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`1.
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`My name is Dr. Eduardo A. PadlanLutz Riechmann, Ph.D. Counsel for Mylan
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`PharmaceuticalsCelltrion Inc. (“MylanCelltrion”) retained me to provide my opinionopinions
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`regarding U.S. Patent No. 6,407,213 (the ‘’213 patent) [Ex. 1001], which is assigned to
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`Genentech, Inc. I understand that MylanCelltrion intends to file a petition for inter partes review
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`of the ‘’213 patent, and will request that the United States Patent and Trademark Office cancel
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`certain claims of the ‘’213 patent as unpatentable in the petition. My opinions in this expert
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`declaration supports Mylan’sCelltrion’s request for inter partes review of the ‘’213 patent, and
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`cancellation of the claims.
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`I.
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`A.
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`2.
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`QUALIFICATIONS AND BACKGROUND
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`Education and Experience
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`I received my Ph.D. in Biology at the University of Bremen in Germany in 1986, and
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`subsequently worked as a postdoctoral fellow in Sir Gregory Winter’s laboratory at the Medical
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`Research Council Laboratory of Molecular Biology (MRC-LMB) in Cambridge in the United
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`Kingdom from 1986—1988. During this time the principle ideas of antibody humanization were
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`conceived and put into practice in the Winter group, where I myself extended these ideas from
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`antibodies against model antigens onto a therapeutic antibody against human lymphocyte surface
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`antigen CD52. For me this was the first time I experienced recombinant DNA technology and I
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`was keen to learn and practice all aspects of antibody engineering including cloning of the rodent
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`antibody genes, their transformation into the genes for their humanized counterparts using site-
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`directed mutagenesis, the transfer of those genes into and expression in eukaryotic cells as well
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`as the purification and analysis of the expressed antibodies. I furthermore learned the computer
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`graphic analysis of antibody structures, which I applied to design changes to my initially poorly
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`binding humanized antibody into an improved version, which was then immediately used to treat
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`Celltrion v. Genentech
`IPR2017-01374
`Genentech Exhibit 2062
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`two patients at the adjacent Cambridge University Hospital. My project was helped by the
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`cutting edge research undertaken at the MRC-LMB, which combined the groups of Drs. Michael
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`Neuberger and Cesar Milstein with their experience in monoclonal and recombinant antibody
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`technology, the groups of Chothia and Lesk providing their insight into antibody variable domain
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`structure with the equally world leading research in site-directed mutagenesis and protein
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`engineering undertaken by the Winter group. To this, the closeness of the Department of
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`Pathology added the experience with the rodent antibody that I humanized and enabled both the
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`fast characterization and then the immediate clinical use of the humanized antibody to help
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`patients. More generally the MRC-LMB is a world-class research laboratory and one of the
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`birthplaces of modern molecular biology. Many techniques have been pioneered at the
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`laboratory, including DNA sequencing, methods for determining the three-dimensional structure
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`of proteins and the development of monoclonal antibodies.
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`3.
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`In 1988 I received a Leukemia Society fellowship for a research position to work until
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`late 1989 with Professor Richard Lerner at the Scripps Research Institute in La Jolla, California,
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`where I helped with the cloning of total antibody repertoire gene libraries from spleen cells after
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`immunization. I also started the heteronuclear, multidimensional Nuclear Magnetic Resonance
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`(NMR) analysis of antibody fragments within the group of Professor Peter Wright at the Scripps
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`Institute. I moved back to Cambridge as a Group Leader at the MRC-LMB facility from 1989-
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`1997, where I expanded my NMR studies of human antibody variable domain structures and
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`their interaction with antigen and Protein A, a bacterial super-antigen frequently used to purify
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`antibodies. I also made antigen specific single domain human antibody fragments from designed
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`antibody heavy chain variable domain libraries using phage display and characterized their
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`binding and folding properties with various biophysical methods. Together with Dr. Phil Holliger
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`I furthermore elucidated the mechanism, with which bacteriophage (as used for phage display
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`experiments) infect bacteria - a vital step both for the natural life cycle of the bacteriophage and
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`for in vitro phage selection experiments with displayed proteins and peptides, and determined its
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`structural basis by both NMR and X-Ray crystallography.
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`4.
