UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`CELLTRION INC.,
`Petitioner
`
`v.
`
`GENENTECH, INC.
`Patent Owner
`
`
`U.S. Patent No. 6,407,213
`
`Case IPR2017-01373
`
`
`
`EXPERT DECLARATION OF LUTZ RIECHMANN, PH.D.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF
`PATENT NO. 6,407,213
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`1 of 220
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`TABLE OF CONTENTS
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`Page
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`I.
`
`C.
`
`QUALIFICATIONS AND BACKGROUND ................................................. 1
`A.
`Education and Experience ..................................................................... 1
`B.
`Bases for Opinions and Materials Considered ...................................... 5
`C.
`Scope of Work ....................................................................................... 5
`LEGAL STANDARDS ................................................................................... 6
`II.
`III. PERSON OF ORDINARY SKILL IN THE ART ........................................ 10
`IV. SUMMARY OF OPINIONS ......................................................................... 12
`V.
`THE ’213 PATENT [EX. 1001] .................................................................... 19
`VI. BACKGROUND ........................................................................................... 36
`A. Antibody Structure and Function ........................................................ 36
`B. Monoclonal Antibodies Expanded Therapeutic and Diagnostic
`Uses of Antibodies .............................................................................. 38
`Immunogenic Reaction in Humans With Monoclonal Antibody
`Therapy ................................................................................................ 40
`D. Molecular Characterization of Antibody Structure and Function ....... 41
`E.
`Antigen Binding Regions .................................................................... 45
`F.
`Framework Region Important for Antigen Binding ........................... 50
`G.
`Chimeric Antibodies ........................................................................... 54
`H. Antibody Humanization ...................................................................... 56
`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
`B. Queen et al. “A Humanized Antibody that Binds to the
`Interleukin 2 Receptor” PNAS 86:10029–33 (1989) (“Queen
`1989”) [Ex. 1034] ................................................................................ 71
`PCT Publication No. WO 90/07861 (“Queen 1990”) [Ex. 1050] ....... 74
`Furey et al. “Structure of a Novel Bence-Jones Protein (Rhe)
`Fragment at 1.6 A Resolution,” J. Mol. Biol. 167:661–92
`(1983) (“Furey”) [Ex. 1125] ................................................................ 79
`Protein Data Bank Database ................................................................ 80
`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
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`C.
`D.
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`E.
`F.
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`I.
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`J.
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`K.
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`Immunoglobulins” J. Mol. Biol. 215:175–82 (1990)
`(“Tramontano”) [Ex. 1051] ................................................................. 83
`G. Kabat et al. “Sequences of Proteins of Immunological Interest”,
`4th Ed., pp. iii, 41-49, 167–76 (1987) (“Kabat 1987”) [Ex. 1052] ...... 84
`H. Hudziak et al. “p185HER2 Monoclonal Antibody Has
`Antiproliferative Effects In Vitro and Sensitizes Human Breast
`Tumor Cells to Tumor Necrosis Factor” Mol. Cell Biol.
`9:1165–72 (1989) (“Hudziak”) [Ex. 1021] ......................................... 84
`Chothia, C. et al. “Domain Association in Immunoglobulin
`Molecules: The Packing of Variable Domains” J. Mol. Biol.
`186:651–63 (1985) (“Chothia 1985”) [Ex. 1063] ............................... 86
`Chothia and Lesk. “Canonical Structures for the Hypervariable
`Regions of Immunoglobulins” J. Mol. Biol. 196:901–17 (1987)
`(“Chothia & Lesk”) [Ex. 1062] ........................................................... 86
`Chothia, C. et al. “Conformations of Immunoglobulin
`Hypervariable Regions” Nature 342:877–83 (1989) (“Chothia
`1989”) [Ex. 1049] ................................................................................ 87
`VIII. UNPATENTABILITY OF THE ’213 PATENT .......................................... 88
`A.
`Claims 1, 2, 25, 29, 63, 66, 71, 75, 76, 78, 80 and 81 of the ’213
`Patent are Anticipated by Kurrle [Ex. 1071] ....................................... 88
`1.
`Claim 1 of the ’213 patent is anticipated by Kurrle .................. 88
`2.
