`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`MYLAN PHARMACEUTICALS, INC., and
`MERCK SHARP & DOHME CORP.
`Petitioners
`
`v.
`
`GENENTECH, INC. AND CITY OF HOPE
`Patent Owners
`____________
`
`U.S. Patent No. 6,331,415
`
`“Methods of Producing Immunoglobulins, Vectors and
`Transformed Host Cells for Use Therein”
`____________
`
`Inter Partes Review No. 2016-007101
`
`PETITIONER’S REPLY BRIEF
`
`
`1 Case IPR2017-00047 has been joined with this proceeding.
`
`
`
`
`
`

`

`
`
`I.
`
`II.
`
`TABLE OF CONTENTS
`
`Page
`
`INTRODUCTION: GENENTECH’S “UNCERTAINTY” AND
`“PREVAILING MINDSET” ARGUMENTS ARE CONTRARY TO
`THE CONTEMPORANEOUS EVIDENCE .................................................. 1
`
`GROUND I: GENENTECH’S ARGUMENTS REGARDING THE
`COMBINATION OF BUJARD WITH RIGGS & ITAKURA
`SHOULD BE REJECTED .............................................................................. 3
`
`A. Genentech’s Reading of Bujard Is Inappropriately Narrow ................. 3
`
`1.
`
`2.
`
`Bujard Teaches A Method for Producing Antibodies ................ 4
`
`Bujard Teaches the Use of Co-Expression of Multiple
`Genes of Interest in a Single Host Cell ....................................... 7
`
`(a) Genentech’s Interpretation of “Multimer” Is
`Wrong ............................................................................... 8
`
`(b) Genentech’s Interpretation of “One or More
`Structural Genes” Is Wrong .............................................. 9
`
`(c)
`
`The Use of Multiple Stop Codons Teaches The
`Inclusion of Multiple Genes of Interest .......................... 10
`
`3.
`
`Bujard Teaches the In Vivo Assembly of a Multimeric
`Protein Encoded by More than One Gene in a Single
`Host Cell ................................................................................... 10
`
`B.
`
`It would have been obvious to combine Bujard with Riggs &
`Itakura .................................................................................................. 11
`
`1.
`
`2.
`
`3.
`
`A POSA Would Have Been Motivated to Combine
`Bujard with Riggs & Itakura ..................................................... 11
`
`The Board Correctly Found That Riggs & Itakura Does
`Not Teach Away ....................................................................... 13
`
`A POSA Would Have Had a Reasonable Expectation of
`Success in Combining Bujard with Riggs & Itakura ................ 13
`
`III. GROUND 2: GENENTECH’S ARGUMENTS REGARDING THE
`COMBINATION OF BUJARD WITH SOUTHERN SHOULD BE
`REJECTED .................................................................................................... 15
`
`A.
`
`Southern Discloses a Two-Vector Approach to Express
`Multiple Proteins of Interest in a Single Host Cell ............................. 16
`
`
`
`i
`
`

`

`
`
`B.
`
`C.
`
`A POSA Would Have Been Motivated to Combine Bujard with
`Southern ............................................................................................... 18
`
`A POSA Would Have Had a Reasonable Expectation of
`Success in Combining Bujard with Southern...................................... 19
`
`D. Genentech’s Arguments That Southern Cannot Invalidate
`Claims 1, 2, and 33 Are Wrong ........................................................... 20
`
`IV. GENENTECH’S SECONDARY CONSIDERATIONS EVIDENCE
`SHOULD BE GIVEN NO WEIGHT ............................................................ 21
`
`A. Genentech Is Not Entitled to a Presumption of Nexus ....................... 21
`
`B.
`
`C.
`
`Genentech Fails to Establish a Nexus Between its Licensing
`Program and the Challenged Claims ................................................... 22
`
`Genentech Fails to Establish a Nexus Between Any Alleged
`Commercial Success and the Challenged Claims ............................... 23
`
`D.
`
`There Was No Skepticism of Those Skilled in the Art ....................... 23
`
`
`
`
`
`
`
`
`ii
`
`

`

`
`
`TABLE OF AUTHORITIES
`
`Cases
`
`Page
`
`Apple, Inc. v. Ameranth, Inc.
`CBM2015-00080 (Aug. 26, 2016) ...................................................................... 21
`
`In re Antor Media Corp.,
`689 F.3d 1282 (Fed. Cir. 2012) .......................................................................... 22
`
`AstraZeneca LP v. Breath Ltd.,
`603 F. App’x 999 (Fed. Cir. 2015) ..................................................................... 14
`
`Biomerieux, Inc. v. Patent Inst. for Envtl. Health Inc.,
`Appeal 2014-007983,
`2015 WL 294327 (PTAB Jan. 20, 2015) ............................................................ 23
`
`In re Bode,
`550 F.2d 656 (C.C.P.A. 1977) .............................................................................. 5
`
`In re Carlson,
`983 F.2d 1032 (1992) ............................................................................................ 4
`
`Demaco Corp. v. F. Von Langsdorff Licensing Ltd.,
`851 F.2d 1387 (Fed. Cir. 1988) .......................................................................... 21
`
`Eolas Techs. Inc. v. Microsoft Corp.,
`399 F.3d 1325 (Fed. Cir. 2005) ............................................................................ 4
`
`In re Ethicon, Inc.,
`844 F.3d 1344 (Fed. Cir. 2017) ............................................................................ 5
`
`Galderma Labs., L.P. v. Tolmar,
`737 F.3d 731 (Fed. Cir. 2013) ............................................................................ 13
`
`GrafTech Int’l Holdings, Inc. v. Laird Techs. Inc.,
`652 Fed. App’x. 973 (Fed. Cir. June 17, 2016) .................................................. 22
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ...................................................................................... 12, 14
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .......................................................................... 13
`
`Therasense, Inc. v. Becton, Dickinson & Co.,
`593 F.3d 1289 (Fed. Cir. 2010) .................................................................... 21, 22
`
`
`
`
`
`
`
`iii
`
`

