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 DR. EDUARDO A. PADLAN
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF
`PATENT NO. 6,407,213
`
`PETITIONER'S EXHIBITS
`
`Exhibit 1003 Page 1 of 223
`
`

`

`TABLE OF CONTENTS
`
`I.
`
`Page
`QUALIFICATIONS AND BACKGROUND..............................................1
`A.
`Education and Experience..................................................................1
`B.
`Bases for Opinions and Materials Considered.................................5
`C.
`Previous Litigation Experience..........................................................5
`D.
`Scope of Work......................................................................................5
`Legal Standards .............................................................................................6
`II.
`III. Person of Ordinary Skill in the Art ...........................................................11
`IV.
`Summary of Opinions .................................................................................12
`V.
`The ’213 Patent [Ex. 1001]..........................................................................19
`VI. Background ..................................................................................................37
`A.
`Antibody Structure and Function....................................................37
`B. Monoclonal Antibodies Expanded Therapeutic and
`Diagnostic Uses of Antibodies ..........................................................39
`Immunogenic Reaction in Humans With Monoclonal
`Antibody Therapy .............................................................................41
`D. Molecular Characterization of Antibody Structure and
`Function..............................................................................................42
`Antigen Binding Regions ..................................................................45
`E.
`Framework Region Important for Antigen Binding .....................51
`F.
`Chimeric Antibodies..........................................................................55
`G.
`Antibody Humanization ...................................................................57
`H.
`VII. Scope and Content of the Prior Art References .......................................70
`A.
`EP 0403156 “Improved Monoclonal Antibodies Against the
`Human Alpha/Beta T-Cell Receptor, Their Production and
`Use” Published December 19, 1990 (“Kurrle”) [Ex. 1071] ...........70
`Queen et al. “A Humanized Antibody that Binds to the
`Interleukin 2 Receptor” PNAS 86:10029-33 (1989) (“Queen
`1989”) [Ex. 1034] ...............................................................................73
`PCT Publication No. WO 90/07861 (“Queen 1990”) [Ex.
`1050]....................................................................................................76
`Furey et al. “Structure of a Novel Bence-Jones Protein
`(Rhe) Fragment at 1.6 Å Resolution,” J. Mol. Biol. 167:661-
`692 (1983) [Ex. 1125].........................................................................80
`Protein Data Bank Database............................................................81
`
`C.
`
`C.
`
`B.
`
`D.
`
`E.
`
`i
`
`PETITIONER'S EXHIBITS
`
`Exhibit 1003 Page 2 of 223
`
`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`
`F.
`
`I.
`
`J.
`
`Tramontano et al. “Framework Residue 71 is a Major
`Determinant of the Position and Conformation of the
`Second Hypervariable Region in the VH Domains of
`Immunoglobulins” J. Mol. Biol. 215:175-182 (1990)
`(“Tramontano”) [Ex. 1051] ..............................................................83
`G. Kabat et al. “Sequences of Proteins of Immunological
`Interest”4th Ed., pp. iii, 41-49, 167-176 (1987) (“Kabat
`1987”) [Ex. 1052] ...............................................................................84
`H. Hudziak et al. “p185HER2 Monoclonal Antibody Has
`Antiproliferative Effects In Vitro and Sensitizes Human
`Breast Tumor Cells to Tumor Necrosis Factor” Mol Cell
`Biol 9:1165-1172 (1989) (“Hudziak”) [Ex. 1021]............................85
`Chothia, C. et al. “Domain Association in Immunoglobulin
`Molecules: The Packing of Variable Domains” J. Mol. Biol.
`186:651-663 (1985) (“Chothia 1985”) [Ex. 1063]............................86
`Chothia and Lesk. “Canonical Structures for the
`Hypervariable Regions of Immunoglobulins” J. Mol. Biol.
`196:901-917 (1987) (“Chothia & Lesk”) [Ex. 1062].......................87
`Chothia, C. et al. “Conformations of Immunoglobulin
`Hypervariable Regions” Nature 342:877-883 (1989)
`(“Chothia 1989”) [Ex. 1049].............................................................87
`VIII. UNPATENTABILITY OF THE ’213 PATENT.......................................88
`A.
`Claims 1, 2, 25, 29, 63, 66, 71, 75, 76, 78, 80 and 81 of the
`’213 Patent are Anticipated by Kurrle [Ex. 1071] .........................88
`1.
`Claim 1 of the ’213 patent is anticipated by Kurrle ............88
`2.
`Dependent claims 2, 25 and 29 are anticipated by
`Kurrle.......................................................................................90
`Independent claim 63 is anticipated by Kurrle....................92
`Independent claim 66 and dependent claims 71, 72, 75
`and 76 are anticipated by Kurrle ..........................................94
`Independent claim 80 and dependent claim 81 are
`anticipated by Kurrle .............................................................95
`Claims 1, 2, 4, 29, 62, 63, 64, 80 and 81 of the ’213 Patent
`are Anticipated by Queen 1990........................................................97
`1.
`Independent Claim 1 of the ’213 Patent is anticipated
`by Queen 1990 [Ex. 1050].......................................................97
`
`K.
`
`B.
`
`3.
`4.
`
`5.
`
`ii
`
`PETITIONER'S EXHIBITS
`
`Exhibit 1003 Page 3 of 223
`
`