`Dependent claims 2, 25 and 29 are anticipated by Kurrle ........ 90
`3.
`Independent claim 63 is anticipated by Kurrle ......................... 91
`4.
`Independent claim 66 and dependent claims 71, 72, 75
`and 76 are anticipated by Kurrle ............................................... 93
`Independent claim 80 and dependent claim 81 are
`anticipated by Kurrle ................................................................. 94
`Claims 1, 2, 4, 29, 62, 63, 64, 80 and 81 of the ’213 Patent are
`Anticipated by Queen 1990 ................................................................. 96
`1.
`Independent Claim 1 of the ’213 Patent is anticipated by
`Queen 1990 [Ex. 1050] ............................................................. 96
`Dependent Claim 2 of the ’213 Patent is anticipated by
`Queen 1990 ............................................................................. 103
`Dependent Claim 4 of the ’213 Patent is anticipated by
`Queen 1990 ............................................................................. 104
`Dependent Claim 29 of the ’213 Patent is anticipated by
`Queen 1990 ............................................................................. 104
`Independent Claim 62 of the ’213 Patent is anticipated by
`Queen 1990 ............................................................................. 105
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`5.
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`B.
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`2.
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`3.
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`4.
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`5.
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`C.
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`D.
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`6.
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`7.
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`8.
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`Independent Claim 63 of the ’213 Patent is anticipated by
`Queen 1990 ............................................................................. 106
`Dependent Claim 65 of the ’213 Patent is anticipated by
`Queen 1990 ............................................................................. 107
`Independent Claim 64 of the ’213 Patent is anticipated by
`Queen 1990 ............................................................................. 109
`Independent Claim 80 of the ’213 Patent is anticipated by
`Queen 1990 ............................................................................. 111
`10. Dependent Claim 81 of the ’213 Patent is anticipated by
`Queen 1990 ............................................................................. 113
`Claims 1, 2, 4,12, 25, 29, 62–67, 69 and 71–81 of the ’213
`Patent are obvious over Queen 1990 in view of Kurrle, and
`Chothia 1985 or Chothia & Lesk ...................................................... 114
`1.
`Claim 1 is obvious over Queen 1990 and Kurrle ................... 116
`2.
`Claims 2, 25 and 29 are obvious over Queen 1990 and
`Kurrle ...................................................................................... 120
`Claim 4 is obvious over Queen 1990 and Kurrle ................... 122
`Claim 12 is obvious over Queen 1990 and Kurrle, in
`view of Furey .......................................................................... 122
`Claim 62 is obvious over Queen 1990 in view of Kurrle ....... 125
`5.
`Claim 63 is obvious over Queen 1990 in view of Kurrle ....... 126
`6.
`Claim 64 is obvious over Queen 1990 in view of Kurrle ....... 127
`7.
`Claim 65 is obvious over Queen 1990 in view of Kurrle ....... 130
`8.
`Claim 66 is obvious over Queen 1990 in view of Kurrle ....... 131
`9.
`10. Claims 67, 71, 72, 74, 75, 76 and 78 are obvious over
`Queen 1990 in view of Kurrle and Chothia 1985 ................... 132
`11. Claim 69 is obvious over Queen 1990 in view of Kurrle ....... 136
`12. Claims 73, 77 and 79 are obvious in view of Queen 1990,
`Kurrle and Chothia & Lesk ..................................................... 136
`13. Claims 80 and 81 are obvious over Queen 1990 in view
`of Kurrle .................................................................................. 142
`Claims 1, 2, 4,12, 25, 29, 62–67, 69 and 71–81 of the ’213
`Patent are obvious in view of Queen 1989 or Queen 1990 and
`the PDB database ............................................................................... 144
`1.
`Independent Claim 1 of the ’213 Patent is obvious in
`view of Queen 1989 and the PDB database ............................ 144
`Independent Claim 1 of the ’213 Patent is obvious in
`view of Queen 1990 and the PDB database ............................ 157
`
`9.
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`3.
`4.
