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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`________________
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`SAMSUNG BIOEPIS CO., LTD., Petitioner,
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`v.
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`GENENTECH, INC., Patent Owner.
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`________________
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`United States Patent No. 6,407,213
`Title: Method for Making Humanized Antibodies
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`
`Case No.: IPR2017-02139
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`________________
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`
`DECLARATION OF DILJEET SINGH ATHWAL, Ph.D
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`BIOEPIS EX. 1190
`Page 1
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`I.
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`TABLE OF CONTENTS
`
`INTRODUCTION ....................................................................................... 1
`A.
`Background, Education, Experience, and Qualifications ................. 1
`B.
`Compensation .................................................................................... 4
`C. Materials Relied Upon and Bases for Opinions ................................ 5
`SUMMARY OF OPINIONS ....................................................................... 5
`II.
`III. RELEVANT LAW ...................................................................................... 7
`A.
`Claim Construction............................................................................ 8
`B. Anticipation ....................................................................................... 8
`C. Obviousness ....................................................................................... 9
`D.
`Person of Ordinary Skill in the Art .................................................12
`IV. SUMMARY OF OPINION .......................................................................13
`V.
`TECHNICAL BACKGROUND ...............................................................20
`A. Antibody Therapy............................................................................20
`B.
`Terminology: Polypeptides and Sequences ....................................22
`C. Mid-Century Advances ...................................................................22
`D.
`Structural Studies and Complementarity ........................................25
`E.
`X-ray Crystallography .....................................................................28
`F.
`Kabat Database and Numbering ......................................................29
`G. Other Systematic Efforts to Organize Antibody Sequence Data
`According to Structure and Function ..............................................31
`Immunogenicity ...............................................................................34
`Humanizing .....................................................................................35
`Antigen Binding Regions ................................................................39
`Framework Region Important for Antigen Binding .......................39
`Antibody Humanization ..................................................................41
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`H.
`I.
`J.
`K.
`L.
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`C.
`D.
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`E.
`F.
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`VI. THE PRIOR ART ......................................................................................48
`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) .....................48
`B. Queen et al., A Humanized antibody that binds to the interleukin 2
`receptor, 86 PROC. NAT’L ACAD. SCI. USA 10029–33 (1989)
`(“Queen 1989”) (Ex. 1034) .............................................................50
`PCT Publication No. WO 90/07861 (“Queen 1990”) (Ex. 1050) ...53
`Furey et al., Structure of A Novel Bence-Jones Protein (Rhe)
`Fragment at 1.6Å Resolution, 167 J. MOLECULAR BIOLOGY 661–
`92 (1983) (Ex. 1125) .......................................................................57
`PDB Database ..................................................................................58
`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, 215 J.
`MOLECULAR BIOLOGY 175–82 (1990) (“Tramontano”) (Ex. 1051)60
`G. Kabat et al., Tabulation and Analysis of Amino Acid and Nucleic
`Acid Sequences of Precursors, V-Regions, C-Regions, J-Chain, T-
`Cell Receptor for Antigen, T-Cell Surface Antigens, β2-
`Microglubins, Major Histocompatibility Antigens, Thy-1
`Complement, C-Reactive Protein, Thymopoietin, Post-gamma
`Globulin, and α2-Macroglobulin, in SEQUENCES OF PROTEINS OF
`IMMUNOLOGICAL INTEREST iii, 41–49, 167–176 (4th ed. 1987)
`(“Kabat 1987”) (Ex. 1052) ..............................................................61
`H. Hudziak et al., p185HER2 Monoclonal Antibody Has
`Antiproliferative Effects In Vitro and Sensitizes Human Breast
`Tumor Cells to Tumor Necrosis Factor, 9(3) MOLECULAR
`CELLULAR BIOLOGY 1165–72 (1989) (“Hudziak”) (Ex. 1021) .......62
`Chothia et al., Domain Association in Immunoglobulin Molecules:
`The Packing of Variable Domains, 186 J. MOLECULAR BIOLOGY
`651–63 (1985) (“Chothia 1985”) (Ex. 1063) ..................................63
`Chothia & Lesk, Canonical Structures for the Hypervariable
`Regions of Immunoglobulins, 196 J. MOLECULAR BIOLOGY 901–17
`(1987) (“Chothia & Lesk”) (Ex. 1062) ...........................................64
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`I.