`

`C.
`
`TABLE OF CONTENTS
`(continued)
`
`Page
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`3.
`4.
`
`Dependent Claim 2 of the ’213 Patent is anticipated by
`Queen 1990.............................................................................103
`Dependent Claim 4 of the ’213 Patent is anticipated by
`Queen 1990.............................................................................104
`Dependent Claim 29 of the ’213 Patent is anticipated
`by Queen 1990 .......................................................................105
`Independent Claim 62 of the ’213 Patent is anticipated
`by Queen 1990 .......................................................................105
`Independent Claim 63 of the ’213 Patent is anticipated
`by Queen 1990 .......................................................................106
`Dependent Claim 65 of the ’213 Patent is anticipated
`by Queen 1990 .......................................................................108
`Independent Claim 64 of the ’213 Patent is anticipated
`by Queen 1990 .......................................................................110
`Independent Claim 80 of the ’213 Patent is anticipated
`by Queen 1990 .......................................................................112
`10. Dependent Claim 81 of the ’213 Patent is anticipated
`by Queen 1990 .......................................................................114
`Claims 1, 2, 4, 12, 25, 29, 62-67, 69 and 71-81 of the ’213
`Patent are obvious over Queen 1990 in view of Kurrle, and
`Chothia 1985 or Chothia & Lesk...................................................114
`1.
`Claim 1 is obvious over Queen 1990 and Kurrle ...............117
`2.
`Claims 2, 25 and 29 are obvious over Queen 1990 and
`Kurrle.....................................................................................120
`Claim 4 is obvious over Queen 1990 and Kurrle ...............122
`Claim 12 is obvious over Queen 1990 and Kurrle, in
`view of Furey .........................................................................123
`Claim 62 is obvious over Queen 1990 in view of Kurrle ...125
`5.
`Claim 63 is obvious over Queen 1990 in view of Kurrle ...126
`6.
`Claim 64 is obvious over Queen 1990 in view of Kurrle ...127
`7.
`Claim 65 is obvious over Queen 1990 in view of Kurrle ...129
`8.
`Claim 66 is obvious over Queen 1990 in view of Kurrle ...132
`9.
`10. Claims 67, 71, 72, 74, 75, 76 and 78 are obvious over
`Queen 1990 in view of Kurrle and Chothia 1985...............133
`11. Claim 69 is obvious over Queen 1990 in view of Kurrle ...136
`12. Claims 73, 77 and 79 are obvious in view of Queen
`1990, Kurrle and Chothia & Lesk.......................................136
`
`iii
`
`PETITIONER'S EXHIBITS
`
`Exhibit 1003 Page 4 of 223
`
`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`
`D.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`13. Claims 80 and 81 are obvious over Queen 1990 in view
`of Kurrle.................................................................................142
`Claims 1, 2, 4, 12, 25, 29, 62-67, 69 and 71-81 of the ’213
`Patent are obvious in view of Queen 1989 or Queen 1990
`and the PDB database.....................................................................144
`1.
`Independent Claim 1 of the ’213 Patent is obvious in
`view of Queen 1989 and the PDB database ........................145
`Independent Claim 1 of the ’213 Patent is obvious in
`view of Queen 1990 and the PDB database ........................160
`Dependent Claims 2, 12, 25 and 29 of the ’213 Patent
`are obvious in view of Queen 1989 or Queen 1990 and
`the PDB database ..................................................................163
`Dependent claim 4 of the ’213 Patent is obvious in view
`of Queen 1990 and the PDB database .................................164
`Independent Claim 62 of the ’213 Patent is obvious in
`view of Queen 1990 and the PDB database ........................164
`Independent Claim 63 of the ’213 Patent is obvious in
`view of Queen 1989 or Queen 1990 and the PDB
`database..................................................................................165
`Independent Claim 64 of the ’213 Patent is obvious in