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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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`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 .......................................................................... 160
`Dependent claim 4 of the ’213 Patent is obvious in view
`of Queen 1990 and the PDB database .................................... 161
`Independent Claim 62 of the ’213 Patent is obvious in
`view of Queen 1990 and the PDB database ............................ 161
`Independent Claim 63 of the ’213 Patent is obvious in
`view of Queen 1989 or Queen 1990 and the PDB
`database ................................................................................... 162
`Independent Claim 64 of the ’213 Patent is obvious in
`view of Queen 1990 and the PDB database ............................ 163
`Independent Claim 66 of the ’213 Patent is obvious in
`view of Queen 1989 or Queen 1990 and the PDB
`database ................................................................................... 165
`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 .................................................................... 167
`10. Dependent Claim 72 of the ’213 patent is obvious in
`view of Queen 1989 or Queen 1990, and the PDB
`database ................................................................................... 168
`11. Dependent Claim 75 of the ’213 patent is obvious in
`view of Queen 1989 or Queen 1990 and the PDB
`database ................................................................................... 170
`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 ......................... 171
`13. Dependent Claims 76–77 and 79 of the ’213 Patent are
`obvious in view of Queen 1989 or Queen 1990 and the
`PDB database, and optionally in view of Tramontano ........... 172
`14. Dependent Claim 69 of the ’213 Patent is obvious in
`view of Queen 1990 and the PDB database ............................ 181
`15. Dependent Claim 65 of the ’213 Patent is obvious in
`view of Queen 1989 or Queen 1990 and the PDB
`database ................................................................................... 181
`Independent Claim 80 of the ’213 Patent is obvious in
`view of Queen 1989 or Queen 1990 and the PDB
`database ................................................................................... 183
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`7.
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`8.
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`9.
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`16.
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`E.
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`F.
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`G.
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`17. Dependent Claim 81 of the ’213 Patent is obvious in
`view of Queen 1989 or Queen 1990 and the PDB
`database ................................................................................... 185
`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 ......... 185
`1.
`Independent Claim 62 of the ’213 Patent is obvious in
`view of Queen 1989, the PDB database and in view of
`Kabat 1987 .............................................................................. 185
`Dependent Claims 4 and 69 of the ’213 Patent are
`obvious in view of Queen 1989 and the PDB database,
`and in view of Kabat 1987, and Hudziak ................................ 189
`Independent Claim 64 of the ’213 Patent is obvious in
`view of Queen 1989 and the PDB database, in view of
`Kabat 1987 .............................................................................. 189
`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 ............................................................................... 191
`1.
`Claim 30 of the ’213 Patent is obvious in view of Queen
`1989 or Queen 1990 and the PDB Database, and in view
`of Hudziak ............................................................................... 191
`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 .................................. 198
`Claim 33 is obvious in view of Queen 1990 and the PDB
`database, and in view of Hudziak ........................................... 199
`Claims 30, 31, 33, 42, and 60 of the ’213 Patent are Obvious
`Over Queen 1990, and Further In View Of Hudziak, Furey and
`Chothia & Lesk ................................................................................. 199
`IX. SECONDARY CONSIDERATIONS .........................................................202
`X.
`CONCLUSION ............................................................................................208
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`2.
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`3.
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`2.
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`3.
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`1. My name is Lutz Riechmann, Ph.D. Counsel for Celltrion Inc.
`
`(“Celltrion”) retained me to provide my opinions regarding U.S. Patent No.
`
`6,407,213 (the ’213 patent) [Ex. 1001], which is assigned to Genentech, Inc. I
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`understand that Celltrion intends to file a petition for inter partes review of the
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`’213 patent, and will request that the United States Patent and Trademark Office
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`cancel certain claims of the ’213 patent as unpatentable in the petition. My
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`opinions in this expert declaration supports Celltrion’s request for inter partes
`
`review of the ’213 patent, and cancellation of the claims.
`
`I.
`
`QUALIFICATIONS AND BACKGROUND
`
`A.
`
`2.