`

`
`
`
`
`EXHIBIT LIST
`
`
`Exhibit
`No.
`
`Description
`
`Abbreviation
`
`1001 U.S. Patent No. 6,331,415
`
`The ‘415 patent
`
`1002 U.S. Patent No. 4,495,280
`
`1003
`
`Riggs and Itakura, Synthetic DNA and Medicine,
`American Journal of Human Genetics, 31:531-
`538 (1979)
`
`1004
`
`Southern and Berg, Transformation of Mammalian
`Cells to Antibiotic Resistance with a Bacterial
`Gene Under Control of the SV40 Early Region
`Promoter, Journal of Molecular and Applied
`Genetics, 1:327341 (1982)
`
`1005 U.S. Patent No. 4,237,224
`
`1006
`
`Declaration of Jefferson Foote, Ph.D., in Support of
`Sanofi And Regeneron’s Petition for Inter Partes
`Review of U.S. Patent No. 6,331,415
`
`1007 U.S. Patent No. 4,816,657
`
`1008
`
`’415 patent reexamination, Office Action
`dated 2/16/07
`
`Bujard, or the
`Bujard Patent
`
`Riggs & Itakura
`
`Southern
`
`Cohen & Boyer,
`or the Cohen &
`Boyer patent
`
`Foote Decl.
`
`The Cabilly I
`patent
`
`Office Action
`(2/16/07)
`
`1009
`
`’415 patent reexamination, Owners’ Resp.
`dated 11/25/05
`
`Owners’ Resp.
`(11/25/05)
`
`iv
`
`

`

`
`
`
`
`Exhibit
`No.
`
`Description
`
`Abbreviation
`
`1010
`
`’415 patent reexamination, Owners’ Resp. (5/21/07)
`
`1011
`
`’415 patent reexamination, Office Action
`dated 9/13/05
`
`Owners’ Resp.
`(5/21/07)
`
`Office Action
`(9/13/05)
`
`1012 U.S. Patent No. 4,816,397
`
`The Boss patent
`
`1013
`
`’415 patent file history, paper no. 17
`
`1014
`
`’415 patent file history, paper no. 14
`
`1015
`
`’415 patent file history, paper no. 18
`
`1016
`
`’415 patent reexamination, Office Action
`dated 8/16/06
`
`1017
`
`’415 patent reexamination, Office Action
`dated 2/25/08
`
`1018 U.S. Patent No. 4,399,216
`
`1019 U.S. Patent No. 5,840,545
`
`1020
`
`Rice and Baltimore, Regulated Expression of an
`Immunoglobulin K Gene Introduced into a Mouse
`Lymphoid Cell Line, Proceedings of the National
`Academy of Sciences USA, 79:7862-7865 (1982)
`
`1021
`
`Ochi et al., Transfer of a Cloned
`Immunoglobulin Light-Chain Gene to Mutant
`Hybridoma Cells Restores Specific Antibody
`
`v
`
`-
`
`-
`
`-
`
`Office Action
`(8/16/06)
`
`Office Action
`(2/25/08)
`
`Axel, or the
`Axel patent
`
`Moore, or the
`Moore patent
`
`Rice &
`Baltimore
`
`Ochi (I)
`
`

`

`
`
`
`
`Exhibit
`No.
`
`Description
`
`Abbreviation
`
`Production, Nature, 302:340-342 (1983)
`
`1022
`
`’415 patent reexamination, Owners’ Resp.
`dated 10/30/06
`
`1023
`
`’415 patent reexamination, Owners’ Resp.
`dated 6/6/08
`
`Owners’ Resp.
`(10/30/06)
`
`Owners’ Resp.
`(6/6/08)
`
`1024
`
`’415 patent reexamination, Appeal Brief
`
`Appeal Brief
`
`1025
`
`’415 patent reexamination, Notice of Intent to
`Issue Ex Parte Reexamination
`
`NIRC
`
`1026
`
`’415 reexamination, Ex Parte
`Reexamination Certificate
`
`Reexam Cert.
`
`1027
`
`T.J.R. Harris, Expression of Eukaryotic Genes in
`E. Coli, in Genetic Engineering 4, 127-185 (1983)
`
`Harris
`
`1028
`
`’415 patent reexamination, Declaration of Dr.
`Timothy John Roy Harris under 37 C.F.R. §
`1.132
`
`Harris Decl.
`
`1029
`
`Kabat et al., Sequences of Proteins of
`Immunological Interest (1983) (excerpt)
`
`1030
`
`Cohen, Recombinant DNA: Fact and
`Fiction, Science, 195:654-657 (1977)
`
`1031
`
`Oi et al., Immunoglobulin Gene Expression in
`Transformed Lymphoid Cells, Proceedings of the
`National Academy of Sciences USA, 80:825-
`829 (1983)
`
`Kabat
`
`Cohen
`
`Oi
`
`vi
`
`

