UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
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`BOEHRINGER INGELHEIM PHARMACEUTICALS, INC.
`Petitioner
`
`v.
`
`GENENTECH, INC.
`Patent Owner
`
`
`
`U.S. Patent No.6,407,213
`
`Case IPR2017-02032
`
`
`
`EXPERT DECLARATION OF GEOFFREY HALE, PH.D.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF
`PATENT NO.6,407,213
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`1 of 217
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`TABLE OF CONTENTS
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`Page
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`I.
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`C.
`
`QUALIFICATIONS AND BACKGROUND ................................................. 1
`A.
`Education and Experience ..................................................................... 1
`B.
`Bases for Opinions and Materials Considered ...................................... 4
`C.
`Scope of Work ....................................................................................... 5
`II.
`LEGAL STANDARDS ................................................................................... 5
`III. PERSON OF ORDINARY SKILL IN THE ART .......................................... 9
`IV. SUMMARY OF OPINIONS ......................................................................... 11
`V.
`THE ’213 PATENT [EX. 1001] .................................................................... 17
`VI. BACKGROUND ........................................................................................... 33
`A. Antibody Structure and Function ........................................................ 33
`B. Monoclonal Antibodies Expanded Therapeutic and Diagnostic Uses
`of Antibodies ....................................................................................... 35
`Immunogenic Reaction in Humans With Monoclonal Antibody
`Therapy ................................................................................................ 37
`D. Molecular Characterization of Antibody Structure and Function ....... 38
`E.
`Antigen Binding Regions .................................................................... 42
`F.
`Framework Region Important for Antigen Binding ........................... 47
`G.
`Chimeric Antibodies ........................................................................... 51
`H. Antibody Humanization ...................................................................... 53
`VII. SCOPE AND CONTENT OF THE PRIOR ART REFERENCES .............. 68
`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] .......................................... 68
`Queen et al. “A Humanized Antibody that Binds to the Interleukin 2
`Receptor” PNAS 86:10029-33 (1989) (“Queen 1989”) [Ex. 1034] .... 71
`C.
`PCT Publication No.WO 90/07861 (“Queen 1990”) [Ex. 1050] ........ 75
`D. U.S. Patent No. 5,530,101 (“the ’101 patent”) [Ex. 1136] ................. 79
`E.
`Jones et al., “Replacing the Complementarity-Determining Regions in
`a Human Antibody with those from a Mouse,” Nature 321:522-25
`(1986) (“Jones”) .................................................................................. 81
`Protein Data Bank Database ................................................................ 83
`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. 215:175-82
`(1990) (“Tramontano”) [Ex. 1051] ..................................................... 86
`
`B.
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`F.
`G.
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`I.
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`J.
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`B.
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`H. Kabat et al. “Sequences of Proteins of Immunological Interest”, 4th
`Ed., pp. iii, 41-49, 167-76 (1987) (“Kabat 1987”) [Ex. 1052] ........... 87
`Chothia and Lesk. “Canonical Structures for the Hypervariable
`Regions of Immunoglobulins” J. Mol. Biol. 196:901-17 (1987)
`(“Chothia & Lesk”) [Ex. 1062] ........................................................... 88
`Riechmann et al, “Reshaping Human Antibodies For Therapy,”
`Nature, 332:323-27 (1988) (“Riechmann”) [Ex. 1069] ..................... 88
`VIII. UNPATENTABILITY OF THE ’213 PATENT .......................................... 89
`A.
`Claims 1, 2, 4, 25, 29, 62, 63, 66, 69, 71, 75, 76, 78, 80 and 81 of the
`’213 Patent are Anticipated by Kurrle [Ex. 1071] .............................. 89
`1.
`Claim 1 of the ’213 patent is anticipated by Kurrle .................. 89
`2.
`Dependent claims 2, 25 and 29 are anticipated by Kurrle ........ 91
`3.
`Independent claim 63 is anticipated by Kurrle ......................... 93
`4.
`Independent claim 66 and dependent claims 71, 72, 75 and 76,
`and 78 are anticipated by Kurrle ............................................... 94
`Claims 4, 62, and 69 are anticipated by Kurrle ........................ 95
`Independent claim 80 and dependent claim 81 are anticipated
`by Kurrle ................................................................................... 97
`Claims 1, 2, 4, 29, 62, 63, 64, 80 and 81 of the ’213 Patent are
`Anticipated by Queen 1990 ................................................................. 99
`1.