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`Between 1997-2008 I acted as Senior Scientific Officer with Sir Gregory Winter at the
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`MRC-LMB, during which time I, as my personal project, made proteins with novel folds from
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`randomly rearranged gene fragments using proteolytic phage selection and analyzed their
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`structures in the context of early protein evolution. I also acted as a guide for postdocs and Ph.D.
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`students in the Winter group to help with various antibody projects. From 2008-2009 I was
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`Director of Display Technology at F-star in Cambridge, where I set up and led a laboratory for
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`the design and selection of antibodies with an additional antigen binding site in their constant
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`domain, and was then re-appointed Senior Scientific Officer with Sir Gregory Winter at the
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`MRC-LMB from 2009-2011.
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`5.
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`Since 2011, I have been a consultant in the antibody engineering field for a variety of
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`industries and legal entities.
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`6.
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`My research interests include antibody and protein engineering, phage display and
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`selection of proteins and peptides, protein evolution and folding as well as the structural analysis
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`of proteins by Nuclear Magnetic Resonance spectroscopy.
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`7.
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`I have published extensively in the field of antibody and protein engineering with over 40
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`publications and patents covering 25 years.
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`8.
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`A full description of my background and qualifications can be found in my curriculum
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`vitae. Ex. 1003A.
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`2.
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`I completed my undergraduate studies in 1960 at the University of the Philippines,
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`majoring in Physics. I obtained my Ph.D in Biophysics from Johns Hopkins University in 1968,
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`working on X-ray crystallography of the hemoglobin protein from Glycera dibranchiata, a
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`marine annelid worm, in the laboratory of Dr. Warner E. Love. I continued to work at Johns
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`Hopkins University, first as a Research Associate from 1969 to 1971, then again as a Research
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`Scientist from 1978 to 1983. I subsequently completed an M.S. in Computer Science at Johns
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`Hopkins University in 1984.
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`3.
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`I was also a scientist at the Laboratory of Molecular Biology, National Institute of
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`Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH) from 1971-
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`1978, as a Visiting Associate and then a Visiting Scientist, where I first started working on
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`antibodies in the laboratory of Dr. David R. Davies. I returned to the NIH in 1983, working as an
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`Expert from 1983 to 1987, as a Visiting Scientist from 1987-1997, and then as a Research
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`Physicist from 1997-2000. I received tenure-track status at the NIH in 1987, continuing my work
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`on antibody structure and function. I retired from the NIH in 2000.
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`4.
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`I have been an Adjunct and Visiting Professor for various academic institutions in the
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`United States and the Philippines, teaching structural biology and protein engineering. From
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`1960-63, and again from 1968-1969, I was on the Faculty at the Department of Physics, College
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`of Arts and Sciences, University of the Philippines, Diliman. I was on the Faculty for the
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`Foundation for Advanced Education in the Sciences, NIH from 1984-1997. In 1992, I also
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`served as an Adjunct Professor, Department of Biochemistry and Molecular Biology, Medical
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`University of South Carolina. I served in various positions from 1998 to 2013, including as a
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`Visiting Professor, College of Science, University of the Philippines (1998-2002), Affiliate
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`Professor, School of Science and Engineering, Ateneo de Manila University (2000-2002),
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`Visiting Professor, Graduate School, University of Santo Tomas (2003) and as Adjunct
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`Professor, Institute of Chemistry, College of Arts and Sciences, University of the Philippines,
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`Los Banos (2002-2005). From 2002 to 2013, I was an Adjunct Professor at the Marine Science
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`Institute, College of Science at the University of the Philippines, Diliman.
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`5.
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`I have served as an editor or co-editor of several research journals, including
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`ImmunoMethods (vol. 1, no. 2 (1992)), Protein Engineering Section, Current Opinion in
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`Biotechnology (vol. 8 (1997)), Selected Essays on Science and Technology for Securing a Better
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`Philippines (vol. 1 (2008)), and Philippine Science Letters (2008-2014). I served as a member on
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`Advisory and Editorial Boards of Molecular Immunology (1980-1999), Macromolecular
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`Structures (1993-1997) and Receptor (1990-1996). I have been a guest lecturer at many
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`academic institutions both in the United States and in the Philippines throughout my career.
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`6.
