1. My name is Edward D. Ball, M.D.Timothy Buss I have been retained
`
`by counsel for Mylan PharmaceuticalsPfizer, Inc. (“MylanPfizer”). I understand that
`
`MylanPfizer intends to petitionfile petitions for inter partes review of U.S. Patent
`
`No. 6,407,213 (“the ’213 patent”) [(Ex. 1001]), which is assigned to Genentech, Inc.
`
`I also understand that MylanPfizer will request that the United States Patent and
`
`Trademark Office cancel certain claims of the ’213 patent as unpatentable in an Inter
`
`Partes Review petitiontheir petitions. I submit this expert declaration, which
`
`addresses and supports Mylan’s Inter Partes Review petition for the ’213 patentin
`
`support of Pfizer’s petitions.
`
`I.
`
`QUALIFICATIONS AND BACKGROUND
`
`A.
`
`2.
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`Education and Experience
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`I received my Bachelors of Science with high honors in Biochemistry
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`from University of Maryland in 1972, and my M.D. from Case Western Reserve
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`University in 1976. I went on to complete a residency in Internal Medicine in 1979
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`at Hartford Hospital in Hartford, Connecticut, and a fellowship in the Department of
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`Hematology & Oncology at University Hospitals of Cleveland from 1979 to 1981.
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`From 1982 to 1983, I was a Fellow in the Department of Hematology & Oncology
`
`at Dartmouth-Hitchcock Medical Center.am currently an independent consultant in
`
`the antibody engineering field. As a consultant, I help clients with a variety antibody
`
`discovery and development issues. In particular, I advise clients on choosing the best
`
`1
`
`Pfizer v. Genentech
`IPR2017-01488
`Genentech Exhibit 2058
`
`
`
`by counsel for Mylan PharmaceuticalsPfizer, Inc. (“MylanPfizer”). I understand that
`
`MylanPfizer intends to petitionfile petitions for inter partes review of U.S. Patent
`
`No. 6,407,213 (“the ’213 patent”) [(Ex. 1001]), which is assigned to Genentech, Inc.
`
`I also understand that MylanPfizer will request that the United States Patent and
`
`Trademark Office cancel certain claims of the ’213 patent as unpatentable in an Inter
`
`Partes Review petitiontheir petitions. I submit this expert declaration, which
`
`addresses and supports Mylan’s Inter Partes Review petition for the ’213 patentin
`
`support of Pfizer’s petitions.
`
`I.
`
`QUALIFICATIONS AND BACKGROUND
`
`A.
`
`2.
`
`Education and Experience
`
`I received my Bachelors of Science with high honors in Biochemistry
`
`from University of Maryland in 1972, and my M.D. from Case Western Reserve
`
`University in 1976. I went on to complete a residency in Internal Medicine in 1979
`
`at Hartford Hospital in Hartford, Connecticut, and a fellowship in the Department of
`
`Hematology & Oncology at University Hospitals of Cleveland from 1979 to 1981.
`
`From 1982 to 1983, I was a Fellow in the Department of Hematology & Oncology
`
`at Dartmouth-Hitchcock Medical Center.am currently an independent consultant in
`
`the antibody engineering field. As a consultant, I help clients with a variety antibody
`
`discovery and development issues. In particular, I advise clients on choosing the best
`
`1
`
`Pfizer v. Genentech
`IPR2017-01488
`Genentech Exhibit 2058
`
`
`
`
`
`methods to immunize and screen monoclonal antibodies, humanize antibodies by
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`CDR grafting onto human frameworks and develop methods for expression and
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`purification of recombinant proteins. At the present time, I am working with two
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`nonprofit research organizations and a gene therapy company on issues relating to
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`antibody generation, engineering, affinity maturation and phage display.
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`3.
`
`I was an Instructor in Medicine in 1979, and an Instructor in Medicine
`
`and Microbiology from 1980 to 1981 at Case Western Reserve University, School
`
`of Medicine. In 1981, I went to Dartmouth Medical School, where I was an
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`Instructor of
`
`Microbiology from 1981 to 1982, Assistant Professor of Microbiology from 1982
`
`to 1983, Assistant Professor of Medicine and Microbiology from 1983 to 1987,
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`Adjunct Assistant Professor of Biochemistry from 1986 to 1987, Adjunct
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`Associate Professor of Biochemistry from 1987 to 1991, and Associate Professor
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`of Medicine and Microbiology from 1987 to 1991.