`Independent Claim 1 of the ’213 Patent is anticipated by Queen
`1990 [Ex. 1050] ......................................................................... 99
`Dependent Claim 2 of the ’213 Patent is anticipated by Queen
`1990 .........................................................................................106
`Dependent Claim 4 of the ’213 Patent is anticipated by Queen
`1990 .........................................................................................107
`Dependent Claim 29 of the ’213 Patent is anticipated by Queen
`1990 .........................................................................................107
`Independent Claim 62 of the ’213 Patent is anticipated by
`Queen 1990 .............................................................................108
`Independent Claim 63 of the ’213 Patent is anticipated by
`Queen 1990 .............................................................................109
`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
`Dependent Claim 81 of the ’213 Patent is anticipated by Queen
`1990 .........................................................................................114
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`5.
`6.
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`2.
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`3.
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`4.
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`5.
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`6.
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`7.
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`8.
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`9.
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`C.
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`D.
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`E.
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`F.
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`3.
`4.
`5.
`6.
`7.
`8.
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`2.
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`3.
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`Claims 1, 2, 4, 25, 29, 62-64, 66-67, 69, 71-73, 75-78, and 80-81 of
`the ’213 Patent are obvious over Queen 1990 in view of Kurrle, and
`Chothia & Lesk .................................................................................115
`1.
`Claim 1 is obvious over Queen 1990 and Kurrle ...................117
`2.
`Claims 2, 25 and 29 are obvious over Queen 1990 and Kurrle
` .................................................................................................121
`Claim 4 is obvious over Queen 1990 and Kurrle ...................123
`Claim 62 is obvious over Queen 1990 in view of Kurrle .......123
`Claim 63 is obvious over Queen 1990 in view of Kurrle .......124
`Claim 64 is obvious over Queen 1990 in view of Kurrle .......126
`Claim 66 is obvious over Queen 1990 in view of Kurrle .......128
`Claims 67, 71, 72, 75, 76 and 78 are obvious over Queen 1990
`in view of Kurrle .....................................................................129
`9.
`Claim 69 is obvious over Queen 1990 in view of Kurrle .......131
`10. Claims 73 and 77 are obvious in view of Queen 1990, Kurrle
`and Chothia & Lesk ................................................................131
`11. Claims 80 and 81 are obvious over Queen 1990 in view of
`Kurrle ......................................................................................134
`Claims 1, 2, 4, 25, 29, 62, 63, 64, 66, 69, 71, 73, 75-78, 80 and 81 are
`Anticipated by Jones [Ex. 1033] .......................................................136
`1.
`Independent Claim 1 of the ’213 Patent is anticipated by Jones
`[Ex. 1033] ................................................................................137
`Claims 2, 25, and 29 of the ’213 Patent is anticipated by Jones
`[Ex. 1033] ................................................................................139
`Independent Claim 66 and Dependent Claims 71, 73, and 75-78
`are Anticipated by Jones .........................................................140
`Claims 4, 62, 64, and 69 are anticipated by Jones ..................141
`Independent Claim 80 and Dependent Claim 81 Are
`Anticipated by Jones ...............................................................144
`Claim 63 is anticipated by Jones, or obvious in view of Jones [Ex.
`1033] and Riechmann [Ex. 1069] .....................................................145
`Claims 1, 2, 4, 25, 29, 62—64, 66-67, 69 and 71-73, 75-78, and 80-81
`of the ’213 Patent are obvious in view of Queen 1989 or Queen 1990
`and the PDB database ........................................................................147
`1.
`Independent Claim 1 of the ’213 Patent is obvious in view of
`Queen 1989 and the PDB database .........................................147
`Independent Claim 1 of the ’213 Patent is obvious in view of
`Queen 1990 and the PDB database .........................................160
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`4.
`5.
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`2.
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`3.
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`4.
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`5.
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`6.
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`7.
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`8.
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`9.
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`Dependent Claims 2, 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, 71-73 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 ................172
`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
`13. Dependent Claims 76-77 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 .........................................183
`Independent Claim 80 of the ’213 Patent is obvious in view of
`Queen 1989 or Queen 1990 and the PDB database ................183
`16. Dependent Claim 81 of the ’213 Patent is obvious in view of
`Queen 1989 or Queen 1990 and the PDB database ................186
`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 .............186
`1.