`view of Queen 1990 and the PDB database ........................166
`Independent Claim 66 of the ’213 Patent is obvious in
`view of Queen 1989 or Queen 1990 and the PDB
`database..................................................................................168
`Dependent Claims 67, 71-74 and 78 of the ’213 Patent
`are obvious in view of Queen 1989 or Queen 1990 and
`the PDB database ..................................................................170
`10. Dependent Claim 72 of the ’213 patent is obvious in
`view of Queen 1989 or Queen 1990, and the PDB
`database..................................................................................171
`11. Dependent Claim 75 of the ’213 patent is obvious in
`view of Queen 1989 or Queen 1990 and the PDB
`database..................................................................................173
`12. Dependent Claim 75 of the ’213 patent is obvious in
`view of Queen 1989 or Queen 1990 and the PDB
`database, and further in view of Tramontano ...................174
`
`7.
`
`8.
`
`9.
`
`iv
`
`PETITIONER'S EXHIBITS
`
`Exhibit 1003 Page 5 of 223
`
`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`
`16.
`
`2.
`
`3.
`
`13. Dependent Claims 76-77 and 79 of the ’213 Patent are
`obvious in view of Queen 1989 or Queen 1990 and the
`PDB database, and optionally in view of Tramontano......175
`14. Dependent Claim 69 of the ’213 Patent is obvious in
`view of Queen 1990 and the PDB database ........................184
`15. Dependent Claim 65 of the ’213 Patent is obvious in
`view of Queen 1989 or Queen 1990 and the PDB
`database..................................................................................184
`Independent Claim 80 of the ’213 Patent is obvious in
`view of Queen 1989 or Queen 1990 and the PDB
`database..................................................................................186
`17. Dependent Claim 81 of the ’213 Patent is obvious in
`view of Queen 1989 or Queen 1990 and the PDB
`database..................................................................................188
`Claims 4, 62, 64 and 69 of the ’213 Patent are obvious in
`view of Queen 1989, the PDB database and in view of Kabat
`1987 ...................................................................................................188
`1.
`Independent Claim 62 of the ’213 Patent is obvious in
`view of Queen 1989, the PDB database and in view of
`Kabat 1987.............................................................................189
`Dependent Claims 4 and 69 of the ’213 Patent are
`obvious in view of Queen 1989 and the PDB database,
`and in view of Kabat 1987, and Hudziak............................192
`Independent Claim 64 of the ’213 Patent is obvious in
`view of Queen 1989 and the PDB database, in view of
`Kabat 1987.............................................................................192
`Claims 30, 31, 33, 42, and 60 of the ’213 Patent are Obvious
`Over Queen 1989 or Queen 1990 and the PDB Database,
`and In View Of Hudziak.................................................................194
`1.
`Claim 30 of the ’213 Patent is obvious in view of Queen
`1989 or Queen 1990 and the PDB Database, and in
`view of Hudziak.....................................................................194
`Dependent Claims 31, 42, and 60 of the ’213 Patent are
`obvious in view of Queen 1989 or Queen 1990 and the
`PDB database, and in view of Hudziak...............................201
`Claim 33 is obvious in view of Queen 1990 and the PDB
`database, and in view of Hudziak........................................202
`Claims 30, 31, 33, 42, and 60 of the ’213 Patent are Obvious
`
`2.
`
`3.
`
`v
`
`E.
`
`F.
`
`G.
`
`PETITIONER'S EXHIBITS
`
`Exhibit 1003 Page 6 of 223
`
`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`
`Over Queen 1990, and Further In View Of Hudziak, Furey
`and Chothia & Lesk ........................................................................203
`SECONDARY CONSIDERATIONS ......................................................206
`CONCLUSION ..........................................................................................208
`
`IX.
`X.
`
`vi
`
`PETITIONER'S EXHIBITS
`
`Exhibit 1003 Page 7 of 223
`
`