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`C.
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`Chothia et al., Conformations of immunoglobulin hypervariable
`regions, 342(21) NATURE 877–83 (1989) (“Chothia 1989”) (Ex.
`1049) ................................................................................................64
`VII. THE ’213 PATENT ...................................................................................65
`VIII. UNPATENTABILITY OF THE ’213 PATENT ......................................81
`A.
`Claims 1–2, 25, 29, 63, 66–67, 71–72, 75–76, 80–81 of the ’213
`Patent are Anticipated by Kurrle (Ex. 1071) ...................................81
`1.
`Claim 1 is anticipated by Kurrle ...........................................81
`Dependent claims 2, 25 and 29 are anticipated by Kurrle ....83
`2.
`3.
`Independent claim 63 is anticipated by Kurrle .....................85
`4.
`Claims 66, 67, 71, 72, 75 and 76 are anticipated by Kurrle .87
`5.
`Independent claim 80 and dependent claim 81 are
`anticipated by Kurrle .............................................................88
`Claims 1, 2, 4, 29, 62–64, 80 and 81 of the ’213 Patent are
`Anticipated by Queen 1990 .............................................................90
`1.
`Claim 1 is anticipated by Queen 1990 (Ex. 1050) ................90
`2.
`Dependent Claim 2 is anticipated by Queen 1990 ................96
`3.
`Dependent Claim 4 is anticipated by Queen 1990 ................97
`4.
`Dependent Claim 29 is anticipated by Queen 1990 ..............97
`5.
`Independent Claim 62 is anticipated by Queen 1990 ...........98
`6.
`Independent Claim 63 is anticipated by Queen 1990 ...........99
`7.
`Independent Claim 64 is anticipated by Queen 1990 .........101
`8.
`Independent Claim 80 is anticipated by Queen 1990 .........103
`9.
`Dependent Claim 81 is anticipated by Queen 1990 ............104
`Claims 1–2, 4, 25, 29, 62–64, 66–67, 69, 71–72, 75–76, 78 and
`80– 81 are obvious over Queen 1990 in view of Kurrle ...............105
`1.
`Claim 1 is obvious over Queen 1990 and Kurrle ...............107
`2.
`Claims 2, 25 and 29 are obvious over Queen 1990 and
`Kurrle ..................................................................................111
`Claim 4 is obvious over Queen 1990 and Kurrle ...............113
`Claim 62 is obvious over Queen 1990 in view of Kurrle ...113
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`3.
`4.
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`D.
`E.
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`F.
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`G.
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`Claim 63 is obvious over Queen 1990 in view of Kurrle ...115
`5.
`Claim 64 is obvious over Queen 1990 in view of Kurrle ...116
`6.
`Claim 66 ..............................................................................118
`7.
`Claims 67, 71, 72, 75, 76 and 78 ........................................119
`8.
`Claim 69 ..............................................................................121
`9.
`10. Claims 80 and 81.................................................................122
`Claim 12 is obvious over Queen 1990 and Kurrle, and Furey ......124
`Claims 73 and 77 are obvious in view of Queen 1990, Kurrle and
`Chothia & Lesk .............................................................................126
`Claim 74 is obvious over Queen 1990 in view of Kurrle and
`Chothia 1985 .................................................................................128
`Claims 79 and 65 are obvious in view of Queen 1990, Kurrle,
`Chothia & Lesk and Chothia 1985 ................................................129
`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 .........................................................................................133
`1.