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`I have also worked as a consultant since 1989 (i.e., before my retirement from the NIH)
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`up to the present. As a consultant, I helped to design humanized antibodies for various
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`biotechnology companies, including Merck Sharpe and Dohme, Biogen Inc., MedImmune Inc.,
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`T Cell Sciences Inc., IDEC Pharmaceuticals Corp., SmithKline Beecham, Medarex Inc., Tanox
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`Biosystems, System Research Inc., Biogen Idec, BioMedicas, Inc., NeoGenix Oncology, Inc.,
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`PharMab Inc., A&G Pharmaceutical Inc., Synthetic Biologics Inc., Bio-Technology General,
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`Ltd. (Israel) and Tanabe Research Laboratories.
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`7.
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`I was and currently am a member in several Professional and Academic Societies,
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`including National Academy of Science and Technology, Philippines, Philippine-American
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`Academy of Science and Engineering, Phi Kappa Phi, International Honor Society, Sigma Pi
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`Sigma Physics Honor Society, Phi Sigma Biological Honor Society, American Crystallographic
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`Association, American Society for Biochemistry and Molecular Biology, American Association
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`of Immunologists, Biophysical Society and the Philippine Society for Biochemistry and
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`Molecular Biology.
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`8.
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`I have many granted patents and pending applications, as well as primary references and
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`review articles published in the field of molecular biology, computational biosciences and
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`antibody humanization, totaling more than 200 scientific patents, papers and references. Many of
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`my research articles have received recognition from the scientific community, including my first
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`research article on the crystal structure of Glycera dibranchiata hemoglobin, that was published
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`in the scientific journal NATURE, and which was featured in the “Science Report” section of
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`THE TIMES OF LONDON shortly after its publication in 1968.
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`9.
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`Other research articles, many before June 1991, highlight our crystallography and
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`structural emphasis of antibodies, including several PROCEEDING OF THE NATIONAL
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`ACADEMY OF SCIENCE (PNAS) journal articles (see Segal et al. “The Three-Dimensional
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`Structure of a Phosphorylcholine-Binding Mouse Immunoglobulin Fab and the Nature of the
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`Antigen Binding Site,” Proc. Nat’l Acad. Sci. U.S.A. 71:4298 (1974), and Padlan and Davies
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`“Variability of Three-Dimensional Structure in Immunoglobulins,” Proc. Nat’l Acad. Sci. U.S.A.
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`92:819 (1975)), that were featured among others in several antibody structure review reports in
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`the journals NATURE and SCIENCE.
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`10.
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`In all, I have over 50 years of hands-on research experience specializing in computer
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`modeling, protein structure and analysis and antibody humanization. Attached as Exhibit 1 is a
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`copy of my curriculum vitae in support of my opinions.
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`B.
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`Bases for Opinions and Materials Considered
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`119. Exhibit 21003B includes a list of the materials I considered, in addition to my experience,
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`education, and training, in providing the opinions contained herein.
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`10.
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`In addition to the materials set forth in Exhibit 1003B, I have also reviewed the Expert
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`Declaration of Dr. Eduardo Padlan, which I understand was filed as Exhibit 1003 in Case Nos.
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`IPR2016-01693 and IPR2016-01694. Because I agreed with many of the statements and opinions
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`set forth therein, I have repeated those herein and revised only as necessary. Dr. Padlan’s
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`declaration also included a number of exhibits (Padlan Exhibits A-O), which he generated in
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`order to support his opinions. I have reviewed these exhibits and found them to be accurate and
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`useful in support of my own opinions. Because I agree with his use of the exhibits,
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`I have also used these same exhibits, where necessary, to support my opinions.
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`Previous Litigation Experience
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`I have served as an expert witness in two patent proceedings:
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`Opposition Proceedings for EP 0 451 216; Expert Declaration filed (dated October 8,
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`C.
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`12.
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`•
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`1996)
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`•
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`Consultant for U.S. Patent No. 6,054,297.
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`DC. Scope of Work
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`1311. I have been retained by MylanCelltrion as a technical expert in this matter to provide
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`various opinions regarding the ‘’213 patent. I receive $400£350 per hour for my servicesor
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`£2,800 per day if I am required to travel abroad. No part of my compensation is dependent upon
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`my opinions given or the outcome of this case. I do not have any current or past affiliation with
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`Genentech, Inc., Celltrion, Inc. or any of the named inventors on the ‘’213 patent.