`

`
`
`
`
`Exhibit
`No.
`
`Description
`
`Abbreviation
`
`1032
`
`European Patent Application Publication
`No. 0044722 A1, published 1/27/82
`
`Kaplan
`
`1033 U.S. Patent No. 4,487,835
`
`1034 U.S. Patent No. 4,371,614
`
`1035 U.S. Patent No. 4,762,785
`
`1036 U.S. Patent No. 4,476,227
`
`1037 U.S. Patent No. 4,362,867
`
`1038 U.S. Patent No. 4,396,601
`
`1039
`
`Milstein, Monoclonal Antibodies from Hybrid
`Myelomas, Proceedings of the Royal Society of
`London, 211:393-412 (1981)
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`1040
`
`Ochi et al., Functional Immunoglobulin M
`Production after Transfection of Cloned
`Immunoglobulin Heavy and Light Chain Genes
`into Lymphoid Cells, Proceedings of the National
`Academy of Sciences USA, 80:6351-6355 (1983)
`
`Ochi (II)
`
`1041
`
`MedImmune, Inc. v. Genentech, Inc., No. 03-
`02567 (C.D. Cal. Aug. 17, 2007), Expert Report of
`E. Fintan Walton
`
`Walton Expert
`Rep.
`
`1042
`
`’415 patent reexamination, Request for
`Reconsideration and/or Petition Under 37
`C.F.R. § 1.183 dated 5/15/09
`
`Request for
`Reconsideration
`
`vii
`
`

`

`
`
`
`
`Description
`
`Abbreviation
`
`Exhibit
`No.
`
`1043
`
`Feldman et al., Lessons from the Commercialization
`of the Cohen-Boyer Patents: The Stanford
`University Licensing Program, in Intellectual
`Property Management in Health and Agricultural
`Innovation: A Handbook of Best Practices, 1797-
`1807 (2007)
`
`Feldman
`
`ReoPro®
`Prescribing
`Info.
`
`Ghrayeb Aff.
`
`1044 ReoPro® Prescribing Information
`
`1045
`
`Genentech v. Centocor, No. 94-01379 (N.D.
`Cal.), Affidavit of John Ghrayeb, Ph.D.
`
`1046
`
`’415 patent reexamination, Declaration of Dr.
`E. Fintan Walton under 37 C.F.R. § 1.132
`
`Walton Decl.
`
`1047
`
`Complaint in MedImmune v. Genentech, No.
`03- 02567 (C.D. Cal.)
`
`1048
`
`Stipulation and order of dismissal in MedImmune
`v. Genentech, No. 03-02567 (C.D. Cal.)
`
`1049
`
`Complaint in Centocor v. Genentech, No. 08-
`CV- 3573 (C.D. Cal.)
`
`1050
`
`Order of dismissal in Centocor v. Genentech,
`No. 08-CV-3573 (C.D. Cal.)
`
`1051
`
`Complaint in Glaxo Group Ltd. v. Genentech,
`No. 10-02764 (C.D. Cal.)
`
`1052 Order of dismissal in Glaxo Group Ltd.
`
`viii
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`

`

`
`
`
`
`Exhibit
`No.
`
`Description
`
`Abbreviation
`
`v. Genentech, No. 10-02764 (C.D. Cal.)
`
`1053
`
`Complaint in Human Genome Sciences
`v. Genentech, No. 11-CV-6519 (C.D.
`Cal.)
`
`1054
`
`Order of dismissal in Human Genome Sciences
`v. Genentech, No. 11-CV-6519 (C.D. Cal.)
`
`1055
`
`Complaint in Eli Lilly and ImClone Systems LLC
`v. Genentech, No. 13-CV-7248 (C.D. Cal.)
`
`1056
`
`Stipulation of dismissal in Eli Lilly and ImClone
`Systems LLC v. Genentech, No. 13-CV-7248
`(C.D. Cal.)
`
`1057
`
`Complaint in Bristol-Myers Squibb v.
`Genentech, No. 13-CV-5400 (C.D. Cal.)
`
`1058
`
`Stipulation of dismissal in Bristol-Myers Squibb
`v. Genentech, No. 13-CV-5400 (C.D. Cal.)
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`1059
`
`Declaration of Kathryn Calame, Ph.D., in Support of
`Mylan Pharmaceuticals Inc.’s Petition for Inter
`Partes Review of U.S. Patent No. 6,331,415
`
`Calame Decl.
`
`1060 Curriculum Vitae of Kathryn Calame, Ph.D.
`
`-
`
`1061
`
`Declaration of William A. Rakoczy in Support of
`Mylan Pharmaceuticals Inc.’s Unopposed Motion for
`Pro Hac Vice Admission in IPR2016-00710
`
`Rakoczy Decl.
`
`1062 Declaration of Eric R. Hunt in Support of Mylan
`Pharmaceuticals Inc.’s Unopposed Motion for Pro
`
`Hunt Decl.
`
`ix
`
`

