μl of 50 mm glycine, ph 2.0. Ex [Perez] at Using the SPR data, Perez compared the binding of the second mab to the binding of the same mab when used as the first (capture) mab and to all other antibodies tested and expressed the results as a percentage of inhibition. This inhibition data for all the antibodies tested is reported in Table 4 of Perez and is shown below:

33 Ex [Perez] at Specifically, Table 4 of Perez shows the percentage of inhibition determined as the ratio of the RU from each second (detecting) mab compared to the RU when the first (capturing) and second (detecting) mab are the same. Ex [Perez] at 667. When the first and second mabs bind simultaneously to the same antigen, they bind to separate, independent epitopes on the antigen. This is reflected by a low % inhibition. Where the second mab is blocked from binding to the antigen, this indicates that the epitope bound by the first and second mabs is the same or overlapping or that binding of the antigen to the first mab results in conformational changes on the antigen which prevents the second mab from binding. This is reflected by a higher % inhibition. Ex [Perez] at 665. Perez considered 50% inhibition or higher to be significant and used the SPR inhibition data to perform epitope mapping i.e., to identify groups of antibodies that appear to bind to the same or overlapping epitopes. Ex [Perez] at

34 53. As described above, each of these antibody competition methods includes specific conditions such as antibody concentrations, incubation times, wash steps, temperatures, etc. 54. In addition, I understand from my own personal knowledge and experience and from my review of Perez that different antibody assays may give different results in terms of whether two antibodies compete with one another for binding to the same antigen. Ex [Perez] at Perez compared antibody-antibody competition data using a flow cytometry assay (Table 2 of Perez) to that obtained using a surface plasmon resonance (SPR) (Table 4 of Perez) for the same antibody test pairs. Although the results in Perez show competition for many of the same antibody pairs using both flow cytometry and SPR, for certain of the antibody pairs the results are different depending on whether the flow cytometry or the SPR assay is used. Ex [Perez] at VI. The 487 Patent and Its Related Applications A. The 487 Priority Application (The 816 Application) 56. The 487 Patent issued from United States Application No. 12/829,231 (the 231 Application ) filed on July 1, Although the 231 Application was filed on July 1, 2010, based on the information provided on the cover of the 487 Patent, it claims a priority date of May 1, 2001 through a series

35 of continuation and division applications to United States Application No. 09/847,816 (the 816 Application ), filed on May 1, Each of these applications which predate the filing of the 231 Application starting with the 816 Application shares a Common Specification ( Common Specification ). 57. The 816 Application discloses the variable region heavy and light chain amino acid sequences for six antibodies: MAbs 6-2, 12B5, 27A1, 5A1, 63, and 1B7. Each of these antibodies is described as being capable of inhibiting activity of both IL-4 and IL-13. Ex [ 816 Application] at 0028:24: Despite these antibodies being characterized as capable of inhibiting activity of both IL-4 and IL-13, the 816 Application fails to provide the results for any test that demonstrates this capability. In fact, other than generally indicating that these antibodies are IL-4 and IL-13 antagonists, the 816 Application fails to describe any measurable characteristics for the disclosed antibodies. For example, the 816 Application does not disclose information pertaining to the potency for inhibiting IL-4 or IL-13 signaling, affinity (e.g., K a or K d ) for binding to IL-4R, or epitope for any of the disclosed antibodies. 58. The below description of how the antibodies of the invention relate to MAb 12B5 (an IgG1 isotype 1 ) exemplifies the shortcomings of the disclosure of the ʼ816 Application: 1 Ex ( 816 Application) at 0053:

36 Particular monoclonal antibodies of the invention are selected from the group consisting of MAb 12B5; a Mab that is crossreactive with 12B5; a MAb that binds to the same epitope as 12B5; a MAb that competes with 12B5 for binding to a cell that expresses human IL-4R; a MAb that possesses a biological activity of 12B5; and an antigen-binding fragment of any of the foregoing antibodies. In one embodiment, the antibody has a binding affinity for human IL-4R that is substantially equivalent to the binding affinity of 12B5 for human IL-4R. Ex [ 816 Application] at 0029: While this portion of the 816 Application mentions the same epitope as 12B5, cross-reactiv[ity] with 12B5, competes with 12B5, and a binding affinity for human IL-4R that is substantially equivalent to the binding affinity of 12B5, the 816 Application does not identify the epitope for the 12B5 antibody, its cross-reactivity, its binding affinity, or any antibodies that compete with the 12B5 antibody. The only information provided about mab 12B5 is its variable region sequences and a statement that it inhibits IL-4 and IL-13 binding and signaling with respect to IL-4R. 60. The steps for generating the 816 Application disclosed antibodies are the same as those commonly known at the time as described in Harlow and Lane (see discussion above). The 816 Application explains that [a]ntibodies specific

