UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner
`
`v.
`
`GENENTECH, INC.
`Patent Owner
`
`U.S. Patent No. 6,407,213
`
`Case IPR2016
`Unassigned
`
`EXPERT DECLARATION OF EDWARD BALL, M.D.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF
`PATENT NO. 6,407,213
`
`PETITIONER'S EXHIBITS
`
`Exhibit 1004 Page 1 of 83
`
`Pfizer v. Genentech
`IPR2017-01488
`Genentech Exhibit 2056
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner
`
`v.
`
`GENENTECH, INC.
`Patent Owner
`
`U.S. Patent No. 6,407,213
`
`Case IPR2016
`Unassigned
`
`EXPERT DECLARATION OF EDWARD BALL, M.D.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF
`PATENT NO. 6,407,213
`
`PETITIONER'S EXHIBITS
`
`Exhibit 1004 Page 1 of 83
`
`Pfizer v. Genentech
`IPR2017-01488
`Genentech Exhibit 2056
`
`
`
`TABLE OF CONTENTS
`
`I.
`
`QUALIFICATIONS AND BACKGROUND .................................................................... 2
`
`II.
`
`III.
`
`IV.
`
`V.
`
`VI.
`
`A.
`
`B.
`
`C.
`
`Education and Experience ...................................................................................... 2
`
`Bases for Opinions and Materials Considered..................................................... 13
`
`Scope of Work....................................................................................................... 13
`
`Summary of Opinions....................................................................................................... 13
`
`Legal Standards................................................................................................................ 16
`
`Person of Ordinary Skill in the Art ................................................................................. 17
`
`The ’213 Patent [Ex. 1001] ............................................................................................... 19
`
`State of the Art of Monoclonal Antibody Therapies and Cancer ................................... 19
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`Early Antibody Therapy....................................................................................... 19
`
`Efforts to Reduce Immunogenicity – Chimerization and
`Humanization........................................................................................................ 24
`
`Breast Cancer and HER-2 .................................................................................... 29
`
`Identification and Characterization of 4D5, a Potential Therapeutic
`Mouse Monoclonal Antibody to HER-2/neu........................................................ 36
`
`Humanization of 4D5 to Enable Therapeutic Use ............................................... 43
`
`i
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`PETITIONER'S EXHIBITS
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`Exhibit 1004 Page 2 of 83
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`
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`1.
`
`My name is Edward D. Ball, M.D. I have been retained by counsel for
`
`Mylan Pharmaceuticals Inc. (“Mylan”). I understand that Mylan intends to petition
`
`for inter partes review of U.S. Patent No. 6,407,213 (the ’213 patent) [Ex. 1001],
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`which is assigned to Genentech, Inc. I also understand that Mylan will request that
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`the United States Patent and Trademark Office cancel certain claims of the ’213 patent
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`as unpatentable in an Inter Partes Review petition. I submit this expert declaration,
`
`which addresses and supports Mylan’s Inter Partes Review petition for the ’213
`
`patent.
`
`I.
`
`QUALIFICATIONS AND BACKGROUND
`A.
`Education and Experience
`2.
`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
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`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
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`Dartmouth-Hitchcock Medical Center.
`
`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
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`Medicine. In 1981, I went to Dartmouth Medical School, where I was an Instructor of
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`PETITIONER'S EXHIBITS
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`Exhibit 1004 Page 3 of 83
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`
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`Microbiology from 1981 to 1982, Assistant Professor of Microbiology from 1982 to
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`1983, Assistant Professor of Medicine and Microbiology from 1983 to 1987, Adjunct
`
`Assistant Professor of Biochemistry from 1986 to 1987, Adjunct Associate Professor
`
`of Biochemistry from 1987 to 1991, and Associate Professor of Medicine and
`
`Microbiology from 1987 to 1991.
`
`4.
`
`In 1991, I went to the University of Pittsburgh Medical Center, where I
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`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 time
`
`period.
`
`5.