`
`Education and Experience
`
`I received my Ph.D. in Biology at the University of Bremen in
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`Germany in 1986, and subsequently worked as a postdoctoral fellow in Sir
`
`Gregory Winter’s laboratory at the Medical Research Council Laboratory of
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`Molecular Biology (MRC-LMB) in Cambridge in the United Kingdom from 1986–
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`1988. During this time the principle ideas of antibody humanization were
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`conceived and put into practice in the Winter group, where I myself extended these
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`ideas from antibodies against model antigens onto a therapeutic antibody against
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`human lymphocyte surface antigen CD52. For me this was the first time I
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`experienced recombinant DNA technology and I was keen to learn and practice all
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`aspects of antibody engineering including cloning of the rodent antibody genes,
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`their transformation into the genes for their humanized counterparts using site-
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`directed mutagenesis, the transfer of those genes into and expression in eukaryotic
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`cells as well as the purification and analysis of the expressed antibodies. I
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`furthermore learned the computer graphic analysis of antibody structures, which I
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`applied to design changes to my initially poorly binding humanized antibody into
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`an improved version, which was then immediately used to treat two patients at the
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`adjacent Cambridge University Hospital. My project was helped by the cutting
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`edge research undertaken at the MRC-LMB, which combined the groups of Drs.
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`Michael Neuberger and Cesar Milstein with their experience in monoclonal and
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`recombinant antibody technology, the groups of Chothia and Lesk providing their
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`insight into antibody variable domain structure with the equally world leading
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`research in site-directed mutagenesis and protein engineering undertaken by the
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`Winter group. To this, the closeness of the Department of Pathology added the
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`experience with the rodent antibody that I humanized and enabled both the fast
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`characterization and then the immediate clinical use of the humanized antibody to
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`help patients. More generally the MRC-LMB is a world-class research laboratory
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`and one of the birthplaces of modern molecular biology. Many techniques have
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`been pioneered at the laboratory, including DNA sequencing, methods for
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`determining the three-dimensional structure of proteins and the development of
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`monoclonal antibodies.
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`3.
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`In 1988 I received a Leukemia Society fellowship for a research
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`position to work until late 1989 with Professor Richard Lerner at the Scripps
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`Research Institute in La Jolla, California, where I helped with the cloning of total
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`antibody repertoire gene libraries from spleen cells after immunization. I also
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`started the heteronuclear, multidimensional Nuclear Magnetic Resonance (NMR)
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`analysis of antibody fragments within the group of Professor Peter Wright at the
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`Scripps Institute. I moved back to Cambridge as a Group Leader at the MRC-LMB
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`facility from 1989–1997, where I expanded my NMR studies of human antibody
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`variable domain structures and their interaction with antigen and Protein A, a
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`bacterial super-antigen frequently used to purify antibodies. I also made antigen
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`specific single domain human antibody fragments from designed antibody heavy
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`chain variable domain libraries using phage display and characterized their binding
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`and folding properties with various biophysical methods. Together with Dr. Phil
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`Holliger I furthermore elucidated the mechanism, with which bacteriophage (as
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`used for phage display experiments) infect bacteria - a vital step both for the
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`natural life cycle of the bacteriophage and for in vitro phage selection experiments
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`with displayed proteins and peptides, and determined its structural basis by both
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`NMR and X-Ray crystallography.
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`4.
`
`Between 1997–2008 I acted as Senior Scientific Officer with Sir
`
`Gregory Winter at the MRC-LMB, during which time I, as my personal project,
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`made proteins with novel folds from randomly rearranged gene fragments using
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`proteolytic phage selection and analyzed their structures in the context of early
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`protein evolution. I also acted as a guide for postdocs and Ph.D. students in the
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`Winter group to help with various antibody projects. From 2008–2009 I was
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`Director of Display Technology at F-star in Cambridge, where I set up and led a
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`laboratory for the design and selection of antibodies with an additional antigen
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`binding site in their constant domain, and was then re-appointed Senior Scientific
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`Officer with Sir Gregory Winter at the MRC-LMB from 2009–2011.
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`5.
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`Since 2011, I have been a consultant in the antibody engineering field
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`for a variety of industries and legal entities.
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`6. My research interests include antibody and protein engineering, phage
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`display and selection of proteins and peptides, protein evolution and folding as
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`well as the structural analysis of proteins by Nuclear Magnetic Resonance
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`spectroscopy.
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`7.
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`I have published extensively in the field of antibody and protein
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`engineering with over 40 publications and patents covering 25 years.
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`8.
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`A full description of my background and qualifications can be found
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`in my curriculum vitae. Ex. 1003A.
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`B.
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`9.