`

`
`
`
`
`Exhibit
`No.
`
`Description
`
`Abbreviation
`
`Hac Vice Admission in IPR2016-00710
`
`1063
`
`Declaration of Heinz J. Salmen in Support of Mylan
`Pharmaceuticals Inc.’s Unopposed Motion for Pro
`Hac Vice Admission in IPR2016-00710
`
`Salmen Decl.
`
`1064
`
`Space filling model of antibody Immunoglobulin
`G (NOT FILED)
`
`-
`
`1065
`
`Amster et al., Synthesis of Part of a Mouse
`Immunoglobulin Light Chain in a Bacterial Clone,
`Nucleic Acids Research, 8:2055-2065 (1980)
`(NOT FILED)
`
`Amster
`
`1066
`
`Kurokawa et al., Expression of Human
`Immunoglobulin E ɛ Chain cDNA in E. Coli, Nucleic
`Acids Research, 11:3077-3085 (1983) (NOT FILED)
`
`Kurokawa
`
`1067
`
`Declaration of David Baltimore in Support of U.S.
`Patent No. 6,331,415 (NOT FILED)
`
`Baltimore Decl.
`
`1068 Reserved
`
`1069
`
`Berg, Dissections and Reconstructions of Genes and
`Chromosomes, Science, 213:296-303 (1981)
`
`1070
`
`Excerpted File History of U.S. Patent
`6,331,415 (NOT FILED)
`
`1071
`
`Stenesh, Dictionary of Biochemistry, 203, 205,
`220, 256 (1975)
`
`1072
`
`Pauza et al., Genes Encoding Escherichia Coli
`Aspartate Transcarbamoylase: The pyrB-pyrI
`
`-
`
`Berg
`
`-
`
`Stenesh
`
`Pauza
`
`x
`
`

`

`
`
`
`
`Exhibit
`No.
`
`Description
`
`Abbreviation
`
`Operon, Proceedings of the National Academy of
`Sciences USA, 79:4020-4024 (1982)
`
`1073
`
`Wild et al., A Mutation in the Catalytic Cistron of
`Aspartate Carbamoyltransferase Affecting
`Catalysis, Regulatory Response and Holoenzyme
`Assembly, Nature, 292:373-375 (1981)
`
`1074 Reserved
`
`Roof et al., The Organization and Regulation of the
`pyrBI Operon in E. Coli Includes a Rho-
`Independent Attenuator Sequence, Molecular and
`General Genetics, 187:391-400 (1982)
`
`Wild
`
`-
`
`Roof
`
`1075
`
`1076
`
`Navre and Schachman, Synthesis of Aspartate
`Transcarbamoylase in Escherichia Coli:
`Transcriptional Regulation of the pyrB-pyrI
`Operon, Proceedings of the National Academy of
`Sciences USA, 80:1207-1211 (1983)
`
`Navre &
`Schachman
`
`1077 U.S. Patent No. 4,418,149 (NOT FILED)
`
`-
`
`1078
`
`1079
`
`Jolly et al., Isolation and Characterization of a
`Full-Length Expressible cDNA for Human
`Hypoxanthine Phosphoribosyltransferase,
`Proceedings of the National Academy of Sciences
`USA, 80:477-481 (1983) (NOT FILED)
`
`Jolly
`
`Stueber and Bujard, Transcription from Efficient
`Promoters Can Interfere with Plasmid
`Replication and Diminish Expression of Plasmid
`Specified Genes, The EMBO Journal, 1:1399-
`1404 (1982) (NOT FILED)
`
`Stueber 1982
`
`xi
`
`

`

`
`
`
`
`Exhibit
`No.
`
`1080
`
`Description
`
`Abbreviation
`
`Stueber et al., A Novel In Vitro Transcription-
`Translation System: Accurate and Efficient
`Synthesis of Single Proteins from Cloned DNA
`Sequences, The EMBO Journal, 3:3143-3148 (1984)
`(NOT FILED)
`
`Stueber 1984
`
`1081 US Patent No. 6,541,224 (NOT FILED)
`
`1082
`
`Notice of Deposition of Julie Davis in
`IPR2016-00710 (NOT FILED)
`
`-
`
`-
`
`1083
`
`Petition for Inter Partes Review of U.S. Patent
`No. 6,331,415 (NOT FILED)
`
`Petition
`
`1084
`
`Deposition Transcript of Kathryn Calame
`in IPR2016-00710 (NOT FILED)
`
`Calame Dep.
`Tr.
`
`1085 U.S. Patent No. 4,740,470 (NOT FILED)
`
`1086 U.S. Patent No. 4,237,224 (NOT FILED)
`
`1087 U.S. Patent No. 4,468,464 (NOT FILED)
`
`-
`
`-
`
`-
`
`1088
`
`Bera, The Story of the Cohen-Boyer Patents,
`Current Science, 96:760-763 (2009) (NOT FILED)
`
`Bera
`
`Settlement Agreement between Petitioner Mylan
`Pharmaceuticals Inc. and Patent Owner
`Genentech, Inc.
`
`1089
`
`(CONFIDENTIAL - FILED AS BOARD ONLY)
`
`1090 Rebuttal Declaration of Roger D. Kornberg in
`
`-
`
`-
`
`xii
`
`