`Independent Claim 62 of the ’213 Patent is obvious in view of
`Queen 1989, the PDB database and in view of Kabat 1987 ...186
`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 ..............................................................................189
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`G.
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`15.
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`2.
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`3.
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`H.
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`Independent Claim 64 of the ’213 Patent is obvious in view of
`Queen 1989 and the PDB database, in view of Kabat 1987 ...190
`Claims 1, 2, 4, 25, 29, 62-64, 66, 67, 69, 71, 73, 75-78, and 80-81 are
`anticipated by the ’101 patent ...........................................................192
`1.
`Independent Claim 1 is Anticipated by the ’101 patent .........192
`2.
`The ’101 patent Anticipates Dependent Claims 2, 4, 25 and 29
` .................................................................................................193
`Independent claim 63 is anticipated by the ’101 patent .........195
`Independent Claim 66 and Dependent Claims 67, 69, 71, 73,
`and 75-78 are Anticipated by the ’101 patent .........................195
`Claims 4, 62, 64, and 69 are anticipated by the ’101 patent ...197
`Independent Claim 80 and Dependent Claim 81 Are
`Anticipated by the ’101 patent ................................................200
`IX. SECONDARY CONSIDERATIONS .........................................................201
`X.
`CONCLUSION ............................................................................................206
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`3.
`4.
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`5.
`6.
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`1.
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`My name is Geoffrey Hale, Ph.D. Counsel for Boehringer Ingelheim
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`International GmbH (“Boehringer”) retained me to provide my opinions regarding
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`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 Boehringer intends to file a petition for inter
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`partes review of the ’213 patent, and will request that the United States Patent and
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`Trademark Office cancel certain claims of the ’213 patent as unpatentable in the
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`petition. My opinions in this expert declaration support Boehringer’s request for
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`inter partes review of the ’213 patent, and cancellation of the claims.
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`I.
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`QUALIFICATIONS AND BACKGROUND
`
`A.
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`2.
`
`Education and Experience
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`I received my Ph.D. in Biochemistry at the University of Cambridge
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`in the UK in 1977. Between 1977 and 1980 I worked as a postdoctoral fellow in
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`the Department of Biochemistry, University of Cambridge, studying the structure
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`and function of proteins. In 1980 I joined the laboratory of Professor Herman
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`Waldmann in the Department of Pathology at the University of Cambridge, where
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`I worked as a postdoctoral fellow from 1980 to 1986 and a Senior Postdoctoral
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`Fellow from 1986 to 1995. From 1990 to 1995 I was also the Manager of the
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`Therapeutic Antibody Centre which was based in the Department of Haematology
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`at the University of Cambridge. During this time monoclonal antibodies were
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`being actively researched as therapeutic agents and I was part of the team which
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`was responsible for the discovery and clinical development of a wide range of
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`therapeutic monoclonal antibodies.
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`3.
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`In 1981 I discovered the “Campath” family of rat monoclonal
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`antibodies. I researched their structure and function in vitro and in vivo and I
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`worked with physicians in Addenbrookes Hospital, Cambridge and elsewhere to
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`conduct clinical trials. Between 1984 and 1989 I directed studies on the functional
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`properties of human immunoglobulins, using, among other things, recombinant
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`chimeric monoclonal antibodies. In 1986 I was involved in discussions with
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`Professor Waldmann and Sir Gregory Winter which led to the decision to select
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`Campath-1G, the antibody I had developed earlier, as the first therapeutic antibody
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`to be humanised. Subsequently I was part of the team responsible for the testing of
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`the humanised antibody Campath-1H and its manufacture for the first clinical
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`study which was reported in 1988. See Ex. 1132.
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`4.
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`In 1990 I established the Therapeutic Antibody Centre in order to
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`provide a dedicated facility for the manufacture of a rapidly increasing number of
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`humanised antibodies and to work with physicians to test them in the clinic.
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`Among others, these included humanised antibodies directed against the antigens
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`CD2, CD3, CD4, CD8, CD18 and CD52.
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`5.
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`My contributions were originally based on my training as a protein
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`chemist at the Department of Biochemistry, and during this period (1980 to 1995) I
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`learned from being part of a multi-disciplinary team which included
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`immunologists, molecular biologists, cell biologists and haematologists. I have
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`continued to work on the research and development of therapeutic monoclonal
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`antibodies to the present day, both in academia and industry, and I have published
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`more than 200 articles in this field. I have lectured on the subject of therapeutic
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`monoclonal antibodies at the University of Cambridge, the University of Oxford
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`and many other institutions worldwide from 1984 to the present day.