`
`I transferred to the University of California, San Diego (“UCSD”),
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`School of Medicine in 1998, where I have been Professor of Medicine and Director
`
`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, and
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`Co-Leader of the Hematologic Malignancy Program from 2005 to 2014 at UCSD
`
`Cancer Center. Since 1999, I am also Medical Director at the UCSD/Sharp LLC
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`Blood and Marrow Transplantation Program in San Diego, CA. Since 2006, I am also
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`Medical Director at Rady Children’s Hospital Blood and Marrow Transplant Program
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`in San Diego, CA.
`
`-3-
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`PETITIONER'S EXHIBITS
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`Exhibit 1004 Page 4 of 83
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`6.
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`My duties at UCSD’s School of Medicine include teaching
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`responsibilities for medical and pharmacy students, rotating residents and fellows in
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`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.
`
`7.
`
`I have been Board Certified by the American Board of Internal Medicine
`
`since 1979. I also received Board Certification in Oncology in 1983 and Hematology
`
`in 1990. I have been licensed by the State of California since 1998.
`
`8.
`
`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 Research,
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`American Society for Blood and Marrow Transplantation, American Society for
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`Clinical Investigation, American Society of Hematology, Association of
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`Hematology/Oncology Program Directors, International Society for Experimental
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`Hematology and the International Society for Hematotherapy and Graft Engineering,
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`Inc.
`
`9.
`
`I have served on numerous scientific boards and committees, including
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`the Bone Marrow Foundation Medical Advisory Board, the Executive Committee of
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`the 2003 Autologous Blood & Marrow Transplant Registry (ABMTR), the Executive
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`-4-
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`PETITIONER'S EXHIBITS
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`Exhibit 1004 Page 5 of 83
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`Committee and Elected Director of the American Society for Blood and Marrow
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`Transplantation (ASBMT), an Elected Councillor of the International Society of
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`Experimental Hematology and an elected Secretary and member of the Executive
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`Committee of the American Society for Blood and Marrow Transplantation.
`
`10.
`
`I also currently serve on numerous committees at the University of
`
`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 (from
`
`2013).
`
`11.
`
`I have been awarded numerous honors for my work, including as a
`
`Tiffany Blake Fellow for the Hitchcock Foundation (1982-83), a National Institutes of
`
`Health New Investigator Award (1983-86), the Scholar Award from the Leukemia &
`
`Lymphoma Society (1986-1991) and the Stohlman Award from the Leukemia Society
`
`of America (1990). I have also been listed as a Top Doctor in America’s Top Doctors
`
`(from 2001 to 2015), as well the US New and World Report and the San Diego
`
`Medical Society.
`
`12.
`
`I have been studying and treating patients with hematological and solid
`
`tumor cancers since the start of my medical career. I began my work in cancer
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`-5-
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`PETITIONER'S EXHIBITS
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`Exhibit 1004 Page 6 of 83
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`research and exploring the use of antibodies as potential therapeutics at Dartmouth in
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`the laboratory of Michael W. Fanger, Ph.D. I authored numerous scientific
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`publications directed to monoclonal antibodies and their effects on 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,” J. Immunol. 128(3):1476
`
`(1982) [Ex. 1005]; Ball, E.D., et al. “Monoclonal antibodies reactive with small cell
`
`carcinoma of the lung,” J. Nat’l Cancer Inst. 72:593 (1984) [Ex. 1006]; Magnani, J.L.,
`
`Ball, E.D., et al. “Monoclonal antibodies PMN 6, PMN 29 and PM-81 bind differently
`
`to glycolipids containing a sugar sequence occurring in lacto-N-fucopentaose III,”
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`Arch. Biochem. Biophys. 233:501 (1984), et seq. [Ex. 1007].
`
`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 carcinoma.
`
`See Memoli, V.A., Jordan, A.G., and Ball, E.D. “A novel monoclonal 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 a promising mouse
`
`monoclonal antibody, SCCL175, by demonstrating its reactivity and specificity to
`
`tissue samples from small cell neuroendocrine carcinoma of the lung. My research
`
`has since grown from my earlier work, where I implement therapeutic tools, such as
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`-6-
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`PETITIONER'S EXHIBITS
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`Exhibit 1004 Page 7 of 83
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`
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`monoclonal antibodies, in the treatment of my patients with hematological diseases,
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`including malignancies.
`
`14.
