UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`MERCK SHARP & DOHME CORP.
`Petitioner
`
`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. 2016-01373
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 6,331,415
`UNDER 35 U.S.C. §§ 311-319 AND 37 C.F.R. §§ 42.100 et seq.
`
`

`

`TABLE OF CONTENTS
`
`I.
`
`II.
`
`III.
`
`IV.
`
`V.
`
`INTRODUCTION ...........................................................................................1
`
`OVERVIEW OF THE ’415 PATENT ............................................................4
`
`A.
`
`B.
`
`C.
`
`D.
`
`The ’415 Patent Specification ...............................................................4
`
`The Challenged Claims .........................................................................6
`
`Construction Of The Challenged Claims ..............................................7
`
`The Prosecution History Of The ’415 Patent........................................7
`
`1.
`
`2.
`
`Interference With The Boss Patent .............................................8
`
`Ex Parte Reexamination Of The ’415 Patent..............................8
`
`PERSON OF ORDINARY SKILL IN THE ART ........................................11
`
`IDENTIFICATION OF THE CHALLENGE (37 C.F.R. §§ 42.104(b))......12
`
`THE PRIOR ART..........................................................................................13
`
`A.
`
`The State Of The Prior Art..................................................................13
`
`1.
`
`2.
`
`3.
`
`4.
`
`Recombinant DNA Technology Was Well Understood
`Prior To April 1983...................................................................13
`
`The Actual “Prevailing Mindset” In 1983 Was That
`Recombinant DNA Technology Could Be Used To
`Produce Multiple Proteins Of Interest In A Single Host
`Cell ............................................................................................16
`
`The Techniques For In Vitro Recovery And
`Reconstitution Of Complex Eukaryotic Proteins Were
`Well-Known In The Prior Art...................................................20
`
`By April 1983, The Limitations Of Hybridoma
`Technology Were Well-Known................................................22
`
`B.
`
`Overview Of The Cited Prior Art........................................................23
`
`i
`
`

`

`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`The Axel Patent Teaches That Antibodies Can Be
`Recombinantly Expressed In Eukaryotic Host Cells................23
`
`The Mulligan Papers Disclose An Improved Vector That
`Expresses Multiple Genes Of Interest And That Is Useful
`In A Wide Variety Of Eukaryotic Host Cells...........................27
`
`Prof. Berg’s Nobel Article Explicitly Teaches The
`Expression of Multiple, Different Genes Of Interest From
`A Single Vector In A Single Host Cell.....................................31
`
`Southern Discloses A Two Vector System With Distinct
`Selectable Markers....................................................................32
`
`The Builder Patent Discloses Techniques For In Vitro
`Recovery And Reconstitution Of Recombinantly
`Expressed Proteins....................................................................35
`
`C.
`
`Near Simultaneous Invention Of The Claimed Invention By
`Three Research Groups Working Independently................................36
`
`VI.
`
`EXPLANATION OF GROUNDS OF UNPATENTABILITY (37
`C.F.R. § 42.104(b)(4))...................................................................................38
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`Ground 1: The Mulligan Papers Combined With The Axel
`Patent Render Claims 1, 3-4, 11-12, 14-17, 19, And 33 Of The
`’415 Patent Obvious ............................................................................38
`
`Ground 2: The Mulligan Papers Combined With the Axel
`Patent In Further View Of The Nobel Article Render Claims 1,
`3-4, 11-12, 14-17, 19, And 33 Of The ’415 Patent Obvious ..............48
`
`Ground 3: The Mulligan Papers Combined With The Axel
`Patent In Further View Of The Builder Patent Render Claims 1,
`3-4, 11-12, 14-17, 19, And 33 Of The ’415 Patent Obvious ..............49
`
`Ground 4: Southern Combined With The Axel Patent Render
`Claims 1-2, 11-12, 14, 18-20 And 33 Of The ’415 Patent
`Obvious................................................................................................51
`
`Ground 5: Southern Combined With The Axel Patent In
`Further View Of The Builder Patent Render Claims 1-2, 11-12,
`14, 18-20 And 33 Of The ’415 Patent Obvious ..................................54
`
`ii
`
`