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`II.
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`Legal StandardsLEGAL STANDARDS
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`1412. For my opinions in this declaration, I understand that it requires applying various legal
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`principles. As I am not an attorney, I have been informed about various legal principles that
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`involve my analysis. I have used my understanding of those principles in forming my opinions. I
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`can summarize those principles as I understand them below.
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`1513. For example, I have been told that MylanCelltrion bears the burden of proving
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`unpatentability in this proceeding by a preponderance of the evidence. I am informed that this
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`preponderance of the evidence standard means that MylanCelltrion must show that
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`unpatentability is more probable than not.
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`1614. I have also been told that when I review and consider the claims, the claims should be
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`construed to be given what is called their broadest reasonable interpretation in light of the
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`specification, when those claims are further viewed from the perspective of a person of ordinary
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`skill in the art. (I discuss who qualifies as the person of ordinary skill in the art in more detail
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`below).)
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`1715. I have been asked to consider the question of anticipation, namely, whether the claims
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`cover something that is new, or novel. I am told that the concept of anticipation requires that
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`each and every element of a challenged claim is present in or otherwise taught by a single prior
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`art reference. I also understand that an anticipatory reference does not need to explicitly describe
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`each element because anticipation can occur when a claimed limitation is necessarily inherent or
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`otherwise implicit in the relevant reference. I further understand that in order for a reference to
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`anticipate a claim, it must describe the subject matter with sufficient detail such that a person of
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`ordinary skill in the art would be able to carry out or put into practice the disclosed ideas.
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`1816. I have been asked to consider the question of obviousness/non- obviousnessnon-
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`obviousness. Again, I am told that this analysis must be from the perspective of the person of
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`ordinary skill in the art, and whether the skilled artisan would consider any differences between
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`the prior art and what is claimed to have been obvious. To make this assessment, I have been
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`informed that the concept of patent obviousness involvesassesses four factual inquiries: (1) the
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`scope and content of the prior art; (2) the differences between the claimed invention and the prior
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`art; (3) the level of ordinary skill in the art; and (4) secondary considerations of non-obviousness.
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`I further note that I have been instructed that one cannot use an existing patent as a guide to
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`select from prior art elements, or otherwise engage in hindsight. Rather, the bettercorrect
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`approach is to consider what the person of ordinary skill in the art knew, and what the art taught;
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`suggested; or motivated the person of ordinary skill in the art to further pursue; and to
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`differentiate between steps that were routinely done (such as in response to known problems,
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`steps or obstacles), and those which, for example, may have represented a different way of
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`solving existing or known problems.
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`1917. I am also informed that when there is some recognized reason to solve a problem, and
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`there are a finite number of identified, predictable and known solutions, a person of ordinary
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`skill in the art has good reason to pursue the known options within his or her technical grasp. If
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`such an approach leads to the expected success, it is likely not the product of innovation but of
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`ordinary skill and common sense. In addition, when a patent claim simply arranges old elements
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`with each performing its known function and yields no more than what one would expect from
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`such an arrangement, the combination is obvious.
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`2018. I understand that before reaching any final conclusion on obviousness, the obviousness
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`analysis requires consideration of objective indicia of non- obviousness, if itnon-obviousness, if
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`such information is offered. These must be considered to ensure that, for example, there were not
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`some unanticipated problems, obstacles or hurdles that may seem easy to overcome in hindsight,
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`but which were not readily overcome prior to the relevant invention date of the patents/claims at
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`issue here. I understand that these objective indicia are also known as “secondary considerations
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`of non-obviousness,” and may include long-felt but unmet need and unexpected results, among
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`others. I also understand, however, that any offered evidence of secondary considerations of non-
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`obviousnessnon-obviousness must be comparable with the scope of the challenged claims. This
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`means that for any offered evidence of secondary considerations of non-obviousness to be given
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`substantial weight, I understand the proponent of that evidence must establish a “nexus” or a
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`sufficient connection or tie between that evidence and the merits of the claimed invention, which
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`I understand specifically incorporates any novel element(s) of the claimed invention. If the
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`secondary consideration evidence offered actually results from something other than the
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`meritsnovel element(s) of the claim, then I understand that there is no nexus or tie to the claimed
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`invention. I also understand it is the patentee that has the burden of proving that a nexus exists.