`
`I have conducted and managed a number of antibody clinical studies in
`
`patients since their therapeutic potential was postulated over thirty years ago. I was
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`involved in one of the early clinical studies that used monoclonal antibodies for the
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`treatment of leukemia. See Ball E.D., et al. “Monoclonal antibodies to myeloid
`
`differentiation antigens: in vivo studies of three patients with acute myelogenous
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`leukemia,” Blood 62:1203 (1983) [Ex. 1009]. To my knowledge, this study was the
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`first reported clinical trial of (1) monoclonal IgM antibodies, (2) monoclonal antibody
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`therapy in patients with acute myelogenous leukemia (AML), and (3) combination
`
`therapy with monoclonal antibodies. In this study, four monoclonal antibodies
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`directed to different antigens expressed on leukemia cells were prepared and
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`administered to three patients with AML. It was observed that the antibodies bound to
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`the patients’ leukemia cells and that peripheral blood leukemia cell counts decreased
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`significantly, although transiently during treatment. The results warranted further
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`study on these antibodies as promising approaches toward treating cancers such as
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`leukemias. See, e.g., Ball E.D., et al. “Phase I clinical trial of serotherapy in patients
`
`with acute myeloid leukemia with an immunoglobulin M monoclonal antibody to
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`CD15,” Clin Cancer Res 1:965 (1995) [Ex. 1010].
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`-7-
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`PETITIONER'S EXHIBITS
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`Exhibit 1004 Page 8 of 83
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`15.
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`I was involved in a Phase I study that examined the monoclonal antibody
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`ipilimumab (YERVOY®) as a possible treatment for relapse of malignancy after
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`allogeneic hematopoietic cell transplantation (allo-HCT). See Bashey A., Ball E.D., et
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`al. “CTLA4 Blockade with Ipilimumab to Treat Relapse of Malignancy after
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`Allogeneic Hematopoietic Cell Transplantation,” Blood 113:1581 (2009) [Ex. 1011].
`
`Ipilimumab, which has been approved for the treatment of melanoma, is an antibody
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`that binds to and blocks the CTLA-4 receptor that downregulates the immune
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`functions in T cells. In this study we assessed the safety and preliminary efficacy of
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`ipilimumab in stimulating the graft-versus-malignancy effect after allo-HCT in
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`patients with recurrent or progressive malignancies after transplantation. We found
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`that administration of ipilimumab to these patients was safe and did not induce graft-
`
`versus-host disease (GVHD) or graft rejection. As for efficacy, we observed
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`antitumor responses in a number of patients with lymphoid malignancies. One patient
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`with refractory mantle cell lymphoma had partial remission and two patients with
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`Hodgkin disease had complete remission following ipilimumab administration.
`
`16.
`
`I was an investigator in an international Phase II clinical study which
`
`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 P.,
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`Ball E.D., et al. “Disabling Immune Tolerance by Programmed Death-1 Blockade
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`-8-
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`PETITIONER'S EXHIBITS
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`Exhibit 1004 Page 9 of 83
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`
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`with Pidilizumab after Autologous Hematopoietic Stem-Cell Transplantation for
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`Diffuse Large B-Cell Lymphoma: Results of an International Phase II Trial,” J Clin
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`Oncol 31:4199 (2013) [Ex. 1012]. Pidilizumab binds to and blocks checkpoint
`
`inhibitor PD-1 which is often co-opted in many tumors by depressing immune
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`response. By blocking PD-1, pidilizumab therefore increases immune response in
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`antitumor lymphocytes. In this study, it was observed that among patients with
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`measurable disease after transplantation, the overall response rate after pidilizumab
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`treatment was 51% and was associated with increased circulating lymphocyte subsets.
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`The positive results in the study warrant further clinical investigation of the use of the
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`humanized antibody pidilizumab in the blockade of PD-1 after stem-cell
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`transplantation.