`

`F.
`
`G.
`
`The Near Simultaneous Invention Of The Claimed Subject
`Matter By Three Separate Research Groups Supports A Finding
`Of Obviousness ...................................................................................55
`
`Secondary Considerations Do Not Support A Finding Of Non-
`Obviousness.........................................................................................56
`
`1.
`
`2.
`
`3.
`
`Licensing Does Not Support Non-Obviousness .......................56
`
`Commercial Success Does Not Support Non-
`Obviousness ..............................................................................57
`
`There Was No Skepticism That Antibodies Could Be
`Produced Recombinantly..........................................................58
`
`H.
`
`This Petition Is Not Duplicative Of Other IPRs Or Of Previous
`Arguments Presented During Prosecution ..........................................59
`
`VII. MANDATORY NOTICES (37 C.F.R. § 42.8).............................................62
`
`A.
`
`B.
`
`C.
`
`Real Party-In-Interest Under 37 C.F.R. § 42.8(b)(1)..........................62
`
`Related Matters Under 37 C.F.R. § 42.8(b)(2) ...................................62
`
`Lead and BackUp Counsel and Service Information Under 37
`C.F.R. § 42.8(b)(3)-(4)........................................................................63
`
`VIII. IPR REQUIREMENTS (37 C.F.R. §§ 42.101, 42.104, and 42.108)............64
`
`A.
`
`Grounds for Standing (37 C.F.R. § 42.104(a)) ...................................64
`
`IX.
`
`X.
`
`PAYMENT OF FEES (37 C.F.R. § 42.15(a) AND § 42.103)) ....................64
`
`CONCLUSION..............................................................................................64
`
`iii
`
`

`

`TABLE OF AUTHORITIES
`
`Cases
`
`Page
`
`In re Applied Materials, Inc.,
`692 F.3d 1289 (Fed. Cir. 2012) ..........................................................................58
`Cabilly v. Boss,
`55 U.S.P.Q. 2d 1238 (Bd. Pat. App. & Int. 1998) ................................................8
`Conopco, Inc. v. Procter & Gamble Co., IPR2013-00505,
`2014 WL 1253037 (PTAB Feb. 12, 2014) .........................................................62
`EWP Corp. v. Reliance Universal, Inc.,
`755 F.2d 898 (Fed. Cir. 1985) ............................................................................57
`Ecolochem, Inc. v. Southern Cal. Edison Co.,
`227 F.3d 1361 (Fed. Cir. 2000) ..........................................................................55
`Geneva Pharms., Inc. v. GlaxoSmithKline PLC,
`349 F.3d 1373 (Fed. Cir. 2003) ..........................................................................62
`Geo M Martin Co. v. All Mach. Sys. Int’l LLC,
`618 F.3d 1294 (Fed. Cir. 2010) ..........................................................................55
`HTC Corp. v. NFC Tech., LLC
`IPR2015-00384, Paper 11 at 9-11 ......................................................................59
`Iron Grip Barbell Co. v. USA Sports, Inc.,
`392 F.3d 1317 (Fed. Cir. 2004) ..........................................................................57
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007)................................................................................42, 43, 45
`In re Kemps,
`97 F.3d 1427 (Fed. Cir. 1996) ............................................................................42
`Leapfrog Enters., Inc. v. Fisher-Price, Inc.,
`485 F.3d 1157 (Fed. Cir. 2007) ..........................................................................41
`Microsoft Corp. v. Parallel Networks Licensing, LLC
`IPR2015-00483, Paper 10 at 15 (Jul. 15, 2015) .................................................61
`Petroleum Geo-Services Inc. v. WesternGeco LLC,
`IPR2015-01478, 2015 WL 1276718 (PTAB Mar. 17, 2015).............................56
`Pharmastem Therapeutics, Inc. v. Viacell, Inc.,
`491 F.3d 1342 (Fed. Cir. 2007) ..........................................................................41
`Research in Motion Corp. v. WI-LAN USA, Inc.,
`IPR2013-00126, 2013 WL 8563788 (PTAB June 20, 2013) ............................61
`
`iv
`
`