37 for IL-4 or IL-4R may be prepared by well-known procedures. Ex [ 816 Application] at 0026:6-9; Ex [ 816 Application] at 0027:14-17 ( Monoclonal antibodies may be produced by conventional procedures, e.g., by immortalizing spleen cells harvested from the transgenic animal after completion of the immunization schedule ). As described above, the procedure for isolating monoclonal antibodies to a target antigen from a host animal was well-known by May 1, 2001, as was using transgenic mice as the host animal. See To isolate the six antibodies disclosed in the 816 Application, the inventors followed the teachings of the prior art to inoculate transgenic mice with IL-4Rα and monitor the murine sera for antibody production. Ex [ 816 Application] at 0049: :11. As explained in Example four of the ʼ816 Application, the mice were kept on protocol [e.g., the immunization schedule] for 2 to 5 months. Ex [ 816 Application] at 0049: Following detection of significant antibody production in the murine sera (e.g., after 2 to 5 months), the murine B-cells were harvested and immortalized, forming hybridomas. Ex [ 816 Application] at 0049: :4. After allowing the hybridoma cultures to proliferate (thus secreting sufficient quantities of monoclonal antibodies for testing), the hybridoma cultures were screened for the ability to block the binding of IL-4 to IL-4R using ELISA. Ex [ 816 Application] at 0050:5-24. Antibodies that were found to block IL

38 4 binding to IL-4R were further tested for IL-4 and IL-13 antagonism by a prior art CD23 assay. Ex [ 816 Application] at 0050: :11. Performing the above steps, the inventors of the ʼ816 Application apparently identified six antibodies (i.e., MAbs 6-2, 12B5, 27A1, 5A1, 63, and 1B7). Ex [ 816 Application] at 0051:13 30 (describing MAb 6-2), 0053: :7 (describing MAb 12B5), 0054:10 11 (describing MAbs 27A1, 5A1, 63 and 1B7). B. The 487 Patent Claims 62. Claim 1 of the 487 Patent claims an isolated human antibody that competes with a reference antibody for binding to [hil-4r]... Although the term reference antibody is not used in the 816 Application, claim 1 states that the light chain of said reference antibody comprises the amino acid sequence of SEQ ID NO:10 and the heavy chain of said reference antibody comprises the amino acid sequence of SEQ ID NO:12. These sequence numbers correspond to the light and heavy chain variable regions of MAb 12B The claimed antibodies (e.g., isolated human antibod[ies] ) are not limited to any particular structure, such as by their amino acid sequences. Instead, the claimed isolated human antibodies are defined solely by how they interact with reference antibodies (i.e., compete). However, nowhere in the 816 Application is it stated that any of the disclosed antibodies competes with a reference antibody. In fact, it fails to disclose what it means for two antibodies to compete, how to

39 measure whether two antibodies compete, and at what threshold antibody-antibody interaction is sufficient to be considered competition. 64. As I explained above in paragraphs 53-55, the results from measuring antibody-antibody competition are highly dependent on the specific experimental protocol and conditions with which one measures competition. For example, the Perez reference shows that antibodies may be determined to compete under one assay, but not under another. See Ex [Perez] at 669 (observing confusing data where... some combinations of mabs, not competitive [as measured by flow cytometry], appear to compete [as measured by surface plasmon resonance]... ). The 816 Application s failure to provide any information pertaining to the competition assay, coupled with its failure to provide even one example of an antibody that competes with the claimed reference antibody, would cause any skilled artisan to doubt whether the inventors of the 487 Patent actually invented the claimed invention by May 1, 2001, when the 816 Application was filed. Indeed, if a skilled artisan were to actually invent a genus of antibodies that compete with a reference antibody, he or she would know to provide the results of the competition assay that was used to determine competition and to explain how the antibodies compete. The 816 Application provides no such disclosure. 65. Each of the dependent claims of the 487 Patent, claim 2 to 17, builds off of claim 1 but fails to provide any meaningful limitation to the genus of

40 antibodies that compete with a reference antibody. Claims 2 and 3 cover the antibody of claim 1 that blocks the reference antibody from binding to IL-4R or blocks antibody-antibody binding in the opposite direction. These claims largely overlap with claim 1 because antibodies that compete with one another for binding to IL-4R also block one another from binding to IL-4R. 66. Claim 4 covers the antibody of claim 1 that inhibits IL-4 from binding to IL-4R. As was the case for competes, claim 4 recites an inhibitory function without providing any indication of structural features or characteristics of antibodies that inhibit or even the cutoff between antibodies that inhibit and those that do not. Unlike the competition function recited in claim 1, however, the 816 Application discloses an IL-4 inhibition assay using ELISA. Ex [ 816 Application] at 0050: Claim 5 covers the antibody of claim 1 that inhibits the binding of IL to human IL-4 receptor. To the extent that claim 5 is interpreted to mean an antibody that inhibits association between IL-4Rα and the IL-13/IL-13Rα complex, there is no description in the 816 application of an antibody preventing this association. 68. Claims 6 and 7 are collectively directed to the antibody of claim 1 that inhibits IL-4 and IL-13 induced signaling. Once again, the 816 Application provides no indication of how much inhibition is required under the claim