`

`1.
`
`My name is Dr. Eduardo A. Padlan. Counsel for Mylan Pharmaceuticals
`
`Inc. (“Mylan”) retained me to provide my opinion regarding U.S. Patent No.
`
`6,407,213 (the ’213 patent) [Ex. 1001], which is assigned to Genentech, Inc. I
`
`understand that Mylan intends to file a petition for inter partes review of the ’213
`
`patent, and will request that the United States Patent and Trademark Office cancel
`
`certain claims of the ’213 patent as unpatentable in the petition. My opinions in this
`
`expert declaration supports Mylan’s request for inter partes review of the ’213 patent,
`
`and cancellation of the claims.
`
`I.
`
`QUALIFICATIONS AND BACKGROUND
`
`A.
`
`2.
`
`Education and Experience
`
`I completed my undergraduate studies in 1960 at the University of the
`
`Philippines, majoring in Physics. I obtained my Ph.D in Biophysics from Johns
`
`Hopkins University in 1968, working on X-ray crystallography of the hemoglobin
`
`protein from Glycera dibranchiata, a marine annelid worm, in the laboratory of Dr.
`
`Warner E. Love. I continued to work at Johns Hopkins University, first as a Research
`
`Associate from 1969 to 1971, then again as a Research Scientist from 1978 to 1983. I
`
`subsequently completed an M.S. in Computer Science at Johns Hopkins University in
`
`1984.
`
`3.
`
`I was also a scientist at the Laboratory of Molecular Biology, National
`
`Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
`
`PETITIONER'S EXHIBITS
`
`Exhibit 1003 Page 8 of 223
`
`

`

`(NIH) from 1971-1978, as a Visiting Associate and then a Visiting Scientist, where I
`
`first started working on antibodies in the laboratory of Dr. David R. Davies. I
`
`returned to the NIH in 1983, working as an Expert from 1983 to 1987, as a Visiting
`
`Scientist from 1987-1997, and then as a Research Physicist from 1997-2000. I
`
`received tenure-track status at the NIH in 1987, continuing my work on antibody
`
`structure and function. I retired from the NIH in 2000.
`
`4.
`
`I have been an Adjunct and Visiting Professor for various academic
`
`institutions in the United States and the Philippines, teaching structural biology and
`
`protein engineering. From 1960-63, and again from 1968-1969, I was on the Faculty
`
`at the Department of Physics, College of Arts and Sciences, University of the
`
`Philippines, Diliman. I was on the Faculty for the Foundation for Advanced
`
`Education in the Sciences, NIH from 1984-1997. In 1992, I also served as an Adjunct
`
`Professor, Department of Biochemistry and Molecular Biology, Medical University of
`
`South Carolina. I served in various positions from 1998 to 2013, including as a
`
`Visiting Professor, College of Science, University of the Philippines (1998-2002),
`
`Affiliate Professor, School of Science and Engineering, Ateneo de Manila University
`
`(2000-2002), Visiting Professor, Graduate School, University of Santo Tomas (2003)
`
`and as Adjunct Professor, Institute of Chemistry, College of Arts and Sciences,
`
`University of the Philippines, Los Banos (2002-2005). From 2002 to 2013, I was an
`
`-2-
`
`PETITIONER'S EXHIBITS
`
`Exhibit 1003 Page 9 of 223
`
`

