IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In the Inter Partes Review of:
`
`Trial Number: To Be Assigned
`
`
`
`U.S. Patent No. 6,407,213
`
`Filed: November 17, 1993
`
`Issued: June 18, 2002
`
`Inventor(s): Paul J. Carter, Leonard G. Presta
`
`Assignee: Genentech, Inc.
`
`
`
`
`
`
`
`
`
`
`
`Title: Method for making humanized antibodies Panel: To Be Assigned
`
`Mail Stop Inter Partes Review
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`
`
`DECLARATION OF JEFFERSON FOOTE, PH.D.
`
`PFIZER EX. 1003
`Page 1
`
`

`

`
`
`TABLE OF CONTENTS
`
`Page
`
`I.
`
`QUALIFICATIONS AND BACKGROUND ................................................. 1
`
`A.
`
`B.
`
`C.
`
`Education and Experience ..................................................................... 1
`
`Bases for Opinions and Materials Considered ...................................... 4
`
`Scope of Work ....................................................................................... 4
`
`LEGAL STANDARDS ................................................................................... 5
`
`PERSON OF ORDINARY SKILL IN THE ART .......................................... 9
`
`II.
`
`III.
`
`IV. SUMMARY OF OPINIONS ......................................................................... 12
`
`V.
`
`THE ’213 PATENT (EX. 1001) .................................................................... 19
`
`VI. BACKGROUND ........................................................................................... 35
`
`A. Antibody Therapy ................................................................................ 35
`
`B.
`
`Terminology: Polypeptides and Sequences ........................................ 36
`
`C. Mid-century Advances ........................................................................ 37
`
`A.
`
`B.
`
`C.
`
`Structural Studies and Complementarity ............................................ 39
`
`X-ray crystallography .......................................................................... 42
`
`Kabat Database and Numbering .......................................................... 44
`
`D. Other Systematic Efforts to Organize Antibody Sequence Data
`According to Structure and Function .................................................. 46
`
`E.
`
`F.
`
`G.
`
`H.
`
`Immunogenicity ................................................................................... 49
`
`Humanizing – the Winter Paradigm .................................................... 50
`
`Antigen Binding Regions .................................................................... 54
`
`Framework Region Important for Antigen Binding ........................... 55
`
`
`
`i
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`PFIZER EX. 1003
`Page 2
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`TABLE OF CONTENTS (CONT’D)
`
`Page
`
`I.
`
`Antibody Humanization ...................................................................... 57
`
`VII. SCOPE AND CONTENT OF THE PRIOR ART REFERENCES .............. 63
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`F.
`
`EP 0403156 “Improved Monoclonal Antibodies Against the
`Human Alpha/Beta T-Cell Receptor, Their Production and
`Use” Published December 19, 1990 (“Kurrle”) (Ex. 1071) ................ 63
`
`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) ................................................ 65
`
`PCT Publication No. WO 90/07861 (“Queen 1990”) (Ex. 1050) ....... 68
`
`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) ................................................................... 73
`
`PDB Database ...................................................................................... 74
`
`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) ............................................................................................ 77
`
`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) ........................................................ 77
`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) ........... 78
`
`
`
`ii
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`PFIZER EX. 1003
`Page 3
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`

`

`TABLE OF CONTENTS (CONT’D)
`
`Page
`
`I.
`
`J.
`
`K.
`
`Chothia et al., Domain Association in Immunoglobulin
`Molecules: The Packing of Variable Domains, 186 J.
`MOLECULAR BIOLOGY 651–63 (1985) (“Chothia 1985”) (Ex.
`1063) .................................................................................................... 80
`
`Chothia & Lesk, Canonical Structures for the Hypervariable
`Regions of Immunoglobulins, 196 J. MOLECULAR BIOLOGY
`901–17 (1987) (“Chothia & Lesk”) (Ex. 1062) .................................. 80
`
`Chothia et al., Conformations of immunoglobulin hypervariable
`regions, 342(21) NATURE 877–83 (1989) (“Chothia 1989”) (Ex.
`1049) .................................................................................................... 81
`
`VIII. UNPATENTABILITY OF THE ’213 PATENT .......................................... 82
`
`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) .............................. 82
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`Claim 1 is anticipated by Kurrle ............................................... 82
`
`Dependent claims 2, 25 and 29 are anticipated by Kurrle ........ 83
`
`Independent claim 63 is anticipated by Kurrle ......................... 85
`
`Claims 66, 67, 71, 72, 75 and 76 are anticipated by
`Kurrle ........................................................................................ 87
`
`Independent claim 80 and dependent claim 81 are
`anticipated by Kurrle ................................................................. 88
`
`B.