`

`
`
`
`
`Exhibit
`No.
`
`Description
`
`Abbreviation
`
`Support of Petitioners’ Reply
`
`1091
`
`Declaration of Marc J. Shulman in Support of
`Petitioners’ Reply
`
`1092
`
`Declaration of Louis G. Dudney, CPA, CFF
`(PROTECTIVE ORDER MATERIAL)
`
`1093
`
`Declaration of Atsuo Ochi in Support of Merck’s
`Reply to Patent Owner’s Response
`
`1094 Declaration of Nobumichi Hozumi
`
`1095
`
`Maniatis, Molecular Cloning: A Laboratory
`Manual, Cold Spring Harbor Laboratory (1982)
`
`1096
`
`1097
`
`1098
`
`1099
`
`Wigler et al., Transfer of purified herpes virus
`thymidine kinase gene to cultured mouse cells,
`Cell 11(1):223-32 (1977)
`
`Wigler et al., Transformation of mammalian cells
`with genes from procaryotes and eucaryotes, Cell
`16(4):777-85 (1979)
`
`Walter L. Miller. Use of Recombinant DNA
`Technology for the Production of Polypeptides,
`Adv. Exp. Med. Biol., 118: 153-174 (1979)
`
`Turnbough et al., Attenuation Control of pyrBI
`Operon Expression in Escherichia coli K-12,
`Proc. Natl. Acad. Sci. USA, 80:368-372 (January
`1983)
`
`xiii
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`

`

`
`
`
`
`Description
`
`Abbreviation
`
`Exhibit
`No.
`
`1100
`
`Baptist, et al., Identification of the Salmonella
`typhimurium cysB Gene Product by Two-
`Dimensional Protein Electrophoresis, J. Bacter.
`151:495-499 (July 1982)
`
`1101
`
`Mosher, et al., Synthesis and Secretion of
`Thrombospondin by Cultured Human Endothelial
`Cells, J. Cell Biol. 93:343-348 (May 1982)
`
`1102
`
`Kornberg, Chromatin Structure: Oligomers of the
`Histones, Science 184:865 (1974)
`
`1103
`
`Kornberg, Chromatin Structure: A Repeating Unit
`of Histones and DNA, Science 184:868 (1974)
`
`1104
`
`Thomas & Kornberg, An octamer of histones in
`chromatin and free in solution, Proc. Nat’l Acad.
`Sci. USA 72:2626 (1975)
`
`1105
`
`Henderson’s Dictionary of Biological Terms at
`274 (9th ed. 1979)
`
`1106
`
`Stenesh, Dictionary of Biochemistry and
`Molecular Biology at 312, 333 (2nd ed. 1989)
`
`1107
`
`Dorland’s Illustrated Medical Dictionary at 1206
`(31st ed. 1990)
`
`1108
`
`Tirri, et al., Elsevier’s Dictionary of Biology at
`443 (1st ed. 1998)
`
`1109
`
`Kahl, The Dictionary of Gene Technology Terms
`at 305 (2001)
`
`xiv
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`

`

`
`
`
`
`Exhibit
`No.
`
`Description
`
`Abbreviation
`
`1110
`
`King, et al, Dictionary of Genetics at 288 (7th ed.
`2006)
`
`1111
`
`’715 (Morrison) File History, 1/3/92 Response
`and Oi & Morrison Declarations
`
`1112
`
`’715 (Morrison) File History, 8/23/93 Response
`and Herzenberg Declarations
`
`1113
`
`Deposition of John Fiddes Ph.D., taken in
`IPR2016-00710
`
`1114
`
`Deposition of Reiner Gentz, taken in IPR2016-
`00710
`
`1115
`
`Deposition of Reiner Gentz taken in IPR2015-
`01624
`
`1116
`
`Deposition of John Fiddes, Ph.D. taken in
`IPR2015-01624
`
`1117
`
`1118
`
`1119
`
`Shulman, Wilde, and Köhler, A better cell line for
`making hybridomas secreting specific antibodies.
`Nature 276: 269-270 (1978)
`
`Köhler, Georges, and Shulman. Immunoglobulin
`M mutants. European Journal of Immunology
`10.6 467-476 (1980)
`
`Hawley et al., N. Mutant immunoglobulin genes
`have repetitive DNA elements inserted into their
`intervening sequences. Proc Natl Acad Sci USA
`79, 7425-7429 (1982)
`
`xv
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`