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`6.
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`Between 1984 and 1996 I supervised three Ph.D. students. In 1995, I
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`moved with Professor Waldmann to the University of Oxford, where I was
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`appointed Research Lecturer at the Department of Pathology. I built a new
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`Therapeutic Antibody Centre, and was its Research Director from 1995 to 2007. In
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`2000 I was appointed Professor of Therapeutic Immunology. In 2004 the Centre
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`was licensed by the UK Medicines and Healthcare Regulatory Agency as a facility
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`for the manufacture of therapeutic proteins according to Good Manufacturing
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`Practice and, based on my experience over the previous nine years, I was
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`recognised as a Qualified Person, authorized to release batches of experimental
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`drugs to the clinic.
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`7.
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`In 2002 I founded a contract research company, BioAnaLab, which
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`was devoted to the analysis of biologic drugs such as therapeutic monoclonal
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`antibodies. I was the Chief Executive Officer from 2004 to 2009 when the
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`company was sold to Millipore Inc. Since then I have served on the board of
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`directors of several biotechnology companies, including one, Absolute Antibody
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`Ltd, which uses technology that traces a direct line from our pioneering research in
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`the 1980s to develop and supply recombinant monoclonal antibodies to academic
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`and pharmaceutical clients around the world. I am currently a self-employed
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`consultant.
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`8.
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`A full description of my background and qualifications can be found
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`in my curriculum vitae at Ex. 1003A.
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`B.
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`9.
`
`Bases for Opinions and Materials Considered
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`Exhibit 1003B includes a list of the materials I considered, in addition
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`to my experience, education, and training, in providing the opinions contained
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`herein.
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`10.
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`In addition to the materials set forth in Exhibit 1003B, I have also
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`reviewed the Expert Declaration of Dr. Lutz Riechmann, which I understand was
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`filed as Exhibit 1003 in Case Nos. IPR2017-01373 and IPR2017-01374. I have
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`also reviewed the Expert Declaration of Dr. Eduardo A. Padlan, which I
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`understand was filed as Exhibit 1003 in Case Nos. IPR2016-01693 and IPR2016-
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`01694. I note that Dr. Riechmann and Dr. Padlan share many of the same
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`opinions, and because I agreed with many of the statements and opinions set forth
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`in their declarations, I have repeated those herein and revised only as necessary.
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`Dr. Riechmann’s declaration also included a number of exhibits (Riechmann
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`Exhibits A-P), which he used to support his opinions. I have reviewed these
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`exhibits and found them to be accurate and useful in support of my own opinions.
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`Because I agree with his use of the exhibits, I have also used these same exhibits,
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`where necessary, to support my opinions.
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`C.
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`11.
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`Scope of Work
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`I have been retained by Boehringer as a technical expert in this matter
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`to provide various opinions regarding the ’213 patent. I receive £300 per hour. No
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`part of my compensation is dependent upon my opinions given or the outcome of
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`this case.
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`II.
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`LEGAL STANDARDS
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`12.
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`For my opinions in this declaration, I understand that it requires
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`applying various legal principles. As I am not an attorney, I have been informed
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`about various legal principles that involve my analysis. I have used my
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`understanding of those principles in forming my opinions. I summarize those
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`principles as I understand them below.
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`13.
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`For example, I have been told that Boehringer bears the burden of
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`proving unpatentability in this proceeding by a preponderance of the evidence. I
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`am informed that this preponderance of the evidence standard means that
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`Boehringer must show that unpatentability is more probable than not.
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`14.
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`I have also been told that when I review and consider the claims, the
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`claims should be construed to be given what is called their broadest reasonable
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`interpretation in light of the specification, when those claims are viewed from the
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`perspective of a person of ordinary skill in the art. (I discuss who qualifies as the
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`person of ordinary skill in the art in more detail below.)
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`15.
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`I have been asked to consider the question of anticipation, namely,
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`whether the claims cover something that is new, or novel. I am told that the
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`concept of anticipation requires that each and every element of a challenged claim
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`is present in or otherwise taught by a single prior art reference. I also understand
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`that an anticipatory reference does not need to explicitly describe each element
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`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
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`reference to anticipate a claim, it must describe the subject matter with sufficient
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`detail such that a person of ordinary skill in the art would be able to carry out or
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`put into practice the disclosed ideas.