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`4.
`
`In 1991,1 went to the University of Pittsburgh Medical Center, where
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`I was a Professor of Medicine until 1998. I also served as the Director of the Bone
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`Marrow Transplant Program, Chief of Hematology and Co-Director of the
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`Leukemia/Lymphoma Program at the Pittsburgh Cancer Institute during the same
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`time period.
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`5.
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`I transferred to the University of California, San Diego (“UCSD”),
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`
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`2
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`
`
`
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`School of Medicine in 1998, where I have been Professor of Medicine and Director
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`and Chief of the Blood and Marrow Transplantation Division and Program. I have
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`also served as the Program Leader in Translational Oncology from 2000 to 2005,
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`and Co-Leader of the Hematologic Malignancy Program from 2005 to 2014 at
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`UCSD Cancer Center. Since 1999, I am also Medical Director at the UCSD/Sharp
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`LLC Blood and Marrow Transplantation Program in San Diego, CA. Since 2006, I
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`am also Medical Director at Rady Children’s Hospital Blood and Marrow
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`Transplant Program in San Diego, CA.
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`6. My duties at UCSD’s School of Medicine include teaching
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`responsibilities for medical and pharmacy students, rotating residents and fellows
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`in hematology/oncology as well administrative duties such as overseeing the bone
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`marrow transplant division. I also direct a basic research laboratory in the Moores
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`Cancer Center focused on experimental therapeutics in leukemia.
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`7.
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`I have been Board Certified by the American Board of Internal
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`Medicine since 1979. I also received Board Certification in Oncology in 1983 and
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`Hematology in 1990. I have been licensed by the State of California since 1998.
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`8.
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`I am or have been a member of numerous professional and scientific
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`societies, including the American Associate of Cancer Research, American
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`Association of Immunologists, American Association for the Advancement of
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`Science, American College of Physicians, American Federation for Clinical
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`
`
`3
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`
`
`
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`Research, American Society for Blood and Marrow Transplantation, American
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`Society for Clinical Investigation, American Society of Hematology, Association
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`of Hematology/Oncology Program Directors, International Society for
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`Experimental Hematology and the International Society for Hematotherapy and
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`Graft Engineering, Inc.
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`9.
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`I have served on numerous scientific boards and committees,
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`including the Bone Marrow Foundation Medical Advisory Board, the Executive
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`Committee of the 2003 Autologous Blood & Marrow Transplant Registry
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`(ABMTR), the Executive
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`Committee and Elected Director of the American Society for Blood and
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`Marrow Transplantation (ASBMT), an Elected Councillor of the International
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`Society of Experimental Hematology and an elected Secretary and member of
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`the Executive Committee of the American Society for Blood and Marrow
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`Transplantation.
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`10.
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`I also currently serve on numerous committees at the University of
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`California, San Diego, School of Medicine, including the Department of Medicine
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`Executive Committee (from 1998), the Moores UCSD Cancer Center Executive
`
`Committee (from 2005), the University of California Research Coordinating
`
`Committee (from 2013-2016), the Protocol Review and Monitoring Committee
`
`(from 2014), the MCC Cancer Cabinet (from 2013) and the UCSD Cancer Council
`
`
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`4
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`
`
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`(from 2013).
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`11.
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`I have been awarded numerous honors for my work, including as a
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`Tiffany Blake Fellow for the Hitchcock Foundation (1982-83), a National
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`Institutes of Health New Investigator Award (1983-86), the Scholar Award from
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`the Leukemia & Lymphoma Society (1986-1991) and the Stohlman Award from
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`the Leukemia Society of America (1990). I have also been listed as a Top Doctor
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`in America’s Top Doctors (from 2001 to 2015), as well the US New and World
`
`Report and the San Diego Medical Society.
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`12.
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`I have been studying and treating patients with hematological and
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`solid tumor cancers since the start of my medical career. I began my work in
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`cancer research and exploring the use of antibodies as potential therapeutics at
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`Dartmouth in the laboratory of Michael W. Fanger, Ph.D. I authored numerous
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`scientific publications directed to monoclonal antibodies and their effects on
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`leukemia and lung cancer while in Dr. Fanger’s laboratory. See, e.g., Ball E.D., et
`
`al. “Studies on the ability of monoclonal antibodies to selectively mediate
`
`complement-dependent cytotoxicity of human myelogenous leukemia blast cells,”
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`J. Immunol. 128(3):1476 (1982) [Ex. 1005]; Ball, E.D., et al. “Monoclonal
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`antibodies reactive with small cell carcinoma of the lung,” J. Nat'l Cancer Inst.