`

`Ritchie v. Vast Res., Inc.,
`563 F.3d 1334 (Fed. Cir. 2009) ..........................................................................57
`Sega of Am., Inc. v. Uniloc USA, Inc.,
`IPR2015-01453, 2015 WL 1090311 (PTAB Mar. 10, 2015).............................56
`Statutes & Regulations
`35 U.S.C. § 102.................................................................................................passim
`35 U.S.C. § 103............................................................................................12, 13, 62
`35 U.S.C. § 146......................................................................................................8, 9
`35 U.S.C. § 315(a)-(b) .............................................................................................64
`35 U.S.C. § 325(d) .............................................................................................59, 60
`37 C.F.R. § 42.8 .................................................................................................62, 63
`37 C.F.R. § 42.10(b) ................................................................................................63
`37 C.F.R. § 42.15(a).................................................................................................64
`37 C.F.R. § 42.101 ...................................................................................................64
`37 C.F.R. § 42.103(a)...............................................................................................64
`37 C.F.R. § 42.104 .................................................................................12, 13, 38, 64
`
`v
`
`

`

`Exhibit
`No.
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`
`EXHIBIT LIST
`
`Exhibit Description
`
`U.S. Patent No. 6,331,415
`
`R.C. Mulligan and P. Berg, Expression of a Bacterial Gene in
`Mammalian Cells, Science, 209:1422-27 (1980)
`
`R.C. Mulligan and P. Berg, Selection for Animal Cells That Express
`the Escherichia coli Gene Coding for Xanthine-Guanine
`Phosphoribosyltransferase, Proc. Natl. Acad. Sci. USA, 78(4):2072-
`76 (1981)
`
`P. Berg, Dissections and Reconstructions of Genes and
`Chromosomes, Science, 213:296-303 (1981)
`
`P.J. Southern and P. Berg, Transformation of Mammalian Cells to
`Antibiotic Resistance with a Bacterial Gene Under Control of the
`SV40 Early Region Promoter, J. Mol. Appl. Genet., 1(4):327-341
`(1982)
`
`U.S. Patent No. 4,399,216
`
`U.S. Patent No. 4,511,502
`
`Declaration of Richard A. Lerner in Support of Merck’s Petition for
`Inter Partes Review of U.S. Patent No. 6,331,415
`
`Declaration of Roger D. Kornberg in Support of Merck’s Petition for
`Inter Partes Review of U.S. Patent No. 6,331,415
`
`’415 Patent Reexamination, Office Action dated 2/16/07
`
`’415 Patent Reexamination, Owners’ Resp. dated 11/25/05
`
`’415 Patent Reexamination, Owners’ Resp. (5/21/07)
`
`’415 Patent File History, Amendment
`
`’415 Patent File History, Paper No. 14
`
`vi
`
`

`

`Exhibit
`No.
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`Exhibit Description
`
`’415 Patent File History, Paper No. 18
`
`U.S. Patent No. 4,816,567
`
`D. Rice and D. Baltimore, Regulated Expression of an
`Immunoglobulin K Gene Introduced into a Mouse Lymphoid Cell Line,
`Proc. Natl. Acad. Sci. USA, 79:7862-7865 (1982)
`
`A. Ochi et al., Transfer of a Cloned Immunoglobulin Light-Chain
`Gene to Mutant Hybridoma Cells Restores Specific Antibody
`Production, Nature, 302:340-342 (1983)
`
`’415 Patent Reexamination, Office Action dated 9/13/05
`
`’415 Patent Reexamination, Office Action dated 8/16/06
`
`’415 Patent Reexamination, Office Action dated 2/25/08
`
`’415 Patent Reexamination, Owners’ Resp. dated 10/30/06
`
`’415 Patent Reexamination, Owners’ Resp. dated 6/6/08
`
`’415 Patent Reexamination, Appeal Brief
`
`McKnight Declaration dated 5/18/07
`
`Harris Declaration dated 10/26/06
`
`’415 Patent Reexamination, Notice of Intent to Issue Ex Parte
`Reexamination
`
`U.S. Patent No. 4,237,224
`
`M. Wigler et al., Transfer of Purified Herpes Virus Thymidine
`Kinase Gene to Cultured Mouse Cells, Cell, 11:223-232 (1977)
`M. Wigler et al., Biochemical Transfer of Single-Copy Eucaryotic
`Genes using Total Cellular DNA as Donor, Cell, 14:725-731 (1978)
`M. Wigler et al., DNA-Mediated Transfer of the Adenine
`Phosphoribosyltransferase Locus into Mammalian Cells, Proc. Natl.
`
`vii
`
`