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`2119. With respect to long-felt need, I understand that the evidence must show that a particular
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`problem existed for a long period of time. More specifically, I understand that for a “need” to be
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`long-felt and unmet 1) the need must be persistent and recognized by those of ordinary skill in
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`the art, 2) the need must not be satisfied by another before the alleged invention, and 3) the
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`claimed invention itself must satisfy the alleged need. I also understand that long-felt need is
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`analyzed as of the date that the problem is identified. Furthermore, I understand that long-felt
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`need should be based upon alleged inadequacies in the technical knowledge of those skilled in
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`the art, not due to business-driven market forces.
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`2220. With respect to failure of others, I understand that the focus of the analysis is on the prior
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`failure of others in the relevant industry, not the inventors. I further understand that, absent a
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`showing of a long-felt, unmet need or the failure of others, the mere passage of time without the
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`claimed invention is not evidence of non- obviousnessnon-obviousness.
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`2321. With respect to unexpected results, I understand that any results upon which a patentee
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`wishes to rely as an indicator of non-obviousness must be based on a comparison of the
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`purported inventions with the closest prior art.
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`2422. I also understand that the concept of simultaneous invention may provide evidence of
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`obviousness, particularly where an invention was arrived at independently within a
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`comparatively short space of time. I further understand that such evidence may indicate that the
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`claimed invention was the product only of ordinary engineering skill.
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`2523. However, I understand that secondary considerations will not overcome a strong showing
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`of obviousness.
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`III.
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`Person of Ordinary Skill in the ArtPERSON OF ORDINARY SKILL IN THE ART
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`2624. As above, I have been informed by counsel that the analysis is to be conducted from the
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`perspective of a person of ordinary skill in the art (a “person of ordinary skill”) at the time of the
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`invention.
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`2725. I have also been informed by counsel that in defining a person of ordinary skill in the art
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`the following factors may be considered: (1) the educational level of the inventor; (2) the type of
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`problems encountered in the art; (3) prior art solutions to those problems; (4) rapidity with which
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`innovations are made; and (5) sophistication of the technology and educational level of active
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`workers in the field.
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`2826. A person of ordinary skill in the art related to the ‘’213 patent would have held a Ph.D. or
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`equivalent in molecular biology, structural biology or a closely related field, or an M.D. with
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`practical academic or industrial experience in antibody development, including humanization of
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`antibodies for therapeutic development. For example, a person of ordinary skill in the art would
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`have the educational background above with experience in humanizing antibodies. This
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`experience is also consistent with the types of problems encountered in the art, which would
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`have included performing three-dimensional computer modeling of immunoglobulin structures,
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`antibody domain and sequence manipulation and swapping, CDR grafting and framework
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`substitution in humanizing antibodies, construction and expression of recombinant antibodies,
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`antibody binding assays (for specificity and affinity), immunogenicity testing and the like. The
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`experience may come from the person of ordinary skill in the art’s own experience, or may come
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`through research or work collaborations with other individual(s) with experience in the medical,
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`pharmaceutical or biotech industry, e.g., as members of a research team or group. For example,
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`the person of ordinary skill in the art may work as part of a team or collaboration to develop a
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`humanized monoclonal antibody for therapeutic use, including consulting with others to select
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`non-human monoclonal antibodies (such as a mouse monoclonal antibody) for humanization, as
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`well as subsequent testing of the humanized antibody and its intermediates. I should further note
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`that in the prior art, computer modeling for humanization was a known methodology. The field
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`was advancing rapidly, and individuals working in the field were highly sophisticated and using
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`the most advanced scientific techniques.
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`IV.
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`Summary of OpinionsSUMMARY OF OPINIONS
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`2927. For the reasons below, which includes my extensive experience well priorfrom 1986 to
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`June 1991 in the antibody structure and humanizationengineering field, it is my opinion that
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`claims 1, 2, 25, 29, 63, 66, 71, 75, 76, 78, 80 and 81 are anticipated over EP 0403156 to Kurrle et
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`al. [Ex. 1071; “Kurrle”]. Kurrle provided a detailed roadmap in disclosing the humanization of a
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`mouse monoclonal antibody against the human alpha/beta T-cell receptor, which included the
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`substitution of claimed human framework residues 4L, 69H, 71H, 73H and 76H, for the non-
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`human mouse monoclonal antibody framework residue.