`
`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 other
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`molecules. Specifically, I have studied extensively on bispecific antibodies for
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`treating leukemias. See, e.g., Ball E.D., et al. “Initial trial of bispecific antibody-
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`mediated immunotherapy of CD15-bearing tumors: cytotoxicity of human tumor cells
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`using a bispecific antibody comprised of anti-CD15 (MoAb PM81) and anti-CD64/Fc
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`gamma RI (MoAb 32),” J Hematother 1:85 (1992) [Ex. 1013]; Chen J, Zhou J.H.,
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`Ball E.D. “Monocyte-mediated lysis of acute myeloid leukemia cells in the presence
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`of the bispecific antibody 251 x 22 (anti-CD33 x anti-CD64).” Clin Can Res 1:1319
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`-9-
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`PETITIONER'S EXHIBITS
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`Exhibit 1004 Page 10 of 83
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`(1995) [Ex. 1014]; Balaian, L. and Ball, E.D. “Direct effect of bispecific anti-CD33 x
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`anti-CD64 antibody on proliferation and signaling in myeloid cells,” Leukemia Res
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`25:1115 (2001) [Ex. 1015]. In these studies, the bispecific antibodies were examined
`
`for their increased cytotoxicity toward cancer cells as they bound to a tumor antigen
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`such as CD15 or CD33 as well as an immune effector, CD64 (FcγRI) present on
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`neutrophils, monocytes and macrophages and plays an important role in antibody-
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`dependent cellular cytotoxicity (ADCC).
`
`18.
`
`I have also conducted research on an antibody-peptide conjugate that
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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 monoclonal
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`antibody 22 can specifically induce FcgammaRI (CD64)-dependent monocyte- and
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`neutrophil-mediated lysis of small cell carcinoma of the lung cells,” Clin Can Res
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`1:425 (1995) [Ex. 1016]; Chen J., Ball, E.D., et al. “Monocyte- and neutrophil-
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`mediated lysis of SCCL by a bispecific molecule comprised of Lys3-BN and mAb22,”
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`Peptides 1994, 819 (1995) [Ex. 1017]; Zhou J.H., Ball E.D., et al. “Immunotherapy of
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`a human small cell lung carcinoma (SCLC) xenograft model by the bispecific
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`molecule (BsMol) mAb22xLys3-Bombesin (M22xL-BN),” 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 studies, the antibody-peptide
`
`conjugate linked a bombesin peptide to an anti-CD64 antibody and was studied for its
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`-10-
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`PETITIONER'S EXHIBITS
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`Exhibit 1004 Page 11 of 83
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`
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`enhanced cytotoxicity toward small cell lung cancers. It was contemplated that this
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`conjugate brought together lung cancer cells with neutrophils and other immune cells
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`for this enhanced cell killing.
`
`19.
`
`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 Balaian, L.
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`“Cytotoxic activity of gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukemia
`
`correlates with the expression of protein kinase Syk,” Leukemia 20:2093 (2006) [Ex.
`
`1019]; Ball E.D., et al. “Update of a phase I/II trial of 5-azacytidine prior to
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`gemtuzumab ozogamicin (GO) for patients with relapsed acute myeloid leukemia with
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`correlative biomarker studies [abstract],” Blood (ASH Annual Meeting Abstracts) 116:
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`Abstract 3286 (2010) [Ex. 1020]. This study 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 and have
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`participated in more than 250 scientific abstracts presented at national and
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`international scientific meetings. I have also been invited to present my clinical and
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`research work both internationally and in the United States, and have chaired and co-
`
`chaired multiple symposiums and conferences in the areas of antibody therapies for
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`various cancers.
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`-11-
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`PETITIONER'S EXHIBITS
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`Exhibit 1004 Page 12 of 83
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`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,
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`Journal of Immunology, Journal of Immunotherapy, Journal of Leukocyte Biology,
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`Leukemia, and New England Journal of Medicine. I have been on the editorial board
`
`of Cell Transplantation, Bone Marrow Transplantation, Gaucher Clinical
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`Perspectives, Journal of Hematotherapy, and Experimental Hematology.
`
`22.
`
`I am a named inventor on five patent families relating to antibodies and
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`their use. These include U.S. Pat. Nos. 5,833,985, entitled “Bispecific molecules for
`
`use in inducing antibody-dependent cytotoxicity of tumors”; 6,071,517, entitled
`
`“Bispecific heteroantibodies with dual effector functions”; 6,340,569, entitled
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`“Monoclonal antibody and antigens specific therefor and methods of using same”;
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`7,977,320, entitled “Method of increasing efficacy of tumor cell killing using
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`combinations of anti-neoplastic agents”; and International Patent Publication WO
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`2006/073982, entitled “Bispecific molecule comprising ligands for cell-surface
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`protein and T-cell surface protein.”