`Independent Claim 1 is obvious in view of Queen 1989 and
`the PDB database ................................................................133
`Independent Claim 1 is obvious in view of Queen 1990 and
`the PDB database ................................................................144
`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 ...............................................................................147
`Dependent claim 4 is obvious in view of Queen 1990 and
`the PDB database ................................................................148
`Independent Claim 62 is obvious in view of Queen 1990 and
`the PDB database ................................................................148
`Independent Claim 63 is obvious in view of Queen 1989 or
`Queen 1990 and the PDB database .....................................149
`Independent Claim 64 is obvious in view of Queen 1990
`and the PDB database .........................................................150
`Independent Claim 66 is obvious in view of Queen 1989 or
`Queen 1990 and the PDB database .....................................152
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`7.
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`8.
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`iv
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`2.
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`3.
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`4.
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`5.
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`I.
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`9.
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`17.
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`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 ...............................................................................154
`10. Dependent Claim 72 is obvious in view of Queen 1989 or
`Queen 1990, and the PDB database ....................................155
`11. Dependent Claim 75 is obvious in view of Queen 1989 or
`Queen 1990 and the PDB database .....................................157
`12. Dependent Claim 75 is obvious in view of Queen 1989 or
`Queen 1990 and the PDB database, and further in view of
`Tramontano .........................................................................158
`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 ...............................................................................159
`14. Dependent Claims 76–77 and 79 of the ’213 Patent are
`obvious in view of Queen 1989 or Queen 1990 and the PDB
`database, in view of Tramontano ........................................167
`15. Dependent Claim 69 is obvious in view of Queen 1990 and
`the PDB database ................................................................168
`16. Dependent Claim 65 is obvious in view of Queen 1989 or
`Queen 1990 and the PDB database .....................................168
`Independent Claim 80 is obvious in view of Queen 1989 or
`Queen 1990 and the PDB database .....................................169
`18. Dependent Claim 81 is obvious in view of Queen 1989 or
`Queen 1990 and the PDB database .....................................172
`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 .........172
`1.
`Independent Claim 62 is obvious in view of Queen 1989,
`the PDB database and in view of Kabat 1987 ....................172
`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 ......................................................................176
`Independent Claim 64 is obvious in view of Queen 1989 and
`the PDB database, in view of Kabat 1987 ..........................176
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`2.
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`3.
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`J.
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`2.
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`3.
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`K.
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`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 ....................................................................................178
`1.
`Claim 30 is obvious in view of Queen 1989 or Queen 1990
`and the PDB Database, and in view of Hudziak .................178
`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 .......................................185
`Claim 33 is obvious in view of Queen 1990 and the PDB
`database, and in view of Hudziak .......................................186
`Claims 30, 31, 33 and 42 are Obvious Over Queen 1990 In View
`Of Hudziak ....................................................................................187
`Claim 42 is Obvious Over Queen 1990, Hudziak, and Furey ......188
`L.
`M. Claim 60 is Obvious Over Queen 1990, Hudziak, and Chothia &
`Lesk ...............................................................................................190
`IX. SECONDARY CONSIDERATIONS .....................................................190
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`I, Diljeet Singh Athwal, Ph.D. declare as follows:
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`I.
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`INTRODUCTION
`
`1.
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`I have been retained by White & Case LLP (“Counsel”), counsel for
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`Samsung Bioepis Co., Ltd. (“Bioepis”), as an expert in the above captioned inter
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`partes review (“IPR”) concerning United States Patent No. 6,407,213 (the “’213
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`Patent”). This declaration sets forth my opinions concerning the invalidity of the
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`’213 Patent; as well as technical background information; the bases for my
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`opinions; my qualifications; and my compensation for services provided in this
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`matter. My opinions and the facts set forth in this declaration are based upon
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`information I reviewed in connection with this matter and over 30 years of
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`education, knowledge, and experience.
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`A.