41 language or at what concentration an antibody must provide the unknown level of inhibition. 69. Claims 8 10 cover antibodies with sequentially increasing binding affinities. These claims highlight the ambiguities discussed above regarding claims 1 7 because claims 8 10 actually provide threshold values for the claim limitations. For example, claim 10 covers the antibody of claim 1 with an affinity of at least 1 x Because the binding affinity constants recited in claims 8 and 9 are lower than the binding affinity constant recited in claim 10, any antibody that meets claim 10 also meets claims 8 and 9. Also, like antibody-antibody competition determinations, I note that the determination of binding affinities is very subjective and dependent on the methodology and specific conditions used to make the determination. 70. Claims 11 and 12 cover the antibody of claim 1 that is full-length and of any isotype (e.g., an antibody comprising any heavy chain constant region). Claim 13 covers an isolated human antibody of claim 1 that is a fragment of an antibody. Claims 14 and 15 cover an isolated human antibody of claim 1 that is a fusion protein and/or a single chain antibody. Claims collectively demonstrate the broad scope of the isolated human antibodies encompassed by claim 1 and other dependent claims. These isolated human antibodies include

42 not only full-length antibodies of any isotype, but also antibody fragments of almost any length, fusion proteins, and single chain antibodies or scfv s. 71. Claim 16 covers an isolated human antibody of claim 1 in a pharmaceutically acceptable diluent, buffer, or excipient. 72. Claim 17 covers an isolated human antibody of claim 1 that is part of a kit, which appears to indicate that the antibody is provided in a labeled container and/or otherwise includes instructions as described in one portion of the 487 patent specification. See 487 Patent 0022(29:21 26) ( Kits for use by medical practitioners include an IL-4 antagonist and a label or other instructions for use in treating any of the conditions discussed herein. ). C. Prosecution History of the 487 Patent and Related Patent Applications 73. As I note above, the 487 Patent was filed on July 1, 2010 as United States Application No 12/829,231 (the 231 Application ). Based on the information provided on the front of the 487 Patent, it claims a priority date of May 1, 2001 through a series of continuation and division applications beginning with United States Application No. 09/847,816 (the 816 Application ), filed on May 1, Specifically, the 231 Application claims priority to U.S. Patent Application No. 12/291,702 (the 702 Application ), which was filed on November 13, 2008; to U.S. Patent Application No. 11/588,696, which was filed on October 27, 2006; to U.S. Patent Application No. 10/324,493, which was filed

43 on December 19, 2002; and to the ʼ816 Application, which was filed on May 1, Immunex has also filed several applications which depend from the 231 Application including United States Application No. 14/175,943 (the 943 Application ). I note that the 943 Application recently issued as U.S. Patent No. 9,587,026. The relationship of these applications and the patents that issued from these applications is depicted below: 74. As I note above, each of the above mentioned applications in the ʼ487 Patent family shares a Common Specification. Based on my review of the Common Specification exemplified by the 816 Application, I understand that it specifically discloses only six antibodies by their corresponding variable region amino acid sequences. These antibodies are referred to in the Common

44 Specification as mab 6-2, mab 12B5, mab 27A1, mab 5A1, mab 63, and mab 1B As I discuss above, the first asserted priority application filed in the 487 Patent family, the 816 Application, was filed by Immunex on May 1, It included claims directed to methods of treating septic arthritis using IL-4 antagonists including soluble IL-4 receptor and antibodies that inhibit the binding of IL-4 to IL-4R. Ex [ 816 Application] at 0056 (Claims). The 816 Application was abandoned and never issued into a patent. 76. The next application, the 493 Application, was filed by Immunex on December 19, It originally included claims directed to IL-4 receptor antibodies having heavy and light chain sequences including the different amino acid sequences corresponding to the six antibodies mentioned in the Common Specification. Ex [ 493 Application] at (Claims). Specifically, the 493 Application claims encompassed antibodies including SEQ ID NOS. 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 and/or 26 and methods relating to those antibodies. During prosecution of the 493 Application, the claims directed to antibody SEQ ID NOS other than 10 and 12 (corresponding to the 12B5 antibody) were withdrawn and additional claims were added. The 493 Application ultimately issued as U.S. Patent No. 7,186,809 with claims generally covering various combinations of antibodies and antibody derivatives which comprise a light chain

45 variable region sequence of SEQ ID NO:10 and/or a heavy chain variable region sequence of SEQ ID NO:12. Ex [ 809 Patent], (Claims). 77. The next application filed in the 487 Patent family, the 696 Application, was filed by Immunex on October 26, The 696 Application originally included claims like those of the 816 Application, directed to methods for treating septic arthritis with IL-4 antagonists. Ex [ 696 Application] at 0051 (Claims). During prosecution of the 696 Application certain claims were cancelled and claim 1 was narrowed to specify that the IL-4 antagonist was an IL-4 receptor antibody including SEQ ID NOS. 10 and/or 12. The 696 Application eventually issued as U.S. Patent No. 7,465,450 with claims generally covering certain methods of treating septic arthritis with antibodies having amino acid sequences with SEQ ID NO: 10 in the light chain and/or SEQ ID NO: 12 in the heavy chain. Ex [ 450 Patent] at 0046 (Claims). 78. While not part of the ʼ487 file history, on July 3, 2008, Regeneron s U.S. Application Publication No. 2008/ (the 035 Publication ) published. Ex [ 035 Publication]. The 035 Publication is generally directed to high affinity antibodies to human IL-4 receptor and includes various claims directed to antibodies having specific heavy chain and light chain variable sequences (claims 3-13). Ex [ 035 Publication], (claims 3-13). Also included in the 035 Publication is data showing that the anti-hil-4r