`

`Exhibit
`No.
`
`Exhibit Description
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`1038
`
`1039
`
`1040
`
`1041
`
`Acad. Sci. USA 76(3):1373-1376 (1979)
`
`M. Wigler et al., Transformation of Mammalian Cells with Genes
`from Prokaryotes and Eukaryotes, Cell, 16:777-785 (1979)
`
`M. Wigler et al., Transformation of Mammalian Cells with
`Prokaryotic and Eukaryotic Genes, Eucaryotic Gene Regulation
`Proc. Inc.-UCLA Symposia, R. Axel and T. Maniatis, Eds,
`Academic Press, 457-475 (1979)
`
`B. Wold and M. Wigler et al., Introduction and Expression of the
`Rabbit -Globin Gene in Mouse Fibroblasts, Proc. Natl. Acad. Sci.
`USA, 76(11):5684-5688 (1979)
`
`M. Wigler et al., Transformation of Mammalian Cells with an
`Amplifiable Dominant-Acting Gene, Proc. Natl. Acad. Sci. USA,
`77(6):3567-70 (1980)
`
`E.C. Lai et al., Ovalbumin is Synthesized in Mouse Cells
`Transformed with the Natural Chicken Ovalbumin Gene, Proc. Natl.
`Acad. Sci. USA, 77(1):244-248 (1980)
`
`L.H. Graf, Jr., et al., Transformation of the Gene Hypoxanthine
`Phosphoribosyltransferase, Somatic Cell Genetics, 5(6):1031-1044
`(1979)
`
`N. Mantei et al., Rabbit B-Globin mRNA Production in Mouse L
`Cells Transformed with Cloned Rabbit B-Globin Chromosomal
`DNA, Nature 281:40-46 (1979)
`
`U.S. Patent No. 4,487,835
`
`R.E. Schrohenloher & R.B. Hester, Reassembly of Immunoglobulin
`M Heavy and Light Chains in Vitro, Scand. J. Immunol., Vol. 5:637-
`646 (1976)
`
`Columbia, Co-transformation, Commercialization & Controversy, The
`Axel Patent Litigation, Harvard Journal of Law & Technology 17:2,
`584-618 (2004)
`
`viii
`
`

`

`Exhibit
`No.
`1042
`
`1043
`
`1044
`
`1045
`
`1046
`
`1047
`
`1048
`
`1049
`
`1050
`
`1051
`
`1052
`
`1053
`
`Exhibit Description
`
`D. Canaani and P. Berg, Regulated Expression of Human Interferon β1
`Gene After Transduction into Cultured Mouse and Rabbit Cells, Proc.
`Natl. Acad. Sci. USA, 79:5166-5170 (1982)
`
`A. Ochi et al., Functional Immunoglobulin M Production after
`Transfection of Cloned Immunoglobulin Heavy and Light Chain Genes
`into Lymphoid Cells, Proc. Natl. Acad. Sci. USA, 80:6351-6355
`(July 11, 1983)
`
`U.S. Patent No. 5,807,715
`
`Vernon T. Oi et al., Immunoglobulin Gene Expression in Transformed
`Lymphoid Cells, Proc. Natl. Acad. Sci. USA, 80:825-829 (1983)
`
`’715 (Morrison) File History, 1/3/92 Response and Oi & Morrison
`Declarations
`
`’715 (Morrison) File History, 8/23/93 Response and Herzenberg
`Declarations
`
`’715 (Morrison) File History, 11/1/94 Office Action
`
`U.S. Patent No. 4,816,397
`
`C.D. Pauza et al., Genes Encoding Escherichia coli Aspartate
`Transcarbamoylase: The pyrB-pyrI Operon, Proc. Natl. Acad. Sci.
`USA, 79:4020-4024 (1982)
`
`J.R. Wild, A Mutation in the Catalytic Cistron of Aspartate
`Carbamoyltransferase Affecting Catalysis, Regulatory Response and
`Holoenzyme Assembly, Nature 292:373-375 (1981)
`
`W.D. Roof, The Organization and Regulation of the pyrBI Operon in
`E. coli Includes a Rho-Independent Attenuator Sequence, Mol Gen
`Genet 187:391-400 (1982)
`
`C.L. Turnbough et al., Attenuation Control of pyrBI Operon
`Expression in Escherichia coli K-12, Proc. Natl. Acad. Sci. USA,
`80:368-372 (1983)
`
`ix
`
`