`

`Adjunct Professor at the Marine Science Institute, College of Science at the University
`
`of the Philippines, Diliman.
`
`5.
`
`I have served as an editor or co-editor of several research journals,
`
`including ImmunoMethods (vol. 1, no. 2 (1992)), Protein Engineering Section,
`
`Current Opinion in Biotechnology (vol. 8 (1997)), Selected Essays on Science and
`
`Technology for Securing a Better Philippines (vol. 1 (2008)), and Philippine Science
`
`Letters (2008-2014). I served as a member on Advisory and Editorial Boards of
`
`Molecular Immunology (1980-1999), Macromolecular Structures (1993-1997) and
`
`Receptor (1990-1996). I have been a guest lecturer at many academic institutions
`
`both in the United States and in the Philippines throughout my career.
`
`6.
`
`I have also worked as a consultant since 1989 (i.e., before my retirement
`
`from the NIH) up to the present. As a consultant, I helped to design humanized
`
`antibodies for various biotechnology companies, including Merck Sharpe and Dohme,
`
`Biogen Inc., MedImmune Inc., T Cell Sciences Inc., IDEC Pharmaceuticals Corp.,
`
`SmithKline Beecham, Medarex Inc., Tanox Biosystems, System Research Inc.,
`
`Biogen Idec, BioMedicas, Inc., NeoGenix Oncology, Inc., PharMab Inc., A&G
`
`Pharmaceutical Inc., Synthetic Biologics Inc., Bio-Technology General, Ltd. (Israel)
`
`and Tanabe Research Laboratories.
`
`-3-
`
`PETITIONER'S EXHIBITS
`
`Exhibit 1003 Page 10 of 223
`
`

`

`7.
`
`I was and currently am a member in several Professional and Academic
`
`Societies, including National Academy of Science and Technology, Philippines,
`
`Philippine-American Academy of Science and Engineering, Phi Kappa Phi,
`
`International Honor Society, Sigma Pi Sigma Physics Honor Society, Phi Sigma
`
`Biological Honor Society, American Crystallographic Association, American Society
`
`for Biochemistry and Molecular Biology, American Association of Immunologists,
`
`Biophysical Society and the Philippine Society for Biochemistry and Molecular
`
`Biology.
`
`8.
`
`I have many granted patents and pending applications, as well as primary
`
`references and review articles published in the field of molecular biology,
`
`computational biosciences and antibody humanization, totaling more than 200
`
`scientific patents, papers and references. Many of my research articles have received
`
`recognition from the scientific community, including my first research article on the
`
`crystal structure of Glycera dibranchiata hemoglobin, that was published in the
`
`scientific journal NATURE, and which was featured in the “Science Report” section of
`
`THE TIMES OF LONDON shortly after its publication in 1968.
`
`9.
`
`Other research articles, many before June 1991, highlight our
`
`crystallography and structural emphasis of antibodies, including several PROCEEDING
`
`OF THE NATIONAL ACADEMY OF SCIENCE (PNAS) journal articles (see Segal et al.
`
`-4-
`
`PETITIONER'S EXHIBITS
`
`Exhibit 1003 Page 11 of 223
`
`