46 antibodies disclosed in the 035 Publication compete for binding to a 12B5 antibody (referred to in the 035 Publication as the control antibody) (see Figs. 1A-1C), inhibit IL-4 binding to IL-4Rα (Example 3 and Table 3), inhibit the biological effects of IL-4 and IL-13 in cells (Examples 4 and 5 and Tables 4 and 5), and generally have binding affinity constants higher than 2 x 10 8 (Example 2 and Table 1 and claim 1). Ex [ 035 Publication]. 79. On November 13, 2008, four months after the publication of Regeneron s 035 Publication, Immunex filed the 702 Application. Ex [ 702 Application]. Unlike the claims that Immunex previously obtained in the 809 and the 450 Patents covering antibodies with light and heavy chains including the disclosed SEQ ID NOS. 10 and 12 and methods of treating septic arthritis with those antibodies, Immunex sought claims that cover all antibodies that compete with a control antibody including SEQ ID NOS. 10 and 12 for binding to IL-4R. This is shown for example, in Claim 1 of the 702 Application, below: 1. An isolated antibody that competes for binding to human IL-4 receptor with a fully human control antibody comprising the light chain variable region sequence (SEQ ID NO: 10) and the heavy chain variable region sequence (SEQ ID NO:12) of antibody 12B5. Ex [ 702 Application] at 0069 (Claim 1) (emphasis added). Immunex also sought other claims like claims 4-7 which were directed to IL-4 and IL-13 binding and signaling (biological effect) inhibition and claims 8-10 which were directed to

47 antibodies having binding affinities of at least 1 x 10 8, 1 x 10 9, and 1 x 10 10, respectively. Ex [ 702 Application] at (Claims). Immunex ultimately abandoned the 702 Application. 80. While the 702 Application was still pending, Immunex filed the 231 Application on July 1, Ex [ 231 Application]. The 231 Application included similar claims to the 702 Application, including the claim that ultimately issued as independent claim 1 of the 487 Patent. Ex [ 231 Application] at 0244 (claim 1). That claim, which is shown below, seeks to cover all isolated human antibodies that compete with a reference antibody including a light chain amino acid sequence of SEQ ID NO:10 and a heavy chain amino acid sequence of SEQ ID NO:12 for binding to human IL-4 receptor: 1. An isolated human antibody that competes with a reference antibody for binding to human IL-4 interleukin-4 (IL-4) receptor, wherein the light chain of said reference antibody comprises the amino acid sequence of SEQ ID NO:10 and the heavy chain of said reference antibody comprises the amino acid sequence of SEQ ID NO:12. Ex [ 487 Patent] at 0046 (Claim 1). 81. Additionally, on September 20, 2010 during prosecution of the 231 Application, Immunex addressed, among other things, the priority of the 487 Patent application. Specifically, Immunex specified that priority of the 487 Patent application was claimed back to May, 1, 2001 the filing date of the 816 application. Immunex also expressly disclaimed priority to three earlier

48 applications U.S. Patent Application Nos. 09/579,808, 09/665,343 and 09/785,934, which are the three earliest applications in the application chain. Specifically, Immunex stated: As noted in the Specification of the present application, priority for the instant application begins with U.S. Pat App. No. 09/847,816, filed May 1, 2001 (3005-US-CIP3). Priority is not claimed to any of U.S. Pat App. No. 09/579,808, filed May 26, 2000 (3005-US-NP), 09/665,343, filed September 19, 2000 (3005-US-CIP), or 09/785,934, filed February 15, 2001, published January 3, 2002 as U.S. Pub. No (3005-US-CIP2). Ex [Response to the Notice to File Missing Parts ( )] at On February 7, 2014, Immunex filed the 943 Application. Ex [ 943 Application]. The ʼ943 Application originally included claims similar to the 487 Patent, including the following independent claim 1 directed to different antibody sequences disclosed in the Common Specification: 1. An isolated antibody that competes with a reference antibody for binding to human IL-4 receptor, wherein: a. the light chain of said reference antibody comprises the amino acid sequence of SEQ ID NO:14 and the heavy chain of said reference antibody comprises the amino acid sequence of SEQ ID NO:16; or b. the light chain of said reference antibody comprises the amino acid sequence of SEQ ID NO:18 and the heavy chain of said reference antibody comprises the amino acid sequence of SEQ ID NO:20; or c. the light chain of said reference antibody comprises the amino acid sequence of SEQ ID NO:22 and the heavy chain of said reference antibody comprises the amino acid sequence of SEQ ID NO:

49 Ex [ 943 Application] at 0201 (Claim 1) (emphasis added); Ex [ 943 Application] at 0101 (Claim 1) (filed Aug. 14, 2015). 83. Like claim 1 of the 487 Patent, original claim 1 of the 943 Application covered a broad genus of antibodies that compete[] with a reference antibody for binding to human IL-4 receptor, wherein the light and heavy chains of the reference antibody include different possible variable chain sequences. Ex [ 943 Application] at 0201 (Original Claim 1). 84. On January 12, 2016, the Patent Examiner rejected claim 1 of the 943 Application for failure to provide proper written description support. Ex [ʼ943 Application, Non-Final Rejection (Jan. 12, 2016)] at The Examiner noted that original claim 1 covered yet to be discovered antibodies by virtue of identifying the claimed antibodies based solely on the function of competing with a reference for binding to a specific target. The Examiner also explained that while the specification discloses that the disclosed antibodies bind to human IL-4 receptor, it does not teach to which region or epitopes those antibodies bind. Ex [ʼ943 Application, Non-Final Rejection (Jan. 12, 2016)] at Specifically, the Examiner stated: The instant claims encompass antibodies that are yet to be discovered, which compete for binding to human IL-4 receptor with a specific antibody.... The instant claims encompass a genus of antibodies that are described only by their function of competing with a reference for binding to a

50 specific target. However, there is no identification of any particular sequence or structure of the antibody that must be conserved in order to provide the required function of competing with the recited antibodies for binding to the human IL-4 receptor.... [W]hile the specification teaches the disclosed antibodies bind the extracellular domain of human IL-4R, it does not teach whether all of the antibodies bind to the same epitope or compete for the same epitope. Ex [ʼ943 Application, Non-Final Rejection (Jan. 12, 2016)] at 5 (emphasis in original). 85. In addition, the Examiner noted that the specification does not disclose antibodies that compete with the recited antibodies. Ex [ʼ943 Application, Non-Final Rejection (Jan. 12, 2016)] at Likewise the Examiner stated that Immunex failed to provide sufficient disclosure for the broadly claimed genus of antibodies because Immunex did not identify any structure which results in an antibody that competes with a reference antibody. In particular, the Examiner explained: To provide evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus.... The specification... fails to disclose and there is no art-recognized correlation between the structure of the genus of yet to be discovered antibodies and the function of competing for binding to human IL-4 receptor with specific reference antibodies. In other words, the specification does not teach the structure which results in an antibody that competes with a reference antibody for binding to human IL-4 receptor. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus

51 [T]he skilled artisan cannot envision the detailed chemical structure of the encompassed genus of variant antibodies that compete for binding to human IL-4 receptor with specific recited antibodies... Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. Ex [ʼ943 Application, Non-Final Rejection (Jan. 12, 2016)] at (emphasis in original). 87. As a result, the Examiner determined that the [a]pplicants were not in possession of the encompassed antibodies that compete with a reference antibody for binding to human IL-4 receptor, wherein the reference antibody comprises specific heavy and light chain sequences, at the time of filing the current application. Ex [ʼ943 App., Non-Final Rejection (Jan. 12, 2016)] at On June 28, 2016, Immunex cancelled claim 1 of the ʼ943 Application. Ex [ʼ943 Application, Amendment & Response to Office Action], at 0072, (cancelling claim 1 and noting that Examiner s written description rejection was rendered moot by the instant amendments to the claims ). It appears that instead of continuing to pursue its broad functional competes with a reference antibody claims, Immunex instead elected to pursue a narrower claim, claim 17. Instead of claiming all isolated human antibodies that compete with a reference antibody, Claim 17 is specifically directed to specific isolated antibodies having specific CDR sequences identified in the Common Specification. Claim 17 is shown below:

52 Ex [ʼ943 Application, Amendment & Response to Office Action] at Claim 17 ultimately issued on March 7, 2017 as claim 1 of the 026 Patent. Ex [U.S. Patent No. 9,587,026] at 0047 (Claim 1). VII. No Application Filed Before the July 1, Application Sufficiently Describes The Claims of the 487 Patent or Enables One of Skill to Practice Their Full Scope Without Excessive Experimentation 90. Based on the above statements made by Immunex during prosecution of the 487 Patent and based on the information on the first page of the 487 Patent, Immunex appears to assert that priority for the instant application [later, the 487 Patent] begins with U.S. Pat App. No. 09/847,816, filed May 1, Ex [Applicants September 20, 2010 Response to Notice of Missing Parts] at I disagree with this assertion

53 91. I understand that the claims of a patent are not entitled to an earlier priority date just because a Patent Owner asserts priority to an earlier patent application on the cover of its patent or in the prosecution history. I also understand that in order for the claims to be entitled to an earlier priority date based on the filing of an earlier patent application, the claims in the patent-at-issue must have what is called written description and enablement support in the earlier application (or applications) to which priority is claimed. I discuss my understanding of these requirements above in the Legal Considerations section. 92. For the reasons discussed below, it is my opinion that the claims of the 487 Patent are not sufficiently described in any application at least prior to the filing of the 231 Application on July 1, Nor, do any these earlier applications enable one of skill in the art to practice the full scope of the 487 Patent claims without excessive experimentation. A. The Common Specification Does Not Specifically Identify Any Antibodies that Compete with the Reference Antibody 93. Based on my review of the Common Specification shared by the 487 Patent priority applications, I did not see any mention of any specific antibodies that are described as competing with a reference antibody, much less a reference antibody having a light chain comprising SEQ ID NO: 10 and a heavy chain comprising SEQ ID NO: 12 (for example, MAb 12B5). In particular, the Common Specification does not specifically disclose any antibody that falls within the broad