`
`Claims 1, 2, 4, 29, 62–64, 80 and 81 of the ’213 Patent are
`Anticipated by Queen 1990 ................................................................. 90
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`Claim 1 is anticipated by Queen 1990 (Ex. 1050) .................... 90
`
`Dependent Claim 2 is anticipated by Queen 1990 .................... 96
`
`Dependent Claim 4 is anticipated by Queen 1990 .................... 97
`
`Dependent Claim 29 is anticipated by Queen 1990 .................. 98
`
`Independent Claim 62 is anticipated by Queen 1990 ............... 98
`
`
`
`iii
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`PFIZER EX. 1003
`Page 4
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`TABLE OF CONTENTS (CONT’D)
`
`Page
`
`6.
`
`7.
`
`8.
`
`9.
`
`Independent Claim 63 is anticipated by Queen 1990 ............... 99
`
`Independent Claim 64 is anticipated by Queen 1990 .............101
`
`Independent Claim 80 is anticipated by Queen 1990 .............103
`
`Dependent Claim 81 is anticipated by Queen 1990 ................104
`
`C.
`
`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.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`Claim 1 is obvious over Queen 1990 and Kurrle ...................106
`
`Claims 2, 25 and 29 are obvious over Queen 1990 and
`Kurrle ......................................................................................111
`
`Claim 4 is obvious over Queen 1990 and Kurrle ...................112
`
`Claim 62 is obvious over Queen 1990 in view of Kurrle .......113
`
`Claim 63 is obvious over Queen 1990 in view of Kurrle .......114
`
`Claim 64 is obvious over Queen 1990 in view of Kurrle .......115
`
`Claim 66 ..................................................................................118
`
`Claims 67, 71, 72, 75, 76 and 78 ............................................119
`
`Claim 69 ..................................................................................120
`
`D.
`
`E.
`
`F.
`
`G.
`
`10. Claims 80 and 81.....................................................................121
`
`Claim 12 is obvious over Queen 1990 and Kurrle, and Furey ..........123
`
`Claims 73 and 77 are obvious in view of Queen 1990, Kurrle
`and Chothia & Lesk ...........................................................................125
`
`Claim 74 is obvious over Queen 1990 in view of Kurrle and
`Chothia 1985 .....................................................................................127
`
`Claims 79 and 65 are obvious in view of Queen 1990, Kurrle,
`Chothia & Lesk and Chothia 1985 ....................................................129
`
`
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`iv
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`PFIZER EX. 1003
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`TABLE OF CONTENTS (CONT’D)
`
`Page
`
`H.
`
`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.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`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
`
`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
`
`
`
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`PFIZER EX. 1003
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`TABLE OF CONTENTS (CONT’D)
`
`Page
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`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
`
`17.
`
`Independent Claim 80 is obvious in view of Queen 1989
`or Queen 1990 and the PDB database ....................................170
`
`18. Dependent Claim 81 is obvious in view of Queen 1989 or
`Queen 1990 and the PDB database .........................................172
`
`I.
`
`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 .........173
`
`1.
`
`2.
`
`3.
`
`Independent Claim 62 is obvious in view of Queen 1989,
`the PDB database and in view of Kabat 1987 ........................173
`
`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
`
`J.
`
`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
`
`
`
`vi
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`PFIZER EX. 1003
`Page 7
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`

`

`TABLE OF CONTENTS (CONT’D)
`
`Page
`
`2.
`
`3.
`
`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
`
`K.
`
`Claims 30, 31, 33 and 42 are Obvious Over Queen 1990 In
`View Of Hudziak ...............................................................................187
`
`L.
`
`Claim 42 is Obvious Over Queen 1990, Hudziak, and Furey; .........188
`
`M. Claim 60 is Obvious Over Queen 1990, Hudziak, and
`Chothia & Lesk .................................................................................190
`
`IX. SECONDARY CONSIDERATIONS .........................................................190
`
`X.
`
`CONCLUSION ............................................................................................194
`
`
`
`
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`vii
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`PFIZER EX. 1003
`Page 8
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`
`
`1. My name is Jefferson Foote. Counsel for Pfizer, Inc. (“Pfizer”)
`
`retained me to provide my opinion regarding U.S. Patent No. 6,407,213 (the ’213
`
`patent) (Ex. 1001), which is assigned to Genentech, Inc. I understand that Pfizer
`
`intends to file petitions for inter partes review of the ’213 patent, and will request
`
`that the United States Patent and Trademark Office cancel certain claims of the
`
`’213 patent as unpatentable in the petitions. My opinions in this expert declaration
`
`support Pfizer’s request for inter partes review of the ’213 patent, and cancellation
`
`of the claims.