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`72:593 (1984) [Ex. 1006]; Magnani, J.L., Ball, E.D., et al. “Monoclonal antibodies
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`PMN 6, PMN 29 and PM-81 bind differently to glycolipids containing a sugar
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`
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`5
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`
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`
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`sequence occurring in lacto-N-fucopentaose III,” Arch. Biochem. Biophys. 233:501
`
`(1984), et seq. [Ex. 1007].
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`13.
`
`In 1988, I published an article in Cancer Research related to
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`characterizing monoclonal antibodies with specificity for small cell lung
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`carcinoma. See Memoli, V.A., Jordan, A.G., and Ball, E.D. “A novel monoclonal
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`antibody, SCCL 175, with specificity for small cell neuroendocrine carcinoma of
`
`the lung,” Cancer Res. 48:7319 (1988) [Ex. 1008]. In this article, we characterized
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`a promising mouse monoclonal antibody, SCCL175, by demonstrating its
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`reactivity and specificity to tissue samples from small cell neuroendocrine
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`carcinoma of the lung. My research has since grown from my earlier work, where I
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`implement therapeutic tools, such as monoclonal antibodies, in the treatment of my
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`patients with hematological diseases, including malignancies.
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`14.
`
`I have conducted and managed a number of antibody clinical studies
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`in patients since their therapeutic potential was postulated over thirty years ago. I
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`was involved in one of the early clinical studies that used monoclonal antibodies
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`for the treatment of leukemia. See Ball E.D., et al. “Monoclonal antibodies to
`
`myeloid differentiation antigens: in vivo studies of three patients with acute
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`myelogenous leukemia,” Blood 62:1203 (1983) [Ex. 1009]. To my knowledge, this
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`study was the first reported clinical trial of (1) monoclonal IgM antibodies, (2)
`
`monoclonal antibody therapy in patients with acute myelogenous leukemia (AML),
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`
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`6
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`
`
`
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`and (3) combination therapy with monoclonal antibodies. In this study, four
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`monoclonal antibodies directed to different antigens expressed on leukemia cells
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`were prepared and administered to three patients with AML. It was observed that
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`the antibodies bound to the patients’ leukemia cells and that peripheral blood
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`leukemia cell counts decreased significantly, although transiently during treatment.
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`The results warranted further study on these antibodies as promising approaches
`
`toward treating cancers such as leukemias. See, e.g., Ball E.D., et al. “Phase I
`
`clinical trial of serotherapy in patients with acute myeloid leukemia with an
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`immunoglobulin M monoclonal antibody to CD15,” Clin Cancer Res 1:965 (1995)
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`[Ex. 1010].
`
`15.
`
`I was involved in a Phase I study that examined the monoclonal
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`antibody ipilimumab (YERVOY®) as a possible treatment for relapse of
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`malignancy after allogeneic hematopoietic cell transplantation (allo-HCT). See
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`Bashey A., Ball E.D., et al. “CTLA4 Blockade with Ipilimumab to Treat Relapse
`
`of Malignancy after Allogeneic Hematopoietic Cell Transplantation,” Blood
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`113:1581 (2009) [Ex. 1011]. Ipilimumab, which has been approved for the
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`treatment of melanoma, is an antibody that binds to and blocks the CTLA-4
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`receptor that downregulates the immune functions in T cells. In this study we
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`assessed the safety and preliminary efficacy of ipilimumab in stimulating the graft-
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`versus-malignancy effect after allo-HCT in patients with recurrent or progressive
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`
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`7
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`
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`malignancies after transplantation. We found that administration of ipilimumab to
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`these patients was safe and did not induce graft- versus-host disease (GVHD) or
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`graft rejection. As for efficacy, we observed antitumor responses in a number of
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`patients with lymphoid malignancies. One patient with refractory mantle cell
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`lymphoma had partial remission and two patients with Hodgkin disease had
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`complete remission following ipilimumab administration.
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`16.