54 claimed genus of antibodies that compete with a reference antibody for binding to human IL-4 receptor. 94. Although the Common Specification discloses variable region amino acid sequences for six antibodies i.e., mabs 6-2, 12B5, 27A1, 5A1, 63, and 1B7, it does not describe or otherwise disclose that any of those six antibodies competes with mab 12B5 or any other reference antibody within the scope of the claims for binding to human IL-4R. Ex [ 816 Application] at 0028: Based on my review of the Common Specification, the term competes is used only six times in the same boilerplate sentence for each of the six IL-4R mabs identified. This boilerplate sentence for the 12B5 antibody is shown below: Particular monoclonal antibodies of the invention are selected from the group consisting of MAb 12B5; a Mab that is cross-reactive with 12B5; a MAb that binds to the same epitope as 12B5; a MAb that competes with 12B5 for binding to a cell that expresses human IL- 4R; a MAb that possesses a biological activity of 12B5; and an antigen-binding fragment of any of the foregoing antibodies. Ex [ 816 Application] at 0029:16-24 (MAb 12B5); 0028:21-39 (MAb 6-2), 0030:14-22 (MAb 27A1); 0031:6-14(MAb 5A1); 0031: :6 (MAb 63); 0032:29-36 (MAb 1B7). 96. In addition to not describing any antibody that competes with the claimed reference antibody, the Common Specification provides no other information that would lead one of skill in the art to conclude that one of the

55 disclosed antibodies competes with the reference antibody. For example, the Common Specification does not describe the epitope on IL-4 receptor to which any of the antibodies bind; it does not specify any antibodies that bind to the same epitope as any other antibody; and it does not describe any antibodies that are cross-reactive with another antibody. At most, the Common Specification describes that the six mabs inhibit IL-4 and IL-13 binding and/or signaling. Ex [ 816 Application] at 0051:14-22; 0053:11-14; 0054:9-0055: The Common Specification also does not describe competing for binding to IL-4 receptor, as required by all of the claims of the 487 Patent. Likewise, the Common Specification does not describe competing for binding to the IL-4 receptor with a reference antibody comprising SEQ ID NOS. 10 and 12. As shown above, the only statement with respect to competition in connection with any antibody that includes a light chain amino acid sequence of SEQ ID NO: 10 and a heavy chain amino acid sequence of SEQ ID. NO. 12 is the generic, unhelpful statement: a MAb that competes with 12B5 for binding to a cell that expresses human IL-4R. Ex [ 816 Application] at 0029: In addition to not specifying any antibodies that compete with a reference antibody that includes a light chain amino acid sequence of SEQ ID NO: 10 and a heavy chain amino acid sequence of SEQ ID. NO. 12, the Common Specification also does not describe any assay that could be used to assess whether

56 a particular claimed antibody competes with a reference antibody. Likewise, the Common Specification does not disclose data or results from any antibodyantibody competition assays that might be helpful to one of skill in the art in understanding what competition assay to perform, the conditions that should be used in such an assay, the criteria for identifying any antibodies that compete, or what results (e.g., percentages) from such assay would indicate competition, much less the identification of any antibodies that compete with the claimed reference antibody. 99. As a result, one of skill in the art would not conclude, as of May 1, 2001 (or as of December 19, 2002, October 27, 2006, or November 13, 2008) that Immunex invented any claimed isolated human antibodies that compete with a reference antibody for binding human IL-4 receptor, let alone all such isolated human antibodies as encompassed by the claims. B. The Six Antibodies Disclosed in the Common Specification Are Not Representative of the Claimed Antibody Genus 100. Even assuming that Immunex had described one (or even all) of the six antibodies disclosed in the Common Specification as competing with the reference antibody which it did not based on my review of the Common Specification, one of skill in the art would still not conclude that Immunex had invented all isolated human antibodies that compete with the claimed reference antibody for binding to human IL-4R

57 101. All claimed isolated human antibodies that compete with the claimed reference antibody for binding to human IL-4R as encompassed by the 487 Patent claims represent a stunningly broad genus. This is because the antibodies are claimed solely by their function of compet[ing] with a reference antibody for binding to human IL-4 [] receptor. 487 Patent, claim It is my opinion that the claimed genus of isolated human antibodies encompassed by this function is overly broad for a number of reasons First, the claims of the 487 Patent do not limit the claimed isolated human antibody to any particular structure, other than specifying that it has to be a human antibody. For example, the claimed isolated human antibody does not require any specific amino acid sequence. All that is required is that the claimed antibody compete with a reference antibody Likewise, based on claims in the 487 Patent, the claimed isolated human antibody is not limited to a full-length antibody of any particular isotype. Rather these claims specify that the claimed isolated human antibody may be a full-length antibody of any isotype, and may also be any antibody fragment, a fusion protein, or a single chain antibody (scfv). Ex [ʼ487 Patent] at 0046 (Claims 11-15); 487 Patent at 0017 (19:18-20) ( [T]he terms antibody and monoclonal antibody... encompass both whole antibodies and antigen-binding fragments thereof. ). Furthermore, the 487 Patent provides a very broad