`

`“The Three-Dimensional Structure of a Phosphorylcholine-Binding Mouse
`
`Immunoglobulin Fab and the Nature of the Antigen Binding Site,” Proc. Nat’l Acad.
`
`Sci. U.S.A. 71:4298 (1974), and Padlan and Davies “Variability of Three-Dimensional
`
`Structure in Immunoglobulins,” Proc. Nat’l Acad. Sci. U.S.A. 92:819 (1975)), that
`
`were featured among others in several antibody structure review reports in the journals
`
`NATURE and SCIENCE.
`
`10.
`
`In all, I have over 50 years of hands-on research experience specializing
`
`in computer modeling, protein structure and analysis and antibody humanization.
`
`Attached as Exhibit 1 is a copy of my curriculum vitae in support of my opinions.
`
`B.
`
`11.
`
`Bases for Opinions and Materials Considered
`
`Exhibit 2 includes a list of the materials I considered, in addition to my
`
`experience, education, and training, in providing the opinions contained herein.
`
`C.
`
`12.
`
`Previous Litigation Experience
`
`I have served as an expert witness in two patent proceedings:
`
` Opposition Proceedings for EP 0 451 216; Expert Declaration filed
`
`(dated October 8, 1996)
`
` Consultant for U.S. Patent No. 6,054,297.
`
`D.
`
`Scope of Work
`
`-5-
`
`PETITIONER'S EXHIBITS
`
`Exhibit 1003 Page 12 of 223
`
`

`

`13.
`
`I have been retained by Mylan as a technical expert in this matter to
`
`provide various opinions regarding the ’213 patent. I receive $400 per hour for my
`
`services. No part of my compensation is dependent upon my opinions given or the
`
`outcome of this case. I do not have any current or past affiliation with Genentech, Inc.,
`
`or any of the named inventors on the ’213 patent.
`
`II.
`
`Legal Standards
`
`14.
`
`For my opinions in this declaration, I understand that it requires applying
`
`various legal principles. As I am not an attorney, I have been informed about various
`
`legal principles that involve my analysis. I have used my understanding of those
`
`principles in forming my opinions. I can summarize those principles as I understand
`
`them below.
`
`15.
`
`For example, I have been told that Mylan bears the burden of proving
`
`unpatentability in this proceeding 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 than not.
`
`16.
`
`I have also been told that when I review and consider the claims, the
`
`claims should be construed to be given what is called their broadest reasonable
`
`interpretation in light of the specification, when those claims are further viewed from
`
`-6-
`
`PETITIONER'S EXHIBITS
`
`Exhibit 1003 Page 13 of 223
`
`

`

`the perspective of a person of ordinary skill in the art. (I discuss who qualifies as the
`
`person of ordinary skill in the art in more detail below).
`
`17.
`
`I have been asked to consider the question of anticipation, namely,
`
`whether the claims cover something that is new, novel. I am told that the concept of
`
`anticipation requires that each and every element of a challenged claim is present in or
`
`otherwise taught by a single reference. I also understand that an anticipatory reference
`
`does not need to explicitly describe each element because anticipation can occur when
`
`a claimed limitation is necessarily inherent or otherwise implicit in the relevant
`
`reference.
`
`18.
`
`I have been asked to consider the question of obviousness/non-
`
`obviousness. Again, I am told that this analysis must be from the perspective of the
`
`person of ordinary skill in the art, and whether the skilled artisan would consider any
`
`differences between the prior art and what is claimed to have been obvious. To make
`
`this assessment, I have been informed that the concept of patent obviousness involves
`
`four factual inquiries: (1) the scope and content of the prior art; (2) the differences
`
`between the claimed invention and the prior art; (3) the level of ordinary skill in the
`
`art; and (4) secondary considerations of non-obviousness. I further note that I have
`
`been instructed that one cannot use an existing patent as a guide to select from prior
`
`art elements, or otherwise engage in hindsight. Rather, the better approach is to
`
`-7-
`
`PETITIONER'S EXHIBITS
`
`Exhibit 1003 Page 14 of 223
`
`