`
`I was an investigator in an international Phase II clinical study which
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`examined the clinical efficacy of humanized monoclonal antibody pidilizumab in
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`patients with diffuse large B-cell lymphoma and primary mediastinal large B-cell
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`lymphoma after autologous hematopoietic stem-cell transplantation. See Armand
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`P., Ball E.D., et al. “Disabling Immune Tolerance by Programmed Death-1
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`Blockade with Pidilizumab after Autologous Hematopoietic Stem-Cell
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`Transplantation for Diffuse Large B-Cell Lymphoma: Results of an International
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`Phase II Trial,” J Clin Oncol 31:4199 (2013) [Ex. 1012]. Pidilizumab binds to and
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`blocks checkpoint inhibitor PD-1 which is often co-opted in many tumors by
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`depressing immune response. By blocking PD-1, pidilizumab therefore increases
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`immune response in antitumor lymphocytes. In this study, it was observed that
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`among patients with measurable disease after transplantation, the overall response
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`rate after pidilizumab treatment was 51% and was associated with increased
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`circulating lymphocyte subsets. The positive results in the study warrant further
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`
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`8
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`
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`clinical investigation of the use of the humanized antibody pidilizumab in the
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`blockade of PD-1 after stem-cell transplantation.
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`17.
`
`I have explored other antibody format types for experimental and
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`therapeutic uses such as multispecific antibodies and antibody conjugates with
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`other molecules. Specifically, I have studied extensively on bispecific antibodies
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`for treating leukemias. See, e.g., Ball E.D., et al. “Initial trial of bispecific
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`antibody- mediated immunotherapy of CD15-bearing tumors: cytotoxicity of
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`human tumor cells using a bispecific antibody comprised of anti-CD15 (MoAb
`
`PM81) and anti-CD64/Fc gamma RI (MoAb 32),” JHematother 1:85 (1992) [Ex.
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`1013]; Chen J, Zhou J.H., Ball E.D. “Monocyte-mediated lysis of acute myeloid
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`leukemia cells in the presence of the bispecific antibody 251 x 22 (anti-CD33 x
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`anti-CD64).” Clin Can Res 1:1319
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`(1995) [Ex. 1014]; Balaian, L. and Ball, E.D. “Direct effect of bispecific
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`anti-CD33 x anti-CD64 antibody on proliferation and signaling in myeloid cells,”
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`Leukemia Res 25:1115 (2001) [Ex. 1015]. In these studies, the bispecific
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`antibodies were examined for their increased cytotoxicity toward cancer cells as
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`they bound to a tumor antigen such as CD15 or CD33 as well as an immune
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`effector, CD64 (FcyRI) present on neutrophils, monocytes and macrophages and
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`plays an important role in antibody- dependent cellular cytotoxicity (ADCC).
`
`18.
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`I have also conducted research on an antibody-peptide conjugate that
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`
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`9
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`
`
`
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`links a bombesin peptide to a monoclonal antibody that binds to CD64. See, e.g.,
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`Chen J., Ball, E.D., et al. “An immunoconjugate of Lys3-bombesin and
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`monoclonal antibody 22 can specifically induce FcgammaRI (CD64)-dependent
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`monocyte- and neutrophil-mediated lysis of small cell carcinoma of the lung cells,”
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`Clin Can Res 1:425 (1995) [Ex. 1016]; Chen J., Ball, E.D., et al. “Monocyte- and
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`neutrophil- mediated lysis of SCCL by a bispecific molecule comprised of Lys -
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`BN and mAb22,” Peptides 1994, 819 (1995) [Ex. 1017]; Zhou J.H., Ball E.D., et
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`al. “Immunotherapy of a human small cell lung carcinoma (SCLC) xenograft
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`model by the bispecific molecule (BsMol) mAb22xLys3-Bombesin (M22xL-BN),”
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`Peptides 1996, 935 (1998) [Ex. 1018]. The bombesin peptide receptor is aberrantly
`
`expressed in a number of cancers such as lung, prostate and colon. Here in these
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`studies, the antibody-peptide conjugate linked a bombesin peptide to an anti-CD64
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`antibody and was studied for its enhanced cytotoxicity toward small cell lung
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`cancers. It was contemplated that this conjugate brought together lung cancer cells
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`with neutrophils and other immune cells for this enhanced cell killing.
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`19.