58 definition of antigen-binding fragments which further expands the scope of the claimed antibodies. In particular, the 487 Patent specifications states that [e]xamples of such fragments include, but are not limited to, Fab and F(ab )2 fragments. Antibody fragments and derivatives produced by genetic engineering techniques are also contemplated for use. Ex [ 487 Patent] at 0017 (19:15-18) (emphasis added). Thus, the claimed isolated human antibodies include not only Fab and F(ab )2 antibody fragments, but all other possible fragments of a full length antibody and all derivatives produced by genetic engineering techniques. This encompasses a substantial number of potential antibodies In addition, the claimed isolated human antibodies are not limited to any particular light chain or heavy chain family, or a particular light chain or heavy chain type. As shown in Table 2.1 (discussed above at 37) from Harlow and Lane above, human antibodies may be one of 5 general isotypes. Ex [Harlow and Lane] at 10. As discussed above, each of these isotypes has a distinct heavy chain type consisting of γ for IgG antibodies, μ for IgM antibodies, α for IgA antibodies, ε for IgE antibodies, and δ for IgD antibodies. In addition the light chain type for each antibody isotype may be either κ or λ. Ex [Harlow and Lane] at 10. Also, as discussed above in 38, human antibodies may be comprised of one of a variety of different heavy and light chain families

59 106. In addition, it is known in the art that different antibody isotypes can alter the binding characteristics of mabs. Ex [Cooper et. al. Role of heavy chain constant domains in antibody-antigen interaction. Apparent specificity differences among streptococcal IgG antibodies expressing identical variable domains. J Immunol 1993; 150: ] at 2231 (finding that structural differences in the C H regions, particularly the C H 2 and C H 3 domains, can influence the apparent specificities of IgG molecules for multivalent Ag. ); Ex [McLean et al. Isotype Can Affect the Fine Specificity of an Antibody for a Polysaccharide Antigen. J Immunol 2002; 169: ] at 1379 ( Our results show that Ab fine specificity can be a function of isotype. ) Additionally, known human antibody heavy chains consist of different variable regions (V regions), diversity regions (D regions), joining regions (J region), and constant regions. Similarly, human antibody light chains consist of different variable regions (V regions), joining regions (J region), and constant regions. These different regions or segments are shown in the Figure 2.9 of Harlow and Lane shown below:

60 Ex [Harlow and Lane] at In humans there can be up to 51 functional V H segments, about 30 functional D segments, and six functional J H segments. Similarly for light chains which may be of either the κ or λ type, there are up to 40 functional V κ segments and five functional J κ segments for κ light chains, and 30 functional V λ segments and 4 functional J λ segments for λ light chains. Further, at the junctions between gene segments variable addition and subtraction of nucleotides occurs and contributes to the diversity of the third hypervariable region (termed N-region diversity). Ex [Walter et al. Analysis of human antibody sequences in Antibody Engineering, A Practical Approach. (1996)] at Thus, because the claimed isolated human antibody is not limited to any particular heavy or light chain type, V, D or J segment type, CDR length, or

61 structure, there is a substantial number of isolated human antibodies potentially within the scope of the claims of the 487 Patent Moreover, because claim 1 of the 487 Patent does not provide any information regarding the claimed isolated human antibody other than it must compete with the reference antibody, such a claimed antibody could be potentially comprised of sequences of almost any combination of amino acids. Specifically, the diversity of the antibody repertoire is generated by somatic recombination of separate gene segments for both the heavy and light chains, N-region diversity, the combination of the heavy and light chains, and somatic hypermutations that result from affinity maturation. Ex [Berman and Alt, 1990 Human heavy chain variable region gene diversity, organization and expression. International Review Immunology, 5: ] at 203. Together this results in a theoretical diversity of at least potential antibodies for the pre-immune naïve B cell repertoire. Ex [Alberts B. et al Molecular Biology of the Cell. 4th edition, Garland Science, New York.] at 1385; Ex [Alberts B. et al Molecular Biology of the Cell. 3rd edition, Garland Science, New York.] However, because the 487 Patent claims provide no structural limitations for the claimed antibody, they provide no guidance for which of the at least potential antibodies potentially fall within the scope of the 487 Patent claims