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`Background, Education, Experience, and Qualifications
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`2.
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`I am currently a Director with Amethyst Pharma Consulting (London)
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`in the United Kingdom. At Amethyst, I provide a number of consulting services
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`related to my expertise in developing antibody based therapeutics and antibody
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`engineering technologies. I have over 30 years of experience studying the
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`relationship between antibody structure and function and applying this experience
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`to developing antibody therapeutics. A copy of my curriculum vitae is attached to
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`this report as Exhibit A.
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`3.
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`I received my B. Sc. in Physics and Cell Biology from King’s
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`College, London (UK) following which I was awarded a BBSRC Ph.D.
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`studentship under the supervision of Professor Tom Blundell from Birkbeck
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`College, London (UK) and Dr. Timothy Harris from Celltech R&D (UK). As part
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`of my Ph.D. research in the mid-1980’s, I developed a novel computer modeling
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`algorithm for macromolecules, which was subsequently implemented in the
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`commercial graphics program “Homology – Tripos.” Using computer generated
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`models of protein structures of interest, combined with novel mutagenesis
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`methodologies my Ph.D. focused on exploring the structure function relationship
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`of the tissue plasminogen activator (t-PA) molecule. The objective was to develop
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`novel engineered forms of t-PA.
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`4.
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`After obtaining my Ph.D., I began working as a senior principal
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`scientist at Celltech R&D in the United Kingdom. At Celltech, I was responsible
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`for the design of every humanized antibody Celltech put into clinical development
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`through the 1990’s. In fact, the early portion of this work led to my being named
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`as an inventor on a series of patents directed toward humanization technology,
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`entitled “Humanised Antibodies” and “CD3 Specific Recombinant Antibody.”
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`Some of those patents include the following: U.S. Patent Nos. (1) 5,859,205, (2)
`
`5,929,212, (3) 6,632,927, (4) 6,750,325, (5) 7,241,877, (6) 7,244,615, (7)
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`7,244,832, (8) 7,262,050, and (9) 7,566,771. I am also a named inventor on
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`2
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`several other families of antibody related patents and patent applications,
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`including, for example, U.S. Patent No. 7,012,135, entitled “Biological Products;”
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`U.S. Patent No. 7,186,820, entitled “Production of humanized antibodies to
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`TNFα;” U.S. Patent No. 7,402,662, entitled “Antibody molecules specific to
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`human tumor necrosis factor alpha;” and, more recently, U.S. Patent App. No.
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`15/257,086, entitled “Humanized Anti-Tau Antibodies;” among several others.
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`5.
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`After leaving Celltech, I have served as a Chief Scientific Officer,
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`along with other titles, for MOKSHA8 and Fourteen22 Inc. from March 2007 until
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`December 2012.
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`6.
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`Between 2012 and 2015, I worked on several antibody development
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`programs, including the design of novel humanized antibodies aimed at treating
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`specific forms of Alzheimer’s disease.
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`7.
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`From January 2016 through March 2017, I served as the Chief
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`Business and Strategy officer for Capella Bioscience in Cambridge and London.
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`In this role, I helped develop novel antibody based therapeutics and also played a
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`business role.
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`8.
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`Throughout my career, I have published a number of antibody and
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`humanization related publications in peer-reviewed scientific journals, including,
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`for example, John Adair, et al., Humanization of the murine anti-human CD3
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`monoclonal antibody OKT3, 5(1) Hum. Antibod. Hybridomas 41-47 (1994); J.S.