`

`Exhibit
`No.
`1054
`
`1055
`
`1056
`
`1057
`
`1058
`
`1059
`
`1060
`
`1061
`
`1062
`
`1063
`
`1064
`
`Exhibit Description
`
`M. Navre and H.K. Schachman, Synthesis of Aspartate
`Transcarbamoylase in Escherichia coli: Transcriptional Regulation of
`the pyrB-pyrI Operon, Proc. Natl. Acad. Sci. USA, 80:1207-1211
`(1983)
`
`T. Maniatis et al., Molecular Cloning, A Laboratory Manual, Cold
`Spring Harbor Laboratory (1982)
`
`T.W. Dolby et al., Cloning and Partial Nucleotide Sequence of Human
`Immunoglobulin µ Chain cDNA from B Cells and Mouse-Human
`Hybridomas, Proc. Natl. Acad. Sci. USA, 77(10):6027-6031 (1980)
`
`F.T. Liu et al., Cloning and Nucleotide Sequence of Mouse
`Immunoglobulin ε Chain cDNA, Proc. Natl. Acad. Sci. USA,
`79:7852-56 (1982)
`
`J.L. Fox, Columbia Awarded Biotechnology Patent, Science
`221(4614):933 (1983)
`
`Colaianni, A. et al, Columbia University’s Axel Patents: Technology
`Transfer and Implications for the Bayh-Dole Act, The Milbank
`Quarterly, Vol. 87-3:683–715 (2009)
`
`D.H. Hamer et al., Expression of the Chromosomal Mouse βmaj-globin
`Gene Cloned in SV40, Nature 281:35-40 (1979)
`
`G.N. Pavlakis et al., Expression of Two Human Growth Hormone
`Genes in Monkey Cells Infected by Simian Virus 40 Recombinants,
`Proc. Natl. Acad. Sci. USA 78(12):7398-7402 (1981)
`
`P.W. Gray et al., Expression of Human Immune Interferon cDNA in E.
`Coli and Monkey Cells, Nature 295:503-508 (1982)
`
`O. Laub et al., Expression of the Human Insulin Gene and cDNA in a
`Heterologous Mammalian System, J. Biol. Chem. 258:6043-6050
`(1983)
`
`C.C. Liu et al., Direct Expression of Hepatitis B Surface Antigen in
`
`x
`
`

`

`Exhibit
`No.
`
`Exhibit Description
`
`Monkey Cells from an SV40 Vector, DNA 1:213-221 (1982)
`
`1065
`
`1066
`
`1067
`
`1068
`
`1069
`
`1070
`
`1071
`
`1072
`
`1073
`
`1074
`
`U.S. Patent No. 5,840,545
`
`European Patent No. EP 0 044 722
`
`D.V. Goeddel et al., Expression in Escherichia Coli of Chemically
`Synthesized Genes for Human Insulin, Proc. Natl. Acad. Sci. USA
`76(1):106-110 (Jan. 1979)
`
`K. Itakura et al., Expression in Escherichia Coli of a Chemically
`Synthesized Gene for the Hormone Somatostatin, Science 198 (4321),
`1056-1063 (1977)
`
`J. Shine et al., Expression of Cloned Beta-Endorphin Gene Sequences
`by Escherichia Coli, Nature 285(5765):456-463 (1980)
`
`Declaration of Michael H. Wigler in Support of Merck’s Petition for
`Inter Partes Review of U.S. Patent No. 6,331,415
`
`K. Weber and D. Kuter, Reversible Denaturation of Enzymes by
`Sodium Dodecyl Sulfate, J. Biol. Chem. 246:4504-4509 (1971)
`
`W.L. Miller, Use of Recombinant DNA Technology for the Production
`of Polypeptides, Adv. Exp. Med. Biol. 118:153-174 (1979)
`
`US. Patent No. 4,196,265
`
`P.A.W. Edwards, Some properties and applications of monoclonal
`antibodies, Biochem J. 200:1-10 (1981)
`
`xi
`
`