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`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. Eduardo Padlan, which I understand was
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`filed as Exhibit 1003 in Case Nos. IPR2016-01693 and IPR2016-01694. Because I
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`agreed with many of the statements and opinions set forth therein, I have repeated
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`those herein and revised only as necessary. Dr. Padlan’s declaration also included a
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`number of exhibits (Padlan Exhibits A-O), which he generated in order to support
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`his opinions. I have reviewed these exhibits and found them to be accurate and
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`useful in support of my own opinions. Because I agree with his use of the exhibits,
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`I have also used these same exhibits, where necessary, to support my opinions.
`
`C.
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`11.
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`Scope of Work
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`I have been retained by Celltrion as a technical expert in this matter to
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`provide various opinions regarding the ’213 patent. I receive £350 per hour or
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`£2,800 per day if I am required to travel abroad. No part of my compensation is
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`dependent upon my opinions given or the outcome of this case. I do not have any
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`current or past affiliation with Genentech, Inc., Celltrion, Inc. or any of the named
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`inventors on the ’213 patent.
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`II.
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`LEGAL STANDARDS
`12. 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. For example, I have been told that Celltrion 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 Celltrion
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`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 the
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`person of ordinary skill in the art, and whether the skilled artisan would consider
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`any differences between the prior art and what is claimed to have been obvious. I
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`have been informed that the concept of patent obviousness assesses four factual
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`inquiries: (1) the scope and content of the prior art; (2) the differences between the
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`claimed invention and the prior art; (3) the level of ordinary skill in the art; and (4)
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`secondary considerations of non-obviousness. I further note that I have been
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`instructed that one cannot use an existing patent as a guide to select from prior art
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`elements, or otherwise engage in hindsight. Rather, the correct approach is to
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`consider what the person of ordinary skill in the art knew, and what the art taught;
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`suggested; or motivated the person of ordinary skill in the art to further pursue.
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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
`
`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. I
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`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
`24. As above, I have been informed by counsel that the 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 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 would
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`have held a Ph.D. or equivalent in molecular biology, structural biology or a
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`closely related field, or an M.D. with practical academic or industrial experience in
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`antibody development, including humanization of antibodies for therapeutic
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`development. For example, a person of ordinary skill in the art would have the
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`educational background above with experience in humanizing antibodies. This
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`experience is also consistent with the types of problems encountered in the art,
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`which would have included performing three-dimensional computer modeling of
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`immunoglobulin structures, antibody domain and sequence manipulation and
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`swapping, CDR grafting and framework substitution in humanizing antibodies,
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`construction and expression of recombinant antibodies, antibody binding assays
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`(for specificity and affinity), immunogenicity testing and the like. The experience
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`may come from the person of ordinary skill in the art’s own experience, or may
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`come through research or work collaborations with other individual(s) with
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`experience in the medical, pharmaceutical or biotech industry, e.g., as members of
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`a research team or group. For example, the person of ordinary skill in the art may
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`work as part of a team or collaboration to develop a humanized monoclonal
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`antibody for therapeutic use, including consulting with others to select non-human
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`monoclonal antibodies (such as a mouse monoclonal antibody) for humanization,
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`as well as subsequent testing of the humanized antibody and its intermediates. I
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`should further note that in the prior art, 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.
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`SUMMARY OF OPINIONS
`27. For the reasons below, which includes my extensive experience from
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`1986 to June 1991 in the antibody engineering field, it is my opinion that claims 1,
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`2, 25, 29, 63, 66, 71, 75, 76, 78, 80 and 81 are anticipated over EP 0403156 to
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`Kurrle et al. [Ex. 1071; “Kurrle”]. Kurrle provided a detailed roadmap in
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`disclosing the humanization of a mouse monoclonal antibody against the human
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`alpha/beta T-cell receptor, which included the substitution of claimed human
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`framework residues 4L, 69H, 71H, 73H and 76H, for the non-human mouse
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`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. From the discussion below, it is also my opinion that claims 1, 2, 4,
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`25, 29, 62–67, 69 and 71, 72, 74, 75, 76, 78 and 80–81 are obvious over Queen
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`1990 [Ex. 1050] in view of Kurrle [Ex. 1071]. Claims 12, 73, 77 and 79 are