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`3
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`Johnston & D.S. Athwal, Recombinant anti-polyamine antibodies: identification of
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`a conserved binding site motif, 12(6) Protein Engineering, Design, & Selection
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`515-521 (June 1999); S. Kumar, et al., Molecular Cloning and Expression of the
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`Fabs of Human Autoantibodies in Escherichia Coli: Determination of the Heavy or
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`Light Chain Contribution to the Anti-DNA/-Cardiolipin Activity of the Fab,
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`275(45) J. Biol. Chem. 35129-35136 (2000); Bryan Smith, et al., Prolonged in
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`Vivo Residence Times of Antibody Fragments Associated with Albumin, 12(5)
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`Bioconjugate Chem. 750-756 (2001); Yanling Lu, et al., Effect of PEGylation on
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`the solution conformation of antibody fragments, 97(6) J. Pharm. Sci. 2062-2079
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`(June 2008).
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`B. Compensation
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`9.
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`I am working as an independent consultant in this matter. I have no
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`financial interest in the outcome of this IPR. I have no financial interest in the
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`Petitioner or the ’213 Patent. I have had no contact with the named inventors of
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`the ’213 Patent concerning this matter.
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`10.
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`I am being compensated at my usual consultancy rate of £320 per
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`hour, exclusive of VAT. In addition, I receive reimbursement for expenses. This
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`compensation is entirely unrelated to the outcome of this matter.
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`C. Materials Relied Upon and Bases for Opinions
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`11. A list of the materials that I have relied upon and otherwise
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`considered in formulating my opinions is set forth in this declaration as Exhibit B.
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`I have also relied on my general knowledge and experience.
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`12.
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`I understand that a third-party – Pfizer Inc. (“Pfizer”) – previously
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`filed IPR petitions challenging claims of the ’213 patent. I have reviewed and
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`considered Pfizer’s IPR petitions and the declarations filed in support of Pfizer’s
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`IPR petitions. Applying my independent judgment and expertise, after having
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`independently reviewed and analyzed all of the materials in Pfizer expert Jefferson
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`Foote, Ph.D. materials considered lists, and having done the additional work of fact
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`checking, including the analysis of relevant antibody structures, and considering
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`whether potential counterarguments may exist, I have come to the same
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`conclusions as Dr. Foote and I agree with the analysis in his declaration as set forth
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`below. Readers of this declaration may note that the language and organization is
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`similar to that of Dr. Foote declaration because it did not seem necessary to rewrite
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`the material which I independently confirmed as acceptable and correct. The
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`opinions in this declaration should be considered mine.
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`II.
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`SUMMARY OF OPINIONS
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`13.
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`I have been asked to assess the validity of the ’213 Patent from a
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`scientific perspective. Specifically, I have been asked to consider whether the ’213
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`Patent is invalid because it is anticipated by and/or obvious over the prior art (i.e.,
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`literature published before June 14, 1991).
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`14. A brief summary of my opinions are as follows:
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` Claims 1, 2, 5, 29, 63, 66, 67 71, 72, 75, 76, 80, and 81 of the ’213 patent are
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`anticipated by Kurrle;
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` Claims 1, 2, 4, 29, 62-64, 80, and 81 of the ’213 patent are anticipated by
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`Queen 1990;
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` Claims 1, 2, 4, 25, 29, 62-64, 66, 67, 69, 71, 72, 75, 76, 78, 80, and 81 of the
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`’213 patent are obvious over Queen 1990 in view of Kurrle;
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` Claim 12 of the ’213 patent is obvious over Queen 1990, Kurrle, and Furey;
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` Claims 73 and 77 of the ’213 patent are obvious over Queen 1990, Kurrle,
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`and Chothia & Lesk;
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` Claim 74 of the ’213 patent is obvious over Queen 1990 in view of Kurrle
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`and Chothia 1985;
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` Claims 79 and 65 of the ’213 patent are obvious over Queen 1990, Kurrle,
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`Chothia & Lesk, and Chothia 1985;
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` Claims 1, 2, 4, 12, 25, 29, 62-67, and 71-81 of the ’213 patent are obvious
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`over Queen 1989 or Queen 1990 and the PDB Database
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` Claims 4, 62, 64, and 69 of the ’213 patent are obvious over Queen 1989, the
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`PDB Database, and Kabat 1987;
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` Claims 30, 31, 33, 42, and 60 of the ’213 patent are obvious over Queen
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`1989 or Queen 1990 and the PDB Database in view of Hudziak;
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` Claims 30, 31, 33, and 42 of the ’213 patent are obvious over Queen 1990 in
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`view of Hudziak;
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` Claim 42 of the ’213 patent is obvious over Queen 1990, Hudziak, and
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`Furey; and
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` Claim 60 is obvious over Queen 1990, Hudziak, and Chothia & Lesk.