`

`
`
`
`
`Exhibit
`No.
`
`Description
`
`Abbreviation
`
`1120
`
`Mulligan and Berg, Expression of a bacterial gene
`in mammalian cells. Science 209: 1422-1427
`(1980)
`
`1121
`
`Deposition of Julie Davis, taken in IPR2016-
`00710 (PROTECTIVE ORDER MATERIAL)
`
`1122
`
`Battersby and Grimes, 2008 Licensing Update at
`99-100 (2008)
`
`1123
`
`1124
`
`1125
`
`1126
`
`1127
`
`Swiss Pharma International AG v. Biogen Idec,
`IPR2016-00916, Patent Owner Preliminary
`Response, Paper 6
`
`Boehringer Ingelheim International GmbH et al.,
`Genentech, Inc. et al., IPR2015-00415, Patent
`Owner's Preliminary Response, Paper 10
`
`Boehringer Ingelheim International GmbH et al.,
`Genentech, Inc. et al. IPR2015-00417, Patent
`Owner Preliminary Response, Paper 9
`
`Mylan Pharmaceuticals, Inc. v. Genentech, Inc.,
`IPR2016-01693, Patent Owner's Preliminary
`Response, Paper 11
`
`Mylan Pharmaceuticals, Inc. v. Genentech, Inc.,
`IPR2016-01694, Patent Owner's Preliminary
`Response, Paper 9
`
`1128
`
`Application For Patent Term Extension for U.S.
`Patent No. 5,670,373
`
`xvi
`
`-
`
`-
`
`-
`
`-
`
`-
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`-
`
`-
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`-
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`-
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`

`

`
`
`
`
`Exhibit
`No.
`
`Description
`
`Abbreviation
`
`1129
`
`Application For Patent Term Extension for U.S.
`Patent No. 6,602,684
`
`1130
`
`Application For Patent Term Extension for U.S.
`Patent No. 7,097,840
`
`1131
`
`1132
`
`Coherus Biosciences Inc. v. AbbVie Biotechnology
`Ltd., IPR2016-00188, Patent Owner’s Preliminary
`Response, Paper 7
`
`Swiss Pharma International AG v. Biogen Idec,
`IPR2016-00915, Patent Owner Preliminary
`Response, Paper 6
`
`1133
`
`Application For Patent Term Extension for U.S.
`Patent No. 6,355,245
`
`1134
`
`Application For Patent Term Extension for U.S.
`Patent No. 7,166,285
`
`1135
`
`Application For Patent Term Extension for U.S.
`Patent No. 6,984,720
`
`1136
`
`Schorsch, Kristen. “How AbbVie has won the
`Humira fight – so far.” Crain’s Chicago
`Business,” November 5, 2016
`
`1137 Ochi, Binder: “DNA, RNA Works,” June 1982
`
`1138
`
`Ochi, Binder: “Gene Transfer, B cell
`hybridomas,” Jan. 1983
`
`1139 Coffino P, Knowles B, Nathenson SG, Scharff
`MD, Suppression of immunoglobulin synthesis by
`
`xvii
`
`-
`
`-
`
`-
`
`-
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`-
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`-
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`-
`
`-
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`-
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`-
`
`-
`
`

`

`
`
`
`
`Exhibit
`No.
`
`Description
`
`Abbreviation
`
`cellular hybridization, Nat New Biol. 1971 May
`19;231(20):87-90
`
`1140
`
`Hozumi et al., Abstract “Expression of Cloned
`Immunoglobulin Genes in Heterologous Cells,”
`Submitted to the Fifth International Congress of
`Immunology in Kyoto
`
`1141
`
`Exhibit 5 to the deposition of Reiner Gentz, taken
`in IPR2015-01624
`
`1142
`
`Exhibit 6 to the deposition of Reiner Gentz, taken
`in IPR2015-01624
`
`1143
`
`Exhibit 7 to the deposition of Reiner Gentz, taken
`in IPR2015-01624
`
`1144
`
`Expert Report of John Fiddes, Ph.D., in Bristol-
`Myers Squibb Company v. Genentech, Inc., and
`City of Hope, Case No. 2:13-cv-05400-MRP-JEM
`
`1145
`
`Declaration of John Fiddes, Ph.D., submitted in
`connection with IPR2015-01624
`
`1146
`
`Ochi, Binder: “Gene Transfer, B cell
`hybridomas,” Jul. 1982
`
`1147
`
`’715 (Morrison) File History, 11/1/94 Office
`Action
`
`1148
`
`Boulianne, G., Hozumi, N., Shulman, M.,
`Production of functional mouse/human antibody,
`Nature 312:643-46 (1984)
`
`xviii
`
`-
`
`-
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`-
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`-
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`-
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`-
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`-
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`-
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`-
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`

`

`
`
`
`
`Exhibit
`No.
`
`Description
`
`Abbreviation
`
`1149
`
`Markman Hearing Transcript in MedImmune v.
`Genentech, No. 03- 02567 (C.D. Cal.)
`
`1150 U.S. Patent No. 5,807,715
`
`
`
`-
`
`-
`
`xix
`
`