`
`I.
`
`QUALIFICATIONS AND BACKGROUND
`A. Education and Experience
`2.
`I am currently the Chief Science Officer of Arrowsmith Technologies
`
`in Seattle. Arrowsmith is a startup biotechnology company developing an
`
`antibody-modulated drug delivery technology that we term “antibody buffering”. I
`
`have over 30 years of experience specializing in antibody structure, antibody
`
`humanization, and biophysical chemistry. A copy of my curriculum vitae is
`
`attached as Exhibit A.
`
`3.
`
`I received my A.B. in Biochemical Sciences from Harvard College in
`
`1977 and my Ph.D. in Biochemistry from the University of California in 1985. My
`
`graduate research focused on the kinetics of aspartate transcarbamylase.
`
`
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`PFIZER EX. 1003
`Page 9
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`4.
`
`After obtaining my Ph.D., I joined the Medical Research Council
`
`(“MRC”) Laboratory of Molecular Biology in Cambridge, where I held
`
`postdoctoral and staff positions. My work focused on engineering humanized
`
`antibodies (under Sir Gregory Winter), the physical effects of antibody somatic
`
`mutations (under César Milstein), and crystallographic structure determination of
`
`antibody fragments. While at MRC, I was a member of the research team that
`
`developed the first humanized antibody.
`
`5.
`
`In 1992, I joined the Fred Hutchinson Cancer Research Center in
`
`Seattle, Washington, first as an Assistant Member and then as an Associate
`
`Member, in a department then called Molecular Medicine, later renamed Human
`
`Biology. During most of this time, I also served as an Affiliate Assistant Professor
`
`and an Affiliate Associate Professor in the Department of Immunology at the
`
`University of Washington. My research included the study of antibody structure,
`
`development of therapeutics, and biophysics of the immune response. I also taught
`
`graduate level courses in the Molecular and Cellular Biology Program and the
`
`Program in Biomolecular Structure and Design, which were jointly run by the two
`
`institutions, and supervised
`
`thesis candidates
`
`in
`
`those programs and
`
`in
`
`Immunology. I remained at the Fred Hutchinson Cancer Research Center until
`
`2004.
`
`
`
`2
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`PFIZER EX. 1003
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`
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`6.
`
`In 2004, I co-founded Absalus, Inc, a biotechnology start up, to
`
`develop antibody super humanization
`
`technology. In 2006, I co-founded
`
`Arrowsmith Technologies, a biotechnology start up formed to develop antibody
`
`buffer technology.
`
`7.
`
`I have also served as a legal consultant for district court and inter
`
`partes review proceedings in a number of cases including those related to
`
`humanization of antibodies.
`
`8.
`
`I have published extensively on antibody humanization during my
`
`career. See Appendix A. I have also been awarded several patents related to
`
`antibodies and antibody humanization, including: U.S. Patent No. 6,881,557,
`
`entitled “Super-humanized antibodies”; U.S. Patent No. 7,709,226, entitled
`
`“Method of humanizing antibodies by matching canonical structure types”; and
`
`U.S. Patent No. 7,732,578, entitled “Super-humanized antibodies”; U.S. Patent No.
`
`9,173,958, entitled “Antibody buffering of a ligand in vivo.” See id.
`
`9.
`
`I have also received several honors for my work in the antibody field,
`
`including: Fellow of the Jane Coffin Childs Memorial Fund for Medical Research
`
`(1985–1988); Merck, Sharpe, and Dohme Fellowship (1989–1992); and Beckman
`
`Young Investigator (1995–1997).
`
`
`
`3
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`PFIZER EX. 1003
`Page 11
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`
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`B.
`Bases for Opinions and Materials Considered
`10. Exhibit B includes a list of the materials I considered, in addition to
`
`my experience, education, and training, in providing the opinions contained herein.
`
`11.
`
`I understand that Mylan, a third-party, has previously filed IPR
`
`petitions challenging certain claims of the ’213 patent. As part of my analysis, I
`
`have considered Mylan’s IPR petitions and the declarations filed in support of
`
`them. I have applied my own judgment and expertise, and after reviewing the
`
`materials in Mylan’s Padlan declaration, as well as conducting my own fact
`
`checking and consideration of potential counterarguments, I have come to the same
`
`ultimate conclusions as Dr. Padlan, as set forth in this declaration. Some of the
`
`language and organization of this declaration is similar to that of Dr. Padlan’s
`
`declaration because I determined that it was unnecessary to rewrite materials that I
`
`deemed acceptable and correct. The opinions I set forth in this declaration are my
`
`own.
`
`C.