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`16.
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`I have been asked to consider the question of obviousness/non-
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`obviousness. Again, I am told that this analysis must be from the perspective of
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`the person of ordinary skill in the art, and whether the skilled artisan would
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`consider any differences between the prior art and what is claimed to have been
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`obvious. I have been informed that the concept of patent obviousness assesses four
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`factual inquiries: (1) the scope and content of the prior art; (2) the differences
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`between the claimed invention and the prior art; (3) the level of ordinary skill in
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`the art; and (4) secondary considerations of non-obviousness. I further note that I
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`have been instructed that one cannot use an existing patent as a guide to select
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`from prior art elements, or otherwise engage in hindsight. Rather, the correct
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`approach is to consider what the person of ordinary skill in the art knew, and what
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`the art taught; suggested; or motivated the person of ordinary skill in the art to
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`further pursue.
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`17.
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`I am also informed that when there is some recognized reason to solve
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`a problem, and there are a finite number of identified, predictable and known
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`solutions, a person of ordinary skill in the art has good reason to pursue the known
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`options within his or her technical grasp. If such an approach leads to the expected
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`success, it is likely not the product of innovation but of ordinary skill and common
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`sense. In addition, when a patent claim simply arranges old elements with each
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`performing its known function and yields no more than what one would expect
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`from such an arrangement, the combination is obvious.
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`18.
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`I understand that before reaching any final conclusion on obviousness,
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`the obviousness analysis requires consideration of objective indicia of non-
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`obviousness, if such information is offered. These must be considered to ensure
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`that, for example, there were not some unanticipated problems, obstacles or
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`hurdles that may seem easy to overcome in hindsight, but which were not readily
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`overcome prior to the relevant invention date of the patents/claims at issue here. I
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`understand that these objective indicia are also known as “secondary
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`considerations of non-obviousness,” and may include long-felt but unmet need and
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`unexpected results, among others. I also understand, however, that any offered
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`evidence of secondary considerations of non-obviousness must be comparable with
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`the scope of the challenged claims. This means that for any offered evidence of
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`secondary considerations of non-obviousness to be given substantial weight, I
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`understand the proponent of that evidence must establish a “nexus” or a sufficient
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`connection or tie between that evidence and the merits of the claimed invention,
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`which I understand specifically incorporates any novel element(s) of the claimed
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`invention. If the secondary consideration evidence offered actually results from
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`something other than the novel element(s) of the claim, then I understand that there
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`is no nexus or tie to the claimed invention. I also understand it is the patentee that
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`has the burden of proving that a nexus exists.
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`19. With respect to long-felt need, I understand that the evidence must
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`show that a particular problem existed for a long period of time. More specifically,
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`I understand that for a “need” to be long-felt and unmet 1) the need must be
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`persistent and recognized by those of ordinary skill in the art, 2) the need must not
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`be satisfied by another before the alleged invention, and 3) the claimed invention
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`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
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`that long-felt need should be based upon alleged inadequacies in the technical
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`knowledge of those skilled in the art, not due to business-driven market forces.
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`20. With respect to failure of others, I understand that the focus of the
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`analysis is on the prior failure of others in the relevant industry, not the inventors.
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`I further understand that, absent a showing of a long-felt, unmet need or the failure
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`of others, the mere passage of time without the claimed invention is not evidence
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`of non-obviousness.
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`21. With respect to unexpected results, I understand that any results upon
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`which a patentee wishes to rely as an indicator of non-obviousness must be based
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`on a comparison of the purported inventions with the closest prior art.
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`22.
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`I also understand that the concept of simultaneous invention may
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`provide evidence of obviousness, particularly where an invention was arrived at
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`independently within a comparatively short space of time. I further understand that
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`such evidence may indicate that the claimed invention was the product only of
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`ordinary engineering skill.
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`23. However, I understand that secondary considerations will not
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`overcome a strong showing of obviousness.
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`III. PERSON OF ORDINARY SKILL IN THE ART
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`24. As noted above, I have been informed by counsel that my analysis is
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`to be conducted from the perspective of a person of ordinary skill in the art (a
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`“person of ordinary skill”) at the time of the invention.
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`25.
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`I have also been informed by counsel that in defining a person of
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`ordinary skill in the art the following factors may be considered: (1) the
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`educational level of the inventor; (2) the type of problems encountered in the art;
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`(3) prior art solutions to those problems; (4) rapidity with which innovations are
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`made; and (5) sophistication of the technology and educational level of active
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`workers in the field.