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`I have also focused on an antibody drug conjugate, gemtuzumab
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`ozogamicin (Mylotarg®) for use in treating AML. See, e.g., Ball, E.D. and
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`Balaian, L. “Cytotoxic activity of gemtuzumab ozogamicin (Mylotarg) in acute
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`myeloid leukemia correlates with the expression of protein kinase Syk,” Leukemia
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`20:2093 (2006) [Ex. 1019]; Ball E.D., et al. “Update of a phase I/II trial of 5-
`
`
`
`10
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`
`
`
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`azacytidine prior to gemtuzumab ozogamicin (GO) for patients with relapsed acute
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`myeloid leukemia with correlative biomarker studies [abstract],” Blood (ASH
`
`Annual Meeting Abstracts) 116: Abstract 3286 (2010) [Ex. 1020]. This study
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`closed to accrual in 2014 and the data are currently being analyzed.
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`20. My research has resulted in peer-reviewed publications, refereed
`
`articles, conference proceedings and abstracts. I have published nearly 200 papers
`
`and over 60 book chapters and invited reviews. I authored and edited five books
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`and have participated in more than 250 scientific abstracts presented at national
`
`and international scientific meetings. I have also been invited to present my clinical
`
`and research work both internationally and in the United States, and have chaired
`
`and cochaired multiple symposiums and conferences in the areas of antibody
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`therapies for various cancers.
`
`21.
`
`I have served as a journal reviewer for Biology of Blood and Marrow
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`Transplantation, Blood. Bone Marrow Transplantation. Cancer, Cancer Research,
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`Clinical Cancer Research, Experimental Hematology, Journal of Clinical
`
`Investigation, Journal of Clinical Oncology, Journal of the National Cancer
`
`Institute, Journal of Immunology, Journal of Immunotherapy, Journal of Leukocyte
`
`Biology, Leukemia, and New England Journal of Medicine. I have been on the
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`editorial board of Cell Transplantation, Bone Marrow Transplantation, Gaucher
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`Clinical Perspectives, Journal of Hematotherapy, and Experimental Hematology.
`
`
`
`11
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`
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`22.
`
`I am a named inventor on five patent families relating to antibodies
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`and their use. These include U.S. Pat. Nos. 5,833,985, entitled “Bispecific
`
`molecules for use in inducing antibody-dependent cytotoxicity of tumors”;
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`6,071,517, entitled “Bispecific heteroantibodies with dual effector functions”;
`
`6,340,569, entitled “Monoclonal antibody and antigens specific therefor and
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`methods of using same”; 7,977,320, entitled “Method of increasing efficacy of
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`tumor cell killing using combinations of anti-neoplastic agents”; and International
`
`Patent Publication WO 2006/073982, entitled “Bispecific molecule comprising
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`ligands for cell-surface protein and T-cell surface protein.”
`
`233. In all, I have more than 3525 years of practical and research experience
`
`specializing in oncology and hematology with an emphasis on treating patients with
`
`antibody therapeutics.design, humanization, and expression. My curriculum vitae is
`
`attached hereto as Exhibit A.
`
`24. My curriculum vitae is attached hereto as Exhibit A.
`
`4.
`
`I received my Higher National Certificate (“HNC”) in applied biology
`
`from Cambridgeshire College of Arts and Technology (now part of Anglia Ruskin
`
`University) in the UK where I attended from 1981-86. While attending
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`Cambridgeshire College of Arts and Technology, I worked as an Assistant Scientific
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`Officer in the Director’s Group, Agricultural and Food Research Council Institute
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`of Animal Physiology and Genetics Research (1981-87).
`
`
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`12
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`
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`5.
`
`In 1987, I became a Scientific Officer at the Medical Research Council
`
`(“MRC”) Group, Department of Neuroendocrinology at the AFRC Institute of
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`Animal Physiology and Genetics Research. My work at the MRC included cloning,
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`expression, and purification of proteins for polyclonal antibody production as well
`
`as associated animal work.
`
`6.
`
`In 1991, I became a Higher Scientific Officer at the Cambridge Centre
`
`for Protein Engineering, Laboratory of Molecular Biology. There, I worked under
`
`Dr. Sir Gregory Winter and focused on, among other things, expression and
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`purification of monoclonal and recombinant humanized antibodies and generation
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`of vectors for antibody phage display. In 1993, I moved to the Fred Hutchinson
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`Cancer Research Center in Seattle, WA. My work there included cloning,
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`expression, and purification of humanized antibodies as well as the development of
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`protocols for the expression and purification of recombinant proteins.