`12.
`
`Scope of Work
`
`I have been retained by Pfizer as a technical expert in this matter to
`
`provide various opinions regarding the ’213 patent. I receive $800 per hour for my
`
`services. No part of my compensation is dependent upon my opinions given or the
`
`outcome of this case.
`
`
`
`4
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`PFIZER EX. 1003
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`
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`II. LEGAL STANDARDS
`13. For my opinions in this declaration, I understand that it requires
`
`applying various legal principles. As I am not an attorney, I have been informed
`
`about various legal principles that involve my analysis. I have used my
`
`understanding of those principles in forming my opinions. I summarize those
`
`principles as I understand them below.
`
`14. For example, I have been told that Pfizer bears the burden of proving
`
`unpatentability in this proceeding by a preponderance of the evidence. I am
`
`informed that this preponderance of the evidence standard means that Pfizer must
`
`show that unpatentability is more probable than not.
`
`15.
`
`I understand a patent typically includes a specification, drawings, and
`
`claims. I am told the specification consists of a written description of the invention
`
`and must provide a sufficient description to enable one skilled in the art to practice
`
`the invention. I am also told the drawings illustrate the invention. The claims, on
`
`the other hand, appear at the end of the specification as numbered paragraphs and
`
`define the metes and bounds of the property right conveyed by the patent.
`
`16.
`
`I have been told that claims can either be independent or dependent. I
`
`know dependent claims refer back to and incorporate at least one other claim. As a
`
`result, dependent claims include all limitations of any claims incorporated by
`
`reference into the dependent claim.
`
`
`
`5
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`
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`17.
`
`I have also been told that when I review and consider the claims, the
`
`claims should be given what is called their broadest reasonable interpretation in
`
`light of the specification, and should be viewed from the perspective of a person of
`
`ordinary skill in the art at the time of the alleged invention.1 (I discuss who
`
`qualifies as the person of ordinary skill in the art in more detail below).
`
`18.
`
`I am told prior art to the ’213 patent includes patents, printed
`
`publications and products in the relevant art that predate the priority date of the
`
`’213 patent.
`
`19.
`
`I have been asked to consider the question of anticipation, namely,
`
`whether the claims cover something that is new, novel. I understand that a claim is
`
`invalid if it is anticipated. I am told that the concept of anticipation requires that
`
`each and every element of a challenged claim is expressly or inherently taught by a
`
`single reference before the date of the alleged invention.
`
`20.
`
`I have also been asked to consider the question of obviousness/non-
`
`obviousness. I understand a claim is invalid if it is obvious. I am told that the
`
`obviousness analysis must be from the perspective of the person of ordinary skill in
`
`the art. I have been informed this analysis involves four factual inquiries: (1)
`
`1 For this declaration, I have been asked to assume the date of the alleged
`
`invention is June 14, 1991, which I understand is the earliest possible priority
`
`date of the ’213 patent.
`
`
`
`6
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`PFIZER EX. 1003
`Page 14
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`

`

`
`
`understanding the scope and content of the prior art; (2) determining the
`
`differences between the claimed invention and the prior art; (3) resolving the level
`
`of ordinary skill in the art; and (4) consideration of secondary considerations of
`
`non-obviousness, which may or may not have some relevancy to whether the claim
`
`is obvious or not.
`
`21.
`
`I further note that I have been instructed that one cannot use an
`
`existing patent as a guide to select from prior art elements, or otherwise engage in
`
`hindsight. Rather, the better approach is to consider what the person of ordinary
`
`skill in the art knew, and what the art taught, suggested, or motivated the person of
`
`ordinary skill in the art to further pursue; and to differentiate between steps that
`
`were routinely done (such as in response to known problems, steps or obstacles),
`
`and those which, for example, may have represented a different way of solving
`
`existing or known problems.
`
`22. Further, I understand that when there is some recognized reason to
`
`solve a problem, and there are a finite number of identified, predictable and known
`
`solutions, a person of ordinary skill in the art has good reason to pursue the known
`
`options within his or her technical grasp. If this leads to expected success, it is
`
`likely not the product of innovation but of ordinary skill and common sense. In
`
`addition, simply arranging old elements with each performing its known function
`
`
`
`7
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`PFIZER EX. 1003
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`
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`and yielding no more than what one would expect from such an arrangement is
`
`obvious.
`
`23.