`
`23.
`
`In all, I have more than 35 years of practical and research experience
`
`specializing in oncology and hematology with an emphasis on treating patients with
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`antibody therapeutics.
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`-12-
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`PETITIONER'S EXHIBITS
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`Exhibit 1004 Page 13 of 83
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`24. My curriculum vitae is attached hereto as Exhibit A.
`
`B.
`
`25.
`
`Bases for Opinions and Materials Considered
`
`Exhibit B includes a list of the materials I considered, in addition to my
`
`experience, education, and training, in providing the opinions contained herein.
`
`C.
`
`26.
`
`Scope of Work
`
`I have been retained by Mylan as a technical expert in this matter to
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`provide various opinions regarding the ’213 patent. I receive $500 per hour for my
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`services. No part of my compensation is dependent upon my opinions given or the
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`outcome of this case. I do not have any other current or past affiliation as an expert
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`witness or consultant with Mylan. I do not have any current or past affiliation with
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`Genentech, Inc., or any of the named inventors on the ’213 patent.
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`II.
`
`Summary of Opinions
`
`27.
`
`To summarize, for the reasons set forth below, it is my opinion that one
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`of ordinary skill in the art would have recognized the power and potential of
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`monoclonal antibodies (MAbs or MoAbs) as therapies for a number of diseases such
`
`as breast cancer while acknowledging the limitation of immunogenic effects upon
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`repeated administration of mouse monoclonal antibodies. Moreover, one of ordinary
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`skill in the art would have recognized that humanization of mouse monoclonal
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`antibodies as developed by Queen 1989 [Ex. 1034] and others would overcome this
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`limitation. With respect to cancer, one skilled in the art would have identified the
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`-13-
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`PETITIONER'S EXHIBITS
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`Exhibit 1004 Page 14 of 83
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`
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`HER-2/neu as a target for breast cancer therapy based on the prevalence of this gene
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`in a significant number of human breast cancer and other types of cancers as well as
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`the overexpression of HER-2/neu to cause cell transformation and tumorigenesis.
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`28. Accordingly, it is my opinion that because of the well-documented pre-
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`1991 reports of excellent specificity and potent anti-proliferative and cytotoxic effects
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`of the mouse monoclonal 4D5 antibody directed to HER-2/neu as presented in
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`Hudziak et al., “p185HER2 Monoclonal Antibody Has Antiproliferative Effects In Vitro
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`and Sensitizes Human Breast Tumor Cells to Tumor Necrosis Factor” Mol Cell Biol
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`9:1165 (1989) [Ex. 1021], a person of ordinary skill in the art would have identified
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`4D5 as a promising candidate for humanization, at least as early as March 1989. After
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`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
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`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 effects
`
`on HER-2 positive SK-BR-3 breast cancer cells. As Hudziak 1989 [Ex. 1021] noted,
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`the 4D5 antibody had the best effect of the tested anti-HER-2 antibodies in inhibiting
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`the growth of these cells leading the authors to conclude that “[m]aximum inhibition
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`was obtained with monoclonal antibody 4D5 which inhibited cellular proliferation by
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`56%.” Id. at 1169. The 4D5 antibody was also shown to downregulate p185HER2 by
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`allowing the protein to be degraded more quickly in the cell. Finally, the 4D5
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`-14-
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`PETITIONER'S EXHIBITS
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`Exhibit 1004 Page 15 of 83
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`antibody sensitized HER-2 positive breast cancer cells to TNF-alpha mediated
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`cytotoxicity.
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`29.