`

`
`
`I.
`
`INTRODUCTION: GENENTECH’S “UNCERTAINTY” AND
`“PREVAILING MINDSET” ARGUMENTS ARE CONTRARY TO
`THE CONTEMPORANEOUS EVIDENCE
`
`Before addressing the instituted grounds, Patent Owners Genentech and City
`
`of Hope (collectively “Genentech”) discuss at length their view of the state of art.
`
`Genentech argues that the “prevailing mindset” was a “one-polypeptide-per-host-
`
`cell approach” and that “uncertainty” in the field would have a prevented a POSA
`
`from expressing an antibody recombinantly. Paper 31, at 10-17. These arguments
`
`are incorrect and contradicted by contemporaneous facts.
`
`The contemporaneous facts directly contradict Genentech’s arguments.
`
`Before the work reflected in the ’415 patent was ever made public, three separate
`
`groups, including the authors of Ochi I and Oi that Genentech relies upon to
`
`support its arguments, acted contrary Genentech’s “uncertainty” and “prevailing
`
`mindset” arguments. Exs. 1012, 1040, 1111-12, 1147 & 1150.
`
`As explained by three co-authors of Ochi I—and corroborated by their
`
`contemporaneous documents—there was no “prevailing mindset” against or
`
`uncertainty in expressing the heavy and light chains in a single host cell. Ex. 1091,
`
`¶¶24-25; Ex. 1093, ¶¶14-15; Ex. 1094, ¶19. In 1982, the Ochi authors began to
`
`recombinantly express an antibody in one host cell. They first showed that an
`
`antibody light chain could be expressed recombinantly and assembled in vivo with
`
`a native heavy chain to form a functional antibody. Ex. 1091, ¶¶16-21; Ex. 1093,
`
`
`
`1
`
`

`

`
`
`¶¶10-13; Ex. 1094, ¶¶10-12. Far from creating uncertainty, the work on the light
`
`chain published in Ochi I validated their experimental protocols and motivated
`
`them to express a complete recombinant antibody. Exs. 1091, ¶21, 1093, ¶¶18-19,
`
`1094, ¶17. Accordingly, the Ochi authors thereafter began work to express the
`
`heavy and light chains in a single host cell, and ultimately published Ochi II in
`
`October 1983 – months before the subject matter of the ’415 patent was made
`
`public. The Ochi authors never contemplated using multiple host cells to express
`
`the heavy and light chains separately. Ex. 1091, ¶¶29-34; Ex. 1093, ¶¶18-19. As
`
`they explain, only the one-host-cell-approach allowed for in vivo assembly in a
`
`eukaryotic host cell, which was preferred. Ex. 1094, ¶14.
`
`Genentech’s citations to the work of others are out of context and do not
`
`reflect the state of the art in April 1983. For example, Genentech quotes Dr.
`
`Milstein’s statements in 1981 – two years before the ’415 patent’s priority date.
`
`However, significant advancements were made in the two years following Dr.
`
`Milstein’s work, including the Southern paper that further refined the pSV2 vector
`
`as a means of transducing eukaryotic host cells with multiple genes.
`
`Beyond the testimony of the Ochi co-authors and the contemporaneous
`
`records from 1982-83, Merck relies on the rebuttal testimony of Roger Kornberg,
`
`who won the Nobel Prize for identifying DNA transcription mechanisms, including
`
`
`
`2
`
`

`

`
`
`those underlying the strong promoters described in Bujard, to show that
`
`Genentech’s reading of this patent is incorrect.
`
`In contrast to Merck’s declarants, Genentech’s declarants lack any particular
`
`knowledge regarding the subject matter of the ’415 patent. Drs. Fiddes and Gentz,
`
`have never recombinantly expressed an antibody. Ex. 1116, 43:9-16; Ex. 1114,
`
`88:6-25. Dr. Fiddes, the only declarant who opined that the ’415 patent claims are
`
`not obvious, did not review the specification of the ’415 patent in connection with
`
`this matter. Ex. 1113, 58:1-17; 25:10-19. Instead, he “just focused on the
`
`claim[s]” and therefore could not identify any problem solved by the ’415 patent or
`
`any questions about its disclosure. Id., 82:8-83:13; 36:17-37:8; see also id., 25:10-
`
`19; 259:12-18. Genentech’s other expert, Dr. Gentz, was chosen because he
`
`worked in the Bujard lab. However, he had no involvement with the Bujard patent
`
`and does not know if the Bujard inventors ever tried to make antibodies using the
`
`techniques described in the patent. Ex. 1114, 88:10-89:24; Ex. 1115, 90:10-13,
`
`116:11-117:15.
`
`II. GROUND I: GENENTECH’S ARGUMENTS REGARDING THE
`COMBINATION OF BUJARD WITH RIGGS & ITAKURA SHOULD
`BE REJECTED
`
`A. Genentech’s Reading of Bujard Is Inappropriately Narrow
`
`Genentech seeks to limit Bujard’s disclosure to a discovery that “strong
`
`promoters can be stably cloned into a recombinant DNA construct if paired with a
`
`
`
`3
`
`