`
`I understand that before reaching any final conclusion on obviousness,
`
`the obviousness analysis requires consideration of objective indicia of non-
`
`obviousness, if it is offered. These must be considered to ensure that, for example,
`
`there were not some unanticipated problems, obstacles or hurdles that may seem
`
`easy to overcome in hindsight, but which were not readily overcome prior to the
`
`relevant invention date of the patents/claims at issue here. I understand that these
`
`objective
`
`indicia are also known as “secondary considerations of non-
`
`obviousness,” and may include long-felt but unmet need and unexpected results,
`
`among others. I also understand, however, that any offered evidence of secondary
`
`considerations of non-obviousness must be comparable with the scope of the
`
`challenged claims. This means that for any offered evidence of secondary
`
`considerations of non-obviousness to be given substantial weight, I understand the
`
`proponent of that evidence must establish a “nexus” or a sufficient connection or
`
`tie between that evidence and the merits of the claimed invention, which I
`
`understand specifically incorporates any novel element(s) of the claimed invention.
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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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`III. PERSON OF ORDINARY SKILL IN THE ART
`27.
`I have been informed by counsel that the obviousness analysis is to be
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`conducted from the perspective of a person of ordinary skill in the art (a “person of
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`ordinary skill”) at the time of the alleged invention.
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`28.
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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 (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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`29.
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`It is my opinion that a person of ordinary skill in the art in 1991
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`related to the ’213 patent 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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`30. 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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`2 A review of To Build a Better Mousetrap, Use Human Parts, Journal of the
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`National Cancer Institute, Vol. 90, No. 1, January 7, 1998 (Ex. 1185) suggests
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`named inventors Paul Carter and Leonard Presta both held Ph.D.s and were
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`working at Genentech at the time of the alleged invention. See Ex. 1185 at 9.
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`laboratory techniques in molecular biology, such as those in the popular how-to
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`handbook, “Molecular Cloning Techniques: A Laboratory Manual”, by Sambrook
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`and Fritsch, 1989. Ex. 1097. This experience is consistent with the types of
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`problems 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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`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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`31. 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 the ’213
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`patent. As mentioned above, the person of ordinary skill in the art may work as
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`part 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. I should
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`further note that in the prior art, computer modeling for humanization was a known
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`methodology. The field was advancing rapidly, and individuals working in the
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`field were highly sophisticated and using the most advanced scientific techniques.
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`32.
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`I understand Mr. Timothy Buss is also submitting a declaration in
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`connection with Pfizer’s IPR petitions. Mr. Buss and I have spoken and I
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`understand that he believes my definition of one of skill in the art is sound and he
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`applies it in his declaration.
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`IV. SUMMARY OF OPINIONS
`33. For the reasons below, it is my opinion that claims 1, 2, 25, 29, 63, 66,
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`67, 71, 72, 75, 76, 80 and 81 are anticipated by Kurrle et al., EP Publication
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`Number 0403156, Improved monoclonal antibodies against the human alpha/beta
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`T-Cell receptor, their production and use (published December 19, 1990) (Ex.
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`1071; “Kurrle”). Kurrle provided a detailed roadmap for humanizing any non-
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`human monoclonal antibody. Kurrle used that roadmap to humanize mouse
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`monoclonal antibodies against the human alpha/beta T-cell receptor, which
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`included the substitution of claimed human framework residues 4L, 69H, 71H,
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`73H and 76H,3 for the non-human mouse monoclonal antibody framework residue.
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`34.
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`It is also my opinion that Queen, International Publication No. WO
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`1990/07861 (published July 26, 1990) (Ex. 1050; “Queen 1990”) provides another
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`3 I have attempted to use bold font for residues that are recited in the challenged
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`claims.
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`detailed roadmap for humanizing any non-human antibody and anticipates claims
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`1, 2, 4, 29, 62–64, 80 and 81. Queen 1990 characterized critical framework
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`residues, including neighboring non-human antigen-specific Complementarity
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`Determining Region (CDR) amino acid residues. A person of ordinary skill in the
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`art (“POSITA”) would have known that claimed framework residues 98L and 36H
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`are immediately adjacent to the CDRs.
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`35.
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`In addition, it is my opinion that:
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`•
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`•
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`•
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`•
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`•
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`claims 1, 2, 4, 25, 29, 62–64, 66–67, 69, 71, 72, 75–76, 78 and 80–81
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`are obvious over Queen 1990 (Ex. 1050) in view of Kurrle (Ex. 1071);
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`claim 12 is obvious over Queen 1990 (Ex. 1050), Kurrle (1071) and
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`Furey4 (Ex. 1125);
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`claims 73 and 77 are obvious over Queen 1990 (Ex. 1050), Kurrle
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`(Ex. 1071) and Chothia & Lesk (Ex. 1062);
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`claim 74 is obvious over Queen 1990 (Ex. 1050), Kurrle (Ex. 1071)
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`and Chothia 1985 (Ex. 106