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`III. RELEVANT LAW
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`15. For the purposes of this declaration, I have been informed about
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`certain aspects of the law that are relevant to my opinion. My understanding of the
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`law is as follows:
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`16.
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`I understand that Bioepis bears the burden of proving unpatentability
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`in this proceeding by a preponderance of the evidence, i.e., that unpatentability is
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`more likely than not.
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`17.
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`I understand that a United States patent consists of drawings, a
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`specification, and claims. I understand that the claims, which appear at the end of
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`the patent, appear as numbered paragraphs and define the patentee’s alleged
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`property right covered by the patent. I further understand that claims may be
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`independent (i.e., they contain only the limitations described in that claim itself) or
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`dependent (i.e., they incorporate the limitations of another enumerated claim as
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`well as those limitations described in the claim itself).
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`A. Claim Construction
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`18.
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`I understand that the claims – for purposes of this proceeding before
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`the U.S. Patent and Trademark Office – must be given their broadest reasonable
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`interpretation, as viewed from the perspective of a person of ordinary skill in the
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`art at the time of the alleged invention. I further understand from counsel that the
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`’213 patent claims an earliest priority date of June 14, 1991.
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`B. Anticipation
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`19.
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`I understand that a patent claim is invalid or unpatentable if the
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`invention was, among other things, patented or described in a printed publication,
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`e.g., patent application, journal article, etc., before the alleged invention claimed in
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`the patent at issue. I also understand that anticipation requires the disclosure of
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`each claim limitation, either expressly or inherently, in a single prior art reference.
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`I further understand that inherent anticipation requires that the prior art reference
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`necessarily and inevitably produce the claimed limitation. And, when considering
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`inherent anticipation, it is not required that a person of ordinary skill in the art
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`would have recognized the inherent disclosure at the time it published originally.
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`C. Obviousness
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`20.
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`I understand a claim is invalid if it is obvious. I am told that the
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`obviousness analysis must be from the perspective of the person of ordinary skill in
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`the art. I have been informed this analysis involves four factual inquiries: (1)
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`understanding the scope and content of the prior art; (2) determining the
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`differences between the claimed invention and the prior art; (3) resolving the level
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`of ordinary skill in the art; and (4) consideration of secondary considerations of
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`non-obviousness, which may or may not have some relevancy to whether the claim
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`is obvious or not.
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`21.
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`I further note that I have been instructed that one cannot use an
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`existing patent as a guide to select from prior art elements, or otherwise engage in
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`hindsight. Rather, the better approach is to consider what the person of ordinary
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`skill in the art knew, and what the art taught, suggested, or motivated the person of
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`ordinary skill in the art to further pursue; and to differentiate between steps that
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`were routinely done (such as in response to known problems, steps or obstacles),
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`and those which, for example, may have represented a different way of solving
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`existing or known problems.
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`22. Further, I understand that when there is some recognized reason to
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`solve 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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`9
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`options within his or her technical grasp. If this leads to expected success, it is
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`likely not the product of innovation but of ordinary skill and common sense. In
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`addition, simply arranging old elements with each performing its known function
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`and yielding no more than what one would expect from such an arrangement is
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`obvious.
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`23.