62 111. The at least number of potential antibodies assumes full-length, fully human antibodies. But the claimed isolated human antibody can also include antibodies of other isotypes, antibody fragments, fusion proteins and scfv s in addition to full length IgG antibodies. Ex [ 487 Patent] at 0046 (Claims 11-15) Second, the claims of the 487 Patent are not limited to a single reference antibody, but rather include multiple reference antibodies. In particular, claim 1 of the 487 Patent specifies that the light chain of said reference antibody comprises the amino acid sequence of SEQ ID NO:10 and the heavy chain of said reference antibody comprises the amino acid sequence of SEQ ID NO:12. Ex [ 487 Patent] at 0046 (Claim 1). The claims, however, do not provide any direction on where in the light chain and heavy chain those particular sequences must appear. Although the specification identifies SEQ ID NO:10 as corresponding to the light chain variable region sequence and SEQ ID NO:12 as corresponding to the heavy chain variable region sequence for mab 12B5 [Ex [ 487 Patent] at 0029 (43:37-54)], the claims themselves do not impose that requirement allowing SEQ ID NO:10 to appear anywhere in the light chain and SEQ ID NO:12 to appear anywhere in the heavy chain Even assuming that SEQ ID NO:10 corresponds to the light chain variable region sequence and SEQ ID NO:12 corresponds to the heavy chain

63 variable region sequence for mab 12B5, as described in the 487 Patent specification, there are still multiple possible reference antibodies. Specifically, the claims do not identify the amino acid sequences for the constant regions or limit the reference antibody to any particular antibody isotype. Thus, the claimed reference antibody could be of any human antibody isotype including IgG, IgG1, IgG2, IgG3, IgG4, IgM, IgA, IgE, and IgD. Thus, because the claimed reference antibody encompasses multiple antibodies, this increases the number of claimed isolated human antibodies that would potentially compete with the reference antibody Third, as I previously mentioned, neither the ʼ487 Patent claims nor the Common Specification provide any guidance, reagents, or conditions for determining whether any of the isolated reference antibodies compete with the claimed reference antibodies for binding to human IL-4 receptor. Based on my review of the ʼ487 Patent claims and the Common Specification, I did not see a specific antibody-antibody competition assay specified. Likewise, I did not see competition assay conditions like concentrations of antibodies to be used, temperatures, incubation time, washing steps, etc. identified. I also did not see any indication of what competition threshold is required for one to conclude that one antibody competes with another antibody. Assuming that all such assays, assay

64 conditions and levels of competition fall within the claims, this adds additional breadth and scope to the 487 Patent claims In addition, the Common Specification does not identify any common structural features that would allow one of ordinary skill in the art to identify or recognize the covered isolated human antibodies that are part of the broad genus of claimed isolated human antibodies. Although the ʼ487 Patent claims the desired goal of competition with the reference antibody, the Common Specification does not describe how that goal should be achieved Moreover, I was asked to assume for the sake of argument that Immunex had disclosed in the Common Specification that one or more of the six antibodies i.e., mabs 6-2, 12B5, 27A1, 5A1, 63, and 1B7 competed with the claimed reference antibody for binding to human IL-4 receptor. With this assumption, I was asked to provide my opinion whether the disclosure of the six antibody variable chain sequences disclosed in the Common Specification would be representative of the genus of antibodies covered by the claims of the ʼ487 Patent claims. Based on my review of the variable chain sequences disclosed for the six antibodies referenced in the Common Specification, it is my opinion that these six antibodies together are not representative of the full genus of claimed antibodies

65 117. In order to perform this assessment I took the variable chain amino acid sequences disclosed for the six antibodies in the Common Specification (disclosed in the three amino acid letter format) and converted those to the single amino acid letter format shown in the table above from Harlow and Lane. I then used the BLAST application available on the National Institute of Health s ( NIH ) website 2 to compare the heavy and light chain amino acid sequences disclosed for each of the six disclosed antibodies to the 12B5 antibody (using default values). To identify the heavy and light chain families for these sequences I used the Abysis 2.7 application also available online. 3 The number of amino acids that correspond to each CDR region was obtained from the Common Specification which identifies the amino acid numbers believed to correspond to each CDR for each disclosed antibody. Ex [ 816 Application] 0029:9-15 (mab 6-2); 0030:4-13 (mab 12B5); 0030: :5 (mab 27A1); 0031:27-36 (5A1); 0032:19-28 (mab 63); 0034:12-21 (mab 1B7). The resulting information is summarized in the table below: 2 MS=blastp&PAGE_TYPE=BlastSearch&BLAST_SPEC=GlobalAln&LINK_LOC =blasttab&last_page=blastn&blast_init=globalaln 3 n.html

66 118. As my analysis in the table above shows, all six of the mabs disclosed in the Common Specification share between % sequence similarity in the variable regions compared to MAb 12B5. In addition all six of the disclosed mabs have the same heavy chain family (V H 3), the same light chain type (κ), one of two light chain families (V κ 1 or V κ 3), and similar CDR lengths. They also have similar CDR structures. Thus, based on my analysis of the six disclosed antibodies, it is evident that there is no disclosure or teaching of antibodies from different heavy chain families (e.g., V H 1, V H 2, V H 4, V H 5, V H 6 or V H 7), different light chain types (e.g., λ), different light chain families (e.g., V κ 2, V κ 4, V κ 5, V κ 6, V κ 7 or V λ 1, V λ 2, V λ 3, V λ 4, V λ 5, V λ 6, V λ 7, V λ 8, V λ 9, V λ 10, V λ 11), different CDR lengths or of variable chain sequence similarities less than 85%, which would also be included in the genus of the ʼ487 Patent