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`3028. It is also my opinion that Queen 1990 [Ex. 1050], in also providing a detailed roadmap
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`for humanizing any non-human monoclonal antibody, anticipated claims 1, 2, 4, 29, 62, 63, 64,
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`80 and 81 of the ‘’213 patent. Queen 1990 characterized critical framework residues, including
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`neighboring non-human antigen-specific Complementarity Determining Region (CDR) amino
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`acid residues. From the well- knownwell-known teachings of Kabat 1987 [Ex. 1052] and Kabat
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`1991 [Ex. 1055], as well as Chothia & Lesk [Ex. 1062], claimed framework residues 98L and
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`36H are immediately adjacent to the CDRs according to the Kabat numbering system.
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`3129. From the discussion below, it is also my opinion that claims 1, 2, 4, 25, 29, 62-67, 69 and
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`71, 72, 74, 75, 76, 78 and 80-81 are obvious over Queen 1990 [Ex. 1050] in view of Kurrle [Ex.
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`1071]. Claims 12, 73, 77 and 79 are also obvious over Queen 1990 and Kurrle, in view of Furey
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`[Ex. 1125] or Chothia & Lesk [Ex. 1062]. As outlined below, Queen 1990 provided a detailed
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`roadmap for one of ordinary skill in the art to humanize a non-human monoclonal antibody,
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`disclosed that human framework residues immediately adjacent to CDRs, which included
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`claimed residues 98L and 36H, should be substituted for the corresponding non-human
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`framework residue in order to maintain CDR conformation and antigen binding. In also
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`acknowledging the importance of neighboring framework residues to the CDRs for maintaining
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`CDR conformation and antigen binding, Kurrle [Ex. 1071] followed through with the
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`substitution of the human framework residues, including at claimed residues including 4L, 69H,
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`71H, 73H, 76H and 93H according to the Kabat numbering system. Furey [Ex. 1125] and
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`Chothia & Lesk [Ex. 1062] moreover provided guidance on the importance of claimed residues
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`66L, 78H and 93H in maintaining antibody conformation, and thus provided explicit motivation
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`to a skilled artisan for making substitutions at these residues. Accordingly, claims 1, 2, 4, 12, 25,
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`29, 62-67, 69 and 71-81 are also obvious in my opinion over Queen 1990 in view of Kurrle, and
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`Chothia & Lesk or Furey.
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`3230. Furthermore, given the availability of antibody crystal structures, and the detailed
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`analysis and characterization of framework residues that contact CDRs and/or important in
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`maintaining CDR conformation and antigen biding, it is also my opinion that claims 1, 2, 12, 29,
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`63, 65-67, 69 and 71-81 of the ‘’213 patent are obvious in view of Queen 1989 [Ex. 1034], and
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`the Protein Databank (PDB) database, as well as the combination of Queen 1990 [Ex. 1050] and
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`the PDB database. Both Queen 1989 and Queen 1990 (together the “Queen references”) provide
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`specific and detailed guidance regarding framework residue substitutions that were necessary for
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`maintaining conformation and thus antigen binding. Both Queen references thus provided the
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`explicit motivation for substituting the claimed framework region amino acid residues in order to
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`reduce immunogenicity while retaining binding affinity and specificity. Together with the known
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`antibody structures available in the PDB databases, those of ordinary skill in the art, including
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`myself, would have had a reasonable expectation of success in doing so.