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`7.
`
`In 2002, I moved to the Sidney Kimmel Cancer Center, where my work
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`involved the cloning and expression of monoclonal antibodies; the design,
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`construction, and expression of murine, chimeric, and humanized antibodies for
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`tumor targeting projects; and the generation of phage antibody libraries from
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`immunized mice to generate novel binders to targets on vascular endothelial cells.
`
`8.
`
`In 2008, I became a Senior Scientist at Ambrx, Inc. In that position, I
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`was responsible for antibody generation and development, including the design and
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`
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`13
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`
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`generation of recombinant proteins and chimeric and humanized antibodies. I also
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`supervised development from initial antigen design through preclinical testing of the
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`humanized antibody lead candidate, generated monoclonal antibodies for internal
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`projects, designed and produced bispecific and multifunctional antibodies and
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`antibody-based proteins, and made Fc modifications to alter effector functions. I was
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`also project leader on several collaborations with large pharmaceutical companies. I
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`remained at Ambrx, Inc. until 2015.
`
`9.
`
`In addition to my full time experience described above, I have also been
`
`involved with a number of consulting projects. From August 2015 to March 2016, I
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`worked as a Research Scientist and Consultant at the California Institute for
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`Biomedical Research. In this position, I worked to troubleshoot antibody related
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`projects and advise on antibody research, humanization, design, expression, and
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`purification. In addition, as discussed above i n | 2 , I am currently an independent
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`consultant in the antibody engineering field.
`
`10.
`
`In connection with my research activities, I have published several
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`articles on antibody design, engineering, and use. In 1998, I published an article on
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`conformational changes in the complementarity determining regions induced by
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`engineering these segments within human framework regions. See Exhibit A at 4
`
`(Publications). In 2001, I published an article on the effects of framework mutations
`
`at Residues 27 and 71 on the CDRs of humanized antibodies. See id. In addition, I
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`
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`14
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`
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`have published articles on the use of human germline framework regions for the
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`humanization of murine antibodies and the preparation of humanized antibodies with
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`reduced immunogenicity by using human genomic V gene framework sequences
`
`whose CDR’s canonical class match closest to the canonical class of murine
`
`antibodies. See id. Finally, I have published on the use of engineered antibodies
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`designed to deliver therapeutic agents to specific tissues and the engineering of a
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`new antibody, J120, and expression and sequence of its antigen, CD34. See id.
`
`11.
`
`I am also a named inventor on several patents and patent applications
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`in the antibody engineering field. See id. at 5 (“Patents”).
`
`B. Bases for Opinions and Materials Considered
`
`2512. Exhibit B includes a list of the materials I considered, in addition to my
`
`my experience, education, and training, in providing the opinions contained herein.
`
`13.
`
`I understand a third-party, Mylan, previously filed IPR petitions
`
`challenging claims of the ’213 patent. I have reviewed and considered Mylan’s IPR
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`petitions and the declarations filed in support of Mylan’s IPR petitions. Applying
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`my independent judgement and expertise, after having independently reviewed and
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`analyzed all of the materials in Mylan expert Dr. Edward Ball’s materials considered
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`lists, and after having done the additional work of fact checking and considering
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`whether potential counterarguments may exist, I have come to the same conclusions
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`as Dr. Ball and I agree with the analysis in his declaration as set forth below. Readers
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`
`
`15
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`
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`of this declaration may note the language and organization is similar to that of Dr.
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`Ball’s declaration because it did not seem a necessary expenditure of resources to
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`rewrite the material which I independently confirmed as acceptable and correct. The
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`opinions in this declaration should be considered mine.
`
`C.
`
`Scope of Work
`
`2614. I have been retained by MylanPfizer as a technical expert in this matter
`
`to provide various opinions regarding the ’213 patent. I receive $500300 per hour
`
`for my services. No part of my compensation is dependent upon my opinions given
`
`or the outcome of this case. I do not have any other current or past affiliation as an
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`expert witness or consultant with MylanPfizer. I do not have any current or past
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`affiliation with Genentech, Inc., or any of the named inventors on the ’213 patent.
`
`II.