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`26. A person of ordinary skill in the art related to the ’213 patent at the
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`relevant time would have held a Ph.D. or equivalent in molecular biology,
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`structural biology or a closely related field, or an M.D. with practical academic or
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`industrial experience in the production of recombinant proteins. For example, a
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`person of ordinary skill in the art would have the educational background above
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`with experience in protein engineering. This experience is also consistent with the
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`types of problems encountered in the art, which could have included performing
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`three-dimensional computer modeling of immunoglobulin structures, antibody
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`domain and sequence manipulation and swapping, CDR grafting and framework
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`substitution in humanizing antibodies, construction and expression of recombinant
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`antibodies, antibody binding assays (for specificity and affinity), immunogenicity
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`10
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`testing and the like. The experience may come from the person of ordinary skill in
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`the art’s own experience, or may come through research or work collaborations
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`with other individual(s) with experience in the medical, pharmaceutical or biotech
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`industry, e.g., as members of a research team or group. For example, the person of
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`ordinary skill in the art could have worked as part of a team or collaboration to
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`develop a humanized monoclonal antibody for therapeutic use, including
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`consulting with others to select non-human monoclonal antibodies (such as a
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`mouse monoclonal antibody) for humanization, as well as subsequent testing of the
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`humanized antibody and its intermediates. I should further note that in the prior
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`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
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`sophisticated and using the most advanced scientific techniques.
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`IV.
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`SUMMARY OF OPINIONS
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`27.
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`For the reasons set forth below, it is my opinion that claims 1, 2, 4, 25,
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`29, 62, 63, 66, 69, 71, 75, 76, 78, 80 and 81 of the ’213 patent are anticipated over
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`EP 0403156 to Kurrle et al. [Ex. 1071; “Kurrle”]. Kurrle provided a detailed
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`roadmap in disclosing the humanization of a mouse monoclonal antibody against
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`the human alpha/beta T-cell receptor, which included the substitution of claimed
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`human framework residues 4L, 69H, 71H, 73H and 76H, for the non-human
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`mouse monoclonal antibody framework residue.
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`28.
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`It is also my opinion that Queen 1990 [Ex. 1050], in also providing a
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`detailed roadmap for humanizing any non-human monoclonal antibody, anticipated
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`claims 1, 2, 4, 29, 62, 63, 64, 80 and 81 of the ’213 patent. Queen 1990
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`characterized critical framework residues, including neighboring non-human
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`antigen-specific Complementarity Determining Region (CDR) amino acid
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`residues. From the well-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
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`residues 98L and 36H are immediately adjacent to the CDRs according to the
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`Kabat numbering system.
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`29.
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`From the discussion below, it is also my opinion that claims 1, 2, 4,
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`25, 29, 62-64, 66-67, 69 and 71, 72, 75, 76, 78 and 80-81 are obvious over Queen
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`1990 [Ex. 1050] in view of Kurrle [Ex. 1071]. Claims 73 and 77 are also obvious
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`over Queen 1990 and Kurrle, in view of Chothia & Lesk [Ex. 1062]. As outlined
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`below, Queen 1990 provided a detailed roadmap for one of ordinary skill in the art
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`to humanize a non-human monoclonal antibody, disclosed that human framework
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`residues immediately adjacent to CDRs, which included claimed residues 98L and
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`36H, should be substituted for the corresponding non-human framework residue in
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`order to maintain CDR conformation and antigen binding. In also acknowledging
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`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
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`the substitution of the human framework residues, including at claimed residues
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`including 4L, 69H, 71H, 73H, 76H and 93H according to the Kabat numbering
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`system. Chothia & Lesk [Ex. 1062] moreover provided guidance on the
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`importance of claimed residue 78H in maintaining antibody conformation, and
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`thus provided explicit motivation to a skilled artisan for making substitutions at
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`these residues. Accordingly, claims 1, 2, 4, 25, 29, 62-64, 66-67, 69 and 71, 72,
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`75, 76, 78 and 80-81 are also obvious in my opinion over Queen 1990 in view of
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`Kurrle, and Chothia & Lesk.
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`30.
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`Furthermore, given the availability of antibody crystal structures, and
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`the detailed analysis and characterization of framework residues that contact CDRs
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`and/or are important in mai