`
`Furthermore, Shepard et al. “Monoclonal Antibody Therapy of Human
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`Cancer: Taking the HER2 Protooncogene to the Clinic,” J. Clin. Immunol. 11:117
`
`(1991) [Ex. 1048] reported that a human tumor xenograft model was used to “support
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`the application of muMab 4D5 to human cancer therapy” and “its ability to inhibit the
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`growth of tumor cells overexpressing p185HER2 in vivo.” Id. at 122. In tumor bearing
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`athymic mice, the authors administered either the 4D5 antibody, a control antibody
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`5B6, or PBS and observed that “[o]n day 20, average tumor weights of animals
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`receiving muMAb 4D5 were significantly less than those receiving the same dose of
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`the control antibody muMab 5B6.” Id. at 123. These observations allow Shepard et
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`al. to conclude that “[t]he muMab 4D5 also serves as a template for antibody
`
`engineering efforts to construct humanized versions more suitable for chronic therapy
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`or other molecules which may be directly cytotoxic for tumor cells overexpressing the
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`HER2 protooncogene.” Id. at 126.
`
`30.
`
`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
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`antibody as a prime candidate for further development as a therapy for breast cancer.
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`It then follows, that one of ordinary skill in the art would logically proceed to develop
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`-15-
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`PETITIONER'S EXHIBITS
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`Exhibit 1004 Page 16 of 83
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`the monoclonal 4D5 antibody as a breast cancer therapeutic via well-established
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`humanization techniques, thereby reducing the antibody’s immunogenicity and
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`restoring antibody-dependent cell-mediated cytotoxicity (ADCC) and effector cell
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`binding.
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`III. Legal Standards
`
`31.
`
`In preparing and forming my opinions set forth in this declaration, I have
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`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
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`summarized below.
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`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 unpatentability is more probable
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`than not. I have taken these principles into account when forming my opinions in this
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`case.
`
`33.
`
`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.
`
`34.
`
`I am told that the concept of patent obviousness involves four factual
`
`inquiries: (1) the scope and content of the prior art; (2) the differences between the
`
`-16-
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`PETITIONER'S EXHIBITS
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`Exhibit 1004 Page 17 of 83
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`
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`claimed invention and the prior art; (3) the level of ordinary skill in the art; and (4)
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`secondary considerations of non-obviousness.
`
`35.
`
`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
`
`performing its known function and yields no more than what one would expect from
`
`such an arrangement, the combination is obvious.
`
`IV. Person of Ordinary Skill in the Art
`
`36. As above, I have been informed by counsel that the obviousness analysis
`
`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 invention.
`
`37.
`
`I have also been informed by counsel that in defining a person of
`
`ordinary skill in the art the following factors may be considered: (1) the educational
`
`level of the inventor; (2) the type of problems encountered in the art; (3) prior art
`
`solutions to those problems; (4) rapidity with which innovations are made; and (5)
`
`sophistication of the technology and educational level of active workers in the field.
`
`-17-
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`PETITIONER'S EXHIBITS
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`Exhibit 1004 Page 18 of 83
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`
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`38.
`
`I understand that a person of ordinary skill in the art related to the ‘213
`
`patent would be part of a team that developed antibody therapeutics. This person
`
`would have held a Ph.D. in chemistry, biological chemistry or a closely related field
`
`or an M.D. with practical academic and/or industrial experience in antibody
`
`development. As a Ph.D., a person of ordinary skill in the art would have experience
`
`necessary for antibody engineering, design, and humanization. The experience may
`
`come from the person of ordinary skill in the art’s own experience, or may come
`
`through the guidance of other individual(s) with experience in the pharmaceutical or
`
`biotech industry, e.g., as members of a research team or group.
`
`39. As an M.D., a person of ordinary skill in the art would have several years
`
`of experience as a medical professional, with direct experience administering
`
`therapeutic agents for the treatment of hematologic and solid tumor cancers. A person
`
`of ordinary skill in the art would also have clinical experience or knowledge of the
`
`diseases and disease pathways targeted by antibody therapeutics being developed and
`
`would be able to critically evaluate and make a determination on which antibody to
`
`further develop or humanize. This experience may come from the person of ordinary
`
`skill in the art’s experience, or through guidance from other individuals with degrees
`
`in medicine or other clinically relevant field, obtaining information from a clinician or
`
`clinical research with knowledge of disease targets for developing a therapeutic
`
`antibody, including in cancer treatment. A person of ordinary skill in the art would
`
`-18-
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`PETITIONER'S EXHIBITS
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`Exhibit 1004 Page 19 of 83
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`
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`also be well-versed in the world-wide literature on antibody therapeutics that was
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`available as of the ’213 patent.