`
`SUMMARY OF OPINIONS
`
`2715. To summarize, for the reasons set forth below, it is my opinion that
`
`one of ordinary skill in the art would have recognized the power and potential of
`
`monoclonal antibodies (MAbs or MoAbs) as therapies for a number of diseases
`
`such asincluding breast cancer while acknowledging the limitation of their use due
`
`to immunogenic effects upon repeated administration of mouse monoclonal
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`antibodies. Moreover, one of ordinary skill in the art would have recognized that
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`humanization of mouse monoclonal antibodies as developed by Queen et al., A
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`Humanized antibody that binds to the interleukin 2 receptor, 86 PROC. NAT’L ACAD.
`
`
`
`16
`
`
`
`
`
`SCI. USA 10029-33 (1989 [) (“Queen 1989”) (Ex. 1034]) and others would
`
`overcome this limitation. With respect to cancer, one skilled in the art would have
`
`identified the
`
`HER-2/neu as a target for breast cancer therapy based on the prevalence of
`
`this gene in a significant number of human breast cancer and other types of cancers
`
`as well as the overexpression of HER-2/neu to cause cell transformation and
`
`tumorigenesis.
`
`2816. Accordingly, it is my opinion that because of the well-documented
`
`pre-1991 reports of excellent specificity and potent anti-proliferative and cytotoxic
`
`effects of the mouse monoclonal 4D5 antibody directed to HER-2/neu as presented
`
`in Hudziak et al., “p185HER2 Monoclonal Antibody Has Antiproliferative Effects In
`
`Vitro and Sensitizes Human Breast Tumor Cells to Tumor Necrosis Factor” Mol
`
`Cell Biol, 9:(3) MOLECULAR CELLULAR BIOLOGY 1165 (1989) [(“Hudziak 1989”) (Ex.
`
`1021]), a person of ordinary skill in the art would have identified 4D5 as a
`
`promising candidate for humanization, at least as early as March 1989. After
`
`singling out 4D5 from a panel of monoclonal antibodies, Hudziak 1989 [(Ex.
`
`1021]) identified the 4D5 antibody as showing good specificity toward the HER-2
`
`receptor extracellular domain and did not cross-react or bind to the EGF receptor
`
`(HER-1).
`
` The 4D5 antibody also demonstrated growth inhibitory and anti-proliferative
`
`
`
`17
`
`
`
`
`
`effects on HER-2 positive SK-BR-3 breast cancer cells. As Hudziak 1989 [(Ex.
`
`1021]) noted, the 4D5 antibody had the best effect of the tested anti-HER-2
`
`antibodies in inhibiting the growth of these cells leading the authors to conclude that
`
`“[m]aximum inhibition was obtained with monoclonal antibody 4D5 which
`
`inhibited cellular proliferation by 56%.” Id. at 116912. The 4D5 antibody was also
`
`shown to downregulate p185HER2 by allowing the protein to be degraded more
`
`quickly in the cell. Finally, the 4D5 antibody sensitized HER-2 positive breast cancer
`
`cells to TNF-alpha mediated cytotoxicity.
`
`2917. Furthermore, Shepard et al. “, Monoclonal Antibody Therapy of Human
`
`Cancer: Taking the HER2 Protooncogene to the Clinic,” 11(3) J. Clin. Immunol.
`
`11:CLINICAL
`
`IMMUNOLOGY, 117 (1991) [(Ex. 1048]) reported that a human tumor xenograft model
`
`was used to “support[] the application of muMAb 4D5 to human cancer therapy”
`
`and “its ability to inhibit the growth of tumor cells overexpressing p185HER2 in vivo.”
`
`Id. at 1228. In tumor bearing athymic mice, the authors administered either the 4D5
`
`antibody, a control antibody 5B6, or PBS and observed that “[o]n day 20, average
`
`tumor weights of animals receiving muMAb 4D5 were significantly less than those
`
`receiving the same dose of the control antibody muMAb 5B6.” Id. at 1239. These
`
`observations allow Shepard et al. to conclude that “[t]he muMAb 4D5 also serves
`
`as a template for antibody engineering efforts to construct humanized versions more
`
`
`
`18
`
`
`
`
`
`suitable for chronic therapy or other molecules which may be directly cytotoxic for
`
`tumor cells overexpressing the HER2 protooncogene.” Id. at 12612.
`
`3018. Thus in my opinion, one of ordinary skill in the art would have
`
`acknowledged and recognized the above-described promising properties of the
`
`mouse monoclonal antibody 4D5 in vitro and in vivo and have strong motivation to
`
`select this antibody as a prime candidate for further development as a therapy for
`
`breast cancer.