`

`consider what the person of ordinary skill in the art knew, and what the art taught;
`
`suggested; or motivated the person of ordinary skill in the art to further pursue; and to
`
`differentiate between steps that were routinely done (such as in response to known
`
`problems, steps or obstacles), and those which, for example, may have represented a
`
`different way of solving existing or known problems.
`
`19.
`
`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
`
`addition, 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.
`
`20.
`
`I understand that before reaching any final conclusion on obviousness,
`
`the obviousness analysis requires consideration of objective indicia of non-
`
`obviousness, if it is offered. These must be considered to ensure that, for example,
`
`there were not some unanticipated problems, obstacles or hurdles that may seem easy
`
`to overcome in hindsight, but which were not readily overcome prior to the relevant
`
`invention date of the patents/claims at issue here. I understand that these objective
`
`-8-
`
`PETITIONER'S EXHIBITS
`
`Exhibit 1003 Page 15 of 223
`
`

`

`indicia are also known as “secondary considerations of non-obviousness,” and may
`
`include long-felt but unmet need and unexpected results, among others. I also
`
`understand, however, that any offered evidence of secondary considerations of non-
`
`obviousness must be comparable with the scope of the challenged claims. This means
`
`that for any offered evidence of secondary considerations of non-obviousness to be
`
`given substantial weight, I understand the proponent of that evidence must establish a
`
`“nexus” or a sufficient connection or tie between that evidence and the merits of the
`
`claimed invention, which I understand specifically incorporates any novel element(s)
`
`of the claimed invention. If the secondary consideration evidence offered actually
`
`results from something other than the merits of the claim, then I understand that there
`
`is no nexus or tie to the claimed invention. I also understand it is the patentee that has
`
`the burden of proving that a nexus exists.
`
`21. With respect to long-felt need, I understand that the evidence must show
`
`that a particular problem existed for a long period of time. More specifically, I
`
`understand that for a “need” to be long-felt and unmet 1) the need must be persistent
`
`and recognized by those of ordinary skill in the art, 2) the need must not be satisfied
`
`by another before the alleged invention, and 3) the claimed invention itself must
`
`satisfy the alleged need. I also understand that long-felt need is analyzed as of the
`
`date that the problem is identified. Furthermore, I understand that long-felt need
`
`-9-
`
`PETITIONER'S EXHIBITS
`
`Exhibit 1003 Page 16 of 223
`
`

`

`should be based upon alleged inadequacies in the technical knowledge of those skilled
`
`in the art, not due to business-driven market forces.
`
`22. With respect to failure of others, I understand that the focus of the
`
`analysis is on the prior failure of others in the relevant industry, not the inventors. I
`
`further understand that, absent a showing of a long-felt, unmet need or the failure of
`
`others, the mere passage of time without the claimed invention is not evidence of non-
`
`obviousness.
`
`23. With respect to unexpected results, I understand that any results upon
`
`which a patentee wishes to rely as an indicator of non-obviousness must be based on a
`
`comparison of the purported inventions with the closest prior art.
`
`24.
`
`I also understand that the concept of simultaneous invention may provide
`
`evidence of obviousness, particularly where an invention was arrived at independently
`
`within a comparatively short space of time. I further understand that such evidence
`
`may indicate that the claimed invention was the product only of ordinary engineering
`
`skill.
`
`25. However, I understand that secondary considerations will not overcome a
`
`strong showing of obviousness.
`
`-10-
`
`PETITIONER'S EXHIBITS
`
`Exhibit 1003 Page 17 of 223
`
`