`

`
`
`‘balanced’ strong terminator.”2 Paper 31, at 25. However, Bujard does not simply
`
`disclose a research tool for identifying strong promoters. Paper 31, at 43; Ex.
`
`2019, ¶243. Bujard teaches that strong promoters should be used on a single
`
`vector to optimize the commercial production of polypeptides, including
`
`antibodies. Ex. 1002, 1:18-45; 6:53-7:20; 5:11-27; Ex. 1090, ¶66.
`
`1.
`
`Bujard Teaches A Method for Producing Antibodies
`
`It is undisputed that Bujard teaches that a vector containing the balanced
`
`promoter and terminator can be used with a “wide a variety of structural genes”
`
`“for production of proteins,” including antibodies. Ex. 1002, 4:14-15; 4:35-36;
`
`5:12-28. Despite this explicit disclosure, Genentech’s non-obviousness expert
`
`argues that Bujard’s reference to “immunoglobulins” did not suggest the
`
`production of antibodies “given the size and complexity of antibodies.” Ex. 2019,
`
`¶204. Yet, by April 1983, proteins more complex than immunoglobulins had been
`
`recombinantly made by co-expressing different polypeptides in a single host cell.
`
`Ex. 1090, ¶¶114-115. For example, in 1982, scientists used a single vector to
`
`express aspartate transcarbamylase (“ATCase”), which is composed of six catalytic
`
`and six regulatory polypeptides, with a molecular weight of 300,000 Daltons—
`
`2 Genentech’s repeated reference to Bujard’s abandonment (Paper 31, at
`25, 64) are legally irrelevant. Eolas Techs. Inc. v. Microsoft Corp., 399 F.3d 1325,
`1334 (Fed. Cir. 2005). Likewise with Genentech’s allegation that Bujard is not a
`well known patent. Paper 31, at 28; In re Carlson, 983 F.2d 1032, 1037 (1992) (A
`POSA “is charged with knowledge of all of the contents of the relevant art.”).
`
`
`
`4
`
`

`

`
`
`nearly twice the size of a typical antibody. Id., ¶115; Ex. 2019, ¶43. Dr. Fiddes
`
`admits he did not consider this fact in rendering his opinions. Ex. 1113, 251:11-
`
`15.
`
`Citing two factually distinguishable Board decisions, Genentech also argues
`
`that Bujard’s identification of antibodies is “legally insufficient” because Bujard
`
`identifies antibodies in a “laundry list” of proteins. Paper 31, at 27. That is not the
`
`law. Less than four months ago, the Federal Circuit affirmed a Board obviousness
`
`determination where the patent at issue claimed a particular elastomer for use in a
`
`vascular stent and the only prior art disclosure of the specific elastomer was from a
`
`long list of elastomers that could be used in medical devices. In re Ethicon, Inc.,
`
`844 F.3d 1344, 1349-50 (Fed. Cir. 2017); see also In re Bode, 550 F.2d 656, 661
`
`(C.C.P.A. 1977) (A prior art reference “must be evaluated for all it teaches….”).
`
`Genentech alleges that Bujard’s list of proteins could not result in a “novel
`
`method of producing antibodies.” Paper 31, at 28. However, as the ’415 patent
`
`itself admits, the techniques needed for recombinant antibody expression were
`
`known as of April 1983. Ex. 1001, 4:6-50. There are no special techniques needed
`
`to recombinantly express an antibody. Ex. 1090, ¶¶113, 125. The fact that Bujard
`
`explicitly confirms the general applicability of its method reinforces what a POSA
`
`would have already known – that recombinant DNA technology is useful for
`
`synthesizing a wide variety of proteins, including large proteins such as antibodies.
`
`
`
`5
`
`

`

`
`
`Likewise, Genentech alleges that the list of “proteins of interest” should be
`
`disregarded because it was copied from other patents. Paper 31, at 27-28.
`
`However, while a portion of Bujard’s list overlaps with other patents, Bujard
`
`intentionally broadened the list to include “immunoglobulins, e.g. IgA, IgD, IgE,
`
`IgG and IgM and fragments thereof,” which is not found in the patents cited by
`
`Genentech. Compare Ex. 1002, 4:32-34 with Exs. 2004, 2036-40, 2042-59; see
`
`also Ex. 1113, at 194-197. A POSA would thus conclude that the Bujard inventors
`
`specifically added antibody proteins to their list because their method is fully
`
`applicable to antibodies..
`
`Finally, Genentech asserts that because Dr. Gentz personally “worked in Dr.
`
`Bujard’s lab in the early 1980s [and] did not use Bujard’s technique to co-express
`
`the subunits of a multimeric eukaryotic protein,” a POSA would not have used
`
`Bujard for that purpose. Paper 31, at 29. However, Dr. Gentz did not join the
`
`Bujard lab until after the Bujard patent application was filed. He never discussed
`
`the patent with anyone in the Bujard lab or with co-inventors Stanley Cohen and
`
`Annie Chang. Ex. 1114, 24:18-25:18; 26:4-27:5. Dr. Gentz does not know if the
`
`Bujard inventors tried to make antibodies using the techniques described in the
`
`patent. Ex. 1115, 116:11-117:15.
`
`
`
`6
`
`

`

`
`
`2.
`
`Bujard Teaches the Use of Co-Expression of Multiple Genes
`of Interest in a Single Host Cell
`
`Genentech argues that Bujard does not teach or suggest the co-expression of
`
`multiple genes of interest in a single host cell. Paper 31, at 24-25. In making these
`
`arguments, Genentech ignores Bujard’s express language and the knowledge of a
`
`POSA. The Board should reject these arguments.
`
`The Bujard vector allows for the co-expression of multiple genes of interest
`
`in a single host cell. The vector Bujard describes is gene