`
`V.
`
`The ’213 Patent [Ex. 1001]
`
`40.
`
`I have read the ’213 patent entitled “Method for Making Humanized
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`Antibodies,” as well as its issued claims. I understand Mylan is challenging claims 1,
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`2, 4, 12, 25, 29-31, 33, 42, 60, 62-67, 69 and 71-81. The challenged claims include
`
`claims that relate to a humanized antibody which binds to p185HER2, i.e., claims 30,
`
`31, 33, 42 and 60. I have been asked by Mylan to comment on antibody therapies,
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`and in particular those that relate to p185HER2 and breast cancer.
`
`VI.
`
`State of the Art of Monoclonal Antibody Therapies and Cancer
`
`A.
`
`41.
`
`Early Antibody Therapy
`
`Because of their specificity to an antigen, antibodies were considered
`
`very early on as potential therapeutics for the treatment of diseases and conditions. In
`
`particular, monoclonal antibodies created from mice, developed by Georges Köhler
`
`and César Milstein in 1975, were of great interest to researchers as these types of
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`antibodies were of a single clonal population of antibodies which all bound to the
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`same antigen with the same specificity. See, e.g., Köhler and Milstein, “Continuous
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`Cultures of Fused Cells Secreting Antibody of Predefined Specificity,” Nature
`
`256:495 (1975) [Ex. 1022]. In this seminal paper, Köhler and Milstein developed the
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`hybridoma cell technique that fused a mouse myeloma cell with antibody-producing
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`-19-
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`PETITIONER'S EXHIBITS
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`Exhibit 1004 Page 20 of 83
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`
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`mouse spleen cells from an immunized donor. It then became “possible to hybridise
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`antibody-producing cells from different origins” and that “[s]uch cells [could] be
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`grown in vitro in massive cultures to provide a specific antibody.” Id. at 497. The
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`authors, who went on to receive the 1984 Nobel Prize for medicine for this work,
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`contemplated that “[s]uch cultures could be valuable for medical and industrial use.”
`
`Id. Monoclonal antibody technology thus enabled the isolation and large scale
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`production of a single specific antibody and opened the door to using antibodies for
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`therapeutic and diagnostic purposes. See, e.g., Prabakaran, S. “The Quest for a Magic
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`Bullet” Science 349:389 (2015) [Ex. 1023] (“Milstein sent samples and protocols of
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`his newly created antibody-secreting cell lines to other research institutions and even
`
`trained scientists to generate their own hybridomas. ... In the years that followed, there
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`was an explosion in Mab research. Some were generated to identify different types of
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`white blood cells, and several proved to be important in investigating HIV/AIDS. The
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`first medical application of this technology used Mabs to purify interferons, signaling
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`proteins that are released by cells in response to the presence of pathogens.”); Marks,
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`L. “The story of Cesar Milstein and Monoclonal Antibodies: A Healthcare Revolution
`
`in the Making” at http://www.whatisbiotechnology.org/exhibitions/milstein (last
`
`accessed September 08, 2015) [Ex. 1024] (“By the time the Nobel Prize was awarded
`
`to Milstein and his colleagues, monoclonal antibodies had become a ubiquitous
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`method for researchers in a multitude of disciplines. The technology not only provided
`
`-20-
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`PETITIONER'S EXHIBITS
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`Exhibit 1004 Page 21 of 83
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`
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`the tool for those involved in basis science, but also for those looking to develop new
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`diagnostics and therapies.”) (emphasis added).
`
`42.
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`Researchers thus immediately recognized the therapeutic potential of
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`monoclonal antibodies, and began administering murine monoclonal antibodies in
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`humans in an attempt to treat a variety of diseases, including cancer and
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`immunological disorders. For example, the first Mab approved for human use, murine
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`monoclonal anti-CD3 antibody, OKT3 (muromonab-CD3) was investigated for its
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`immunosuppressive activities in preventing organ graft rejection. See, e.g., Cosimi et
`
`al., “Treatment of Acute Renal Allograft Rejection with OKT3 Monoclonal
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`Antibody,” Trans
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