`

`III. Person of Ordinary Skill in the Art
`
`26. As above, I have been informed by counsel that the 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.
`
`27.
`
`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.
`
`28. A person of ordinary skill in the art related to the ’213 patent would have
`
`held a Ph.D. or equivalent in molecular biology, structural biology or a closely related
`
`field, or an M.D. with practical academic or industrial experience in antibody
`
`development, including humanization of antibodies for therapeutic development. For
`
`example, a person of ordinary skill in the art would have the educational background
`
`above with experience in humanizing antibodies. This experience is also consistent
`
`with the types of problems encountered in the art, which would have included
`
`performing three-dimensional computer modeling of immunoglobulin structures,
`
`antibody domain and sequence manipulation and swapping, CDR grafting and
`
`framework substitution in humanizing antibodies, construction and expression of
`
`-11-
`
`PETITIONER'S EXHIBITS
`
`Exhibit 1003 Page 18 of 223
`
`

`

`recombinant antibodies, antibody binding assays (for specificity and affinity),
`
`immunogenicity testing and the like. The experience may come from the person of
`
`ordinary skill in the art’s own experience, or may come through research or work
`
`collaborations with other individual(s) with experience in the medical, pharmaceutical
`
`or biotech industry, e.g., as members of a research team or group. For example, the
`
`person of ordinary skill in the art may work as part of a team or collaboration to
`
`develop a humanized monoclonal antibody for therapeutic use, including consulting
`
`with others to select non-human monoclonal antibodies (such as a mouse monoclonal
`
`antibody) for humanization, as well as subsequent testing of the humanized antibody
`
`and its intermediates. I should further note that in the prior art, computer modeling for
`
`humanization was a known methodology. The field was advancing rapidly, and
`
`individuals working in the field were highly sophisticated and using the most
`
`advanced scientific techniques.
`
`IV.
`
`Summary of Opinions
`
`29.
`
`For the reasons below, which includes my extensive experience well
`
`prior to June 1991 in the antibody structure and humanization field, it is my opinion
`
`that claims 1, 2, 25, 29, 63, 66, 71, 75, 76, 78, 80 and 81 are anticipated over EP
`
`0403156 to Kurrle et al. [Ex. 1071; “Kurrle”]. Kurrle provided a detailed roadmap in
`
`disclosing the humanization of mouse monoclonal antibody against the human
`
`-12-
`
`PETITIONER'S EXHIBITS
`
`Exhibit 1003 Page 19 of 223
`
`

`

`alpha/beta T-cell receptor, which included the substitution of claimed human
`
`framework residues 4L, 69H, 71H, 73H and 76H, for the non-human mouse
`
`monoclonal antibody framework residue.
`
`30.
`
`It is also my opinion that Queen 1990 [Ex. 1050], in also providing a
`
`detailed roadmap for humanizing any non-human monoclonal antibody, anticipated
`
`claims 1, 2, 4, 29, 62, 63, 64, 80 and 81 of the ’213 patent. Queen 1990 characterized
`
`critical framework residues, including neighboring non-human antigen-specific
`
`Complementarity Determining Region (CDR) amino acid residues. From the well-
`
`known teachings of Kabat 1987 [Ex. 1052] and Kabat 1991 [Ex. 1055], as well as
`
`Chothia & Lesk [Ex. 1062], claimed framework residues 98L and 36H are
`
`immediately adjacent to the CDRs according to the Kabat numbering system.
`
`31.
`
`From the discussion below, it is also my opinion that claims 1, 2, 4, 25,
`
`29, 62-67, 69 and 71, 72, 74, 75, 76, 78 and 80-81 are obvious over Queen 1990 [Ex.
`
`1050] in view of Kurrle [Ex. 1071]. Claims 12, 73, 77 and 79 are also obvious over
`
`Queen 1990 and Kurrle, in view of Furey [Ex. 1125] or Chothia & Lesk [Ex. 1062].
`
`As outlined below