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`I understand that before reaching any final conclusion on obviousness,
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`the obviousness analysis
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`requires consideration of objective
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`indicia of
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`nonobviousness, if it is offered. These must be considered to ensure that, for
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`example, there were not some unanticipated problems, obstacles or hurdles that
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`may seem easy to overcome in hindsight, but which were not readily overcome
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`prior to the relevant invention date of the patents/claims at issue. I understand that
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`these objective
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`indicia are also known as “secondary considerations of
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`nonobviousness,” and may include long-felt but unmet need and unexpected
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`results, among others. I also understand, however, that any offered evidence of
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`secondary considerations of non-obviousness must be comparable with the scope
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`of the challenged claims. This means that for any offered evidence of secondary
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`considerations of non-obviousness to be given substantial weight, I understand the
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`proponent of that evidence must establish a “nexus” or a sufficient connection or
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`tie between that evidence and the merits of the claimed invention, which I
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`understand specifically incorporates any novel element(s) of the claimed invention.
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`If the secondary consideration evidence offered actually results from something
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`other than the merits of the claim, then I understand that there is no nexus or tie to
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`the claimed invention. I also understand it is the patentee that has the burden of
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`proving that a nexus exists.
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`24. 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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`25. 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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`26. However, I understand that secondary considerations will not
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`overcome a strong showing of obviousness.
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`11
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`D.
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`Person of Ordinary Skill in the Art
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`27.
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`I understand that in defining a person of ordinary skill in the art the
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`following factors may be considered: (1) the educational level of the inventor; (2)
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`the type of problems encountered in the art; (3) prior art solutions to those
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`problems; (4) rapidity with which innovations are made; and (5) sophistication of
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`the technology and educational level of active workers in the field.
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`28.
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`In my opinion a person of ordinary skill in the art related to the ’213
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`patent, as of June 14, 1991, would be an individual that developed protein
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`therapeutics. This person would have a Ph.D. or equivalent (for example,
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`knowledge gained through 4–5 years of work experience) in molecular biology,
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`immunology, biochemistry or a closely related field, and may work as a member of
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`a team. A team member or advisor or consultant would have an M.D. with clinical
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`experience in the disease or disease area (e.g., oncology) for which the antibody
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`development is intended.
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`29. For example, as a Ph.D. or equivalent, the person of ordinary skill in
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`the art would have the educational background above with experience in common
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`laboratory techniques in molecular biology, cell culture, protein purification, and
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`cell-based assays. This experience is consistent with the types of problems
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`encountered in the art of protein engineering, which would have included
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`performing three-dimensional computer modeling of protein structures, domain
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`12
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`and sequence manipulation and swapping, construction and expression of
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`recombinant proteins, antibody binding assays (for specificity and affinity),
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`immunogenicity testing and the like. The experience may come from the person of
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`ordinary skill in the art’s own experience, or may come through research or work
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`collaborations with other
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`individual(s) with experience
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`in
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`the medical,
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`pharmaceutical or biotech industry, e.g., as members of a research team or group.
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`30. A person of ordinary skill in the art would also be well-versed in the
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`world-wide literature on antibody therapeutics that was available as of June 14,
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`1991. As mentioned above, the person of ordinary skill in the art may work as part
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`of a team or collaboration to develop a humanized monoclonal antibody for
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`therapeutic use, including consulting with others to select non-human monoclonal
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`antibodies (such as a mouse monoclonal antibody) for humanization, as well as
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`subsequent testing of the humanized antibody and its intermediates. In the prior art
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`(i.e., before, at least, June 14, 1991), computer modeling for humanization was a
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`known methodology. The field was advancing rapidly, and individuals working in
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`the field were highly sophisticated and using the most advanced scientific
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`techniques.
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`IV. SUMMARY OF OPINION
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`31. The limitation of using mouse antibodies as therapeutics and hence
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`the motivation of overcoming these limitations had been defined by Winter (Ex.
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`13
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`1033). Queen and others recognized that in order to have a robust and reproducible
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`method of humanizing antibodies, it was necessary to take into account not only
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`the Complementarity Determining Regions (“CDR’s”) but also framewor