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`3331. In fact during the samebetween 1986 and 1988, well before the time period that the ‘’213
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`patent was filed, when I was asked by various groups within the National Institutes of Health, as
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`well as other research institutions and companies, to humanize non-human (mouse) monoclonal
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`antibodies, and used the same antibody modeling systems and atomic distance calculations to
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`determine framework region amino acid residues that were substitution candidates for antibody
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`humanization. engineered the first fully humanized antibody, CAMPATH-1, within the Winter
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`group at the Medical Research Council, United Kingdom, I was faced with the problem to
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`restore the antigen affinity of the original, in this case rat, antibody after the straightforward
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`replacement of the CDRs alone. While it was the case that CAMPATH-1 ultimately did not
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`require any change to the residues listed in the claims, I used not only my own knowledge of
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`antibody structure and function, but also the extensive structural and functional information that
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`was publicly available, includingprimarily originating from the laboratories of Chothia & Lesk,
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`the Winter Laboratory group at the Medical Research Council, United Kingdom, as well as our
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`own laboratory at the National Institutes of Healthand the antibody structures available in the
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`Protein Databank deposited by other research groups, to identify all framework amino acid
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`residues, which could potentially impact antigen affinity including those listed in the claims of
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`the ’231 patent. I used standard, publically available antibody modeling systems and atomic
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`distance calculations to determine framework region amino acid residues that were substitution
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`candidates for restoring antigen affinity. It is my opinion that substituting these previously
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`identified framework amino acid residues that were important for CDR contact and maintenance
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`of conformation, as well as buried residues for maintaining intrachain antibody contact and
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`VL:VH residues that maintained interchain antibody contact, would have been obvious in 1991
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`and required only routine skills and techniques. Those of ordinary skill in the art thus would have
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`had the motivation and reasonable expectation of success that substituting these previously
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`identified residues would have been important in maintaining antibody conformation and antigen
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`binding. This includes claimed amino acid residues 73H (claims 76, 77 and 79), 78H (claims 77
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`and 79) and 93H (claim 79), in addition to claimed position 71H, which was already well-known
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`to those of ordinary skill in the art from the work performed by Tramontano et al. [Ex. 1051] as
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`important for maintaining conformation and antigen binding. Thus, claims 1, 2, 12, 29, 63, 65-67
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`and 71-81 of the ‘’213 patent are obvious in view of either Queen 1989 or Queen 1990 and the
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`PDB database.
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`- 15-
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`

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`3432. It is also my opinion that claims 30, 31, 33, 42 and 60 are obvious in view of Queen 1989
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`[Ex. 1034] or Queen [Ex. 1050] and the PDB database, and also in combination with Hudziak
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`[Ex. 1021], which discussed the importance of mouse monoclonal antibody 4D5 specifically as a
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`potential therapeutic agent for the treatment of HER2-positive breast cancer, a difficult to treat
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`form of breast cancer. For the same reasons, it is my opinion that claims 30, 31, 33, 42 and 60
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`are also obvious over Queen 1990 and Hudziak, in view of Furey [Ex. 1125] or Chothia & Lesk
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`[Ex. 1062].
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`3533. I have reviewed and understand from the declaration of Dr. Edward T. BallRobert
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`Leonard, B.Sc., M.B., M.D., an expert in the field of oncology who has developed and
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`administered monoclonal antibodies for the treatment of cancer, including breast cancer, that a
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`skilled artisan, from Hudziak and others well before June 1991, would have considered the
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`p185HER2 gene product to be a promising target for therapeutic development because of its
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`demonstrated correlation with breast cancer cell proliferation and signaling, as well as the
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`beneficial effects observed upon inhibition of the p185HER2 protein - e.g., abrogation of breast
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`cancer cell proliferation and progression. From his analysis, I agree with Dr. Ball’sLeonard’s
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`conclusions that the p185HER2 protein would have been a desirable target in the treatment of
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`cancer, including breast cancer, and would have included a monoclonal antibody therapeutic
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`because of the specificity afforded by monoclonal antibody therapeutic agents.
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`3634. Dr. BallLeonard further discussed the detailed information provided by Hudziak and
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`others regarding the promise and potential of anti-p185HER2 monoclonal antibody, 4D5, in
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`downregulating breast cancer cell and tumor proliferation in vivo and the authors even single out
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`mouse monoclonal anti-panti- p185HER2 antibody 4D5, stating that out of a panel of
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`monoclonal antibodies tested, “one of these, 4D5, strongly inhibits the growth of several breast
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`- 16-
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`

`

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`tumor cell lines… . . . is specific for p185HER2 and shows no cross-reactivity with the closely
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`related human EGF receptor.” See Hudziak at 1171 [Ex. 1021 at 7]. Thus, as concluded by Dr.
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`BallLeonard, a skilled artisan well before June 1991 would have recognized the promising
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`therapeutic properties of