`
` It then follows, that one of ordinary skill in the art would logically proceed
`
`to develop the monoclonal 4D5 antibody as a breast cancer therapeutic via well-
`
`established humanization
`
`techniques,
`
`thereby
`
`reducing
`
`the
`
`antibody’s
`
`immunogenicity and restoring antibody-dependent cell-mediated cytotoxicity
`
`(ADCC) and effector cell binding.
`
`III. LEGAL STANDARDS
`
`3119. In preparing and forming my opinions set forth in this declaration, I
`
`have been informed regarding the relevant legal principles. I have used my
`
`understanding of those principles in forming my opinions. My understanding of
`
`those principles is summarized below.
`
`32.
`
`I have been told that Mylan bears the burden of proving
`
`unpatentability by a preponderance of the evidence. I am informed that this
`
`preponderance of the evidence standard means that Mylan must show that
`
`
`
`19
`
`
`
`
`
`unpatentability is more probable than not. I have taken these principles into
`
`account when forming my opinions in this case.
`
`20.
`
`I understand a patent has three primary parts: the specification, the
`
`drawings, and the claims. The specification consists of a written description of the
`
`invention and must provide a sufficient description to enable one skilled in the art to
`
`practice the invention. The drawings illustrate the invention. The claims appear at
`
`the end of the specification as numbered paragraphs. I am told the claims define the
`
`metes and bounds of the property right conveyed by the patent.
`
`21.
`
`I understand claims can be independent or dependent. Dependent
`
`claims refer back to and incorporate at least one other claim. Dependent claims
`
`include all the limitations of any claims incorporated by reference into the dependent
`
`claim.
`
`3322. I have also been told that claims should be construed given their
`
`broadest reasonable interpretation in light of the specification from the perspective
`
`of a person of ordinary skill in the art. at the time of the alleged invention.I
`
`23.
`
`I understand prior art to the ’213 patent includes patents, printed
`
`publications and products in the relevant art that predate the priority date of the ’213
`
`
`I I have been asked to assume the priority date of the ’213 patent (June 14, 1991) is
`
`the date of the alleged invention.
`
`
`
`20
`
`
`
`
`
`patent.
`
`24.
`
`I am told a claim is invalid if it is anticipated or obvious. I understand
`
`anticipation requires that every element and limitation of the claim was previously
`
`described in a single prior art reference, either expressly or inherently, before the
`
`date of the alleged invention.
`
`3425. I am told that the concept of patent obviousness involves four factual
`
`inquiries: (1)To determine whether a claim is obvious, I understand the scope and
`
`content of the prior art; (2) the are to be determined, differences between the claimed
`
`invention and the prior art; (3) and the claims at issue are to be ascertained, and the
`
`level of ordinary skill in the pertinent art; and (4) resolved. I also understand that
`
`secondary considerations of non-obviousness.such as commercial success, long felt
`
`but unsolved needs, failure of others, etc., may have some relevancy to whether or
`
`not the claim is obvious or nonobvious. I understand that obviousness is assessed at
`
`the time of the alleged invention.
`
`3526. I am also informed that when there is some recognized reason to solve
`
`a problem, and there are a finite number of identified, predictable and known
`
`solutions, a person of ordinary skill in the art has good reason to pursue the known
`
`options within his or her technical grasp. If such an approach leads to the expected
`
`success, it is likely not the product of innovation but of ordinary skill and common
`
`sense. In such a circumstance, when a patent simply arranges old elements with each
`
`
`
`21
`
`
`
`
`
`performing its known function and yields no more than what one would expect from
`
`such an arrangement, the combination is obvious.
`
`27.
`
`I have been told that Pfizer bears the burden of proving unpatentability
`
`by a preponderance of the evidence. I am informed that this preponderance of the
`
`evidence standard means that Pfizer must show that unpatentability is more probable
`
`than not. I have taken these principles into account when forming my opinions in
`
`this case.
`
`IV. PERSON OF ORDINARY SKILL IN THE ART
`
`3628. As above, I have been informed by counsel that the obviousness
`
`analysis is to be
`
`is to be conducted from the perspective of a person of ordinary skill in the art (a
`
`“person of ordinary skill”) at the time of the alleged invention.
`
`3729. I have also been informed by counsel that in defining a person of
`
`ordinary skill in
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