`

`Merck Sharp & Dohme Corp. (“Petitioner”) requests inter partes review
`
`(“IPR”) pursuant to 35 U.S.C. §§ 311-319 and 37 C.F.R. §§ 42.100 et seq. of claims
`
`1-4, 11-12, 14-20, and 33 (the “Challenged Claims”) of U.S. Patent No. 6,331,415
`
`(Ex. 1001), which issued on December 18, 2001 to Cabilly et al. and is assigned to
`
`Genentech, Inc. and City of Hope (“Owners”). Petitioner submits herewith the
`
`supporting declarations of Prof. Roger Kornberg, a Nobel Laureate in protein
`
`chemistry; Prof. Richard Lerner, a pioneer in recombinant antibody techniques who
`
`revolutionized means for making monoclonal antibody therapeutics; and Prof.
`
`Michael Wigler, the lead developer of the “Wigler method” of co-transformation, a
`
`seminal platform for eukaryotic protein production.
`
`I.
`
`INTRODUCTION
`
`The ’415 patent relates to the production of immunoglobulins, or antibodies,
`
`using recombinant DNA techniques.1 In broad terms, the ’415 patent claims the
`
`production and assembly of immunoglobulin heavy and light chains using
`
`recombinant DNA techniques in a single host cell. However, recombinant DNA
`
`technology was a well-established means for producing complex eukaryotic proteins
`
`prior to the filing of the ’415 patent. And the structure and function of
`
`immunoglobulins had been known for years prior to the ’415 patent.
`
`
`term “immunoglobulin”
`the claim
`1 For purposes of
`this Petition,
`interchangeable with “antibody.” Ex. 1001, 1:23-24.
`
`is
`
`1
`
`

`

`It is undisputed that the prior art U.S. Patent No. 4,399,216 (“the Axel
`
`patent,” Ex. 1006), explicitly taught the use of recombinant DNA techniques to make
`
`antibodies in eukaryotic host cells. IPR2016-00383, Preliminary Response, 45 n.11.
`
`Owners have consistently sought to distinguish the prior art, including the Axel
`
`patent, based on the requirement in the Challenged Claims that the heavy and light
`
`chains be expressed in a single host cell. According to Owners, the “prevailing
`
`mindset” among persons of ordinary skill in the art (“POSAs”) in April 1983 was that
`
`only one desired protein “of interest”2 should be expressed in a single host cell. In
`
`other words, a POSA seeking to recombinantly express an immunoglobulin would
`
`have used two host cells, one expressing the heavy chain and the other expressing the
`
`light chain.
`
`Owners’ notion of a “prevailing mindset” is simply a fiction that was created
`
`years after the ’415 patent was filed and is refuted by the prior art. Numerous prior art
`
`references, never previously cited to the Patent and Trademark Office (“PTO”), teach
`
`that multiple, different, eukaryotic proteins of interest can and should be
`
`recombinantly co-expressed in a single host cell. Significantly, Paul Berg, who was
`
`awarded the Nobel Prize in Chemistry for his development of recombinant DNA,
`
`provided a high-profile disclosure of this teaching.
`
`
`2 A “protein of interest” is any desired protein sought to be isolated from the host
`cell after it is recombinantly expressed. Ex. 1012, 49; Ex. 1009, ¶67.
`
`2
`
`

`

`In 1980, Prof. Berg developed a new expression vector for use in eukaryotic
`
`host cells―the pSV2 vector—which explicitly extended the Axel patent techniques to
`
`a wider variety of eukaryotic host cells. In Prof. Berg’s publications, he describes
`
`how a single pSV2 vector can be used to co-express multiple proteins of interest.
`
`Likewise, Prof. Berg’s Nobel Lecture, given in December 1980 and published in
`
`1981, gives detailed teachings on how a single pSV2 vector can be used to “transduce
`
`several genes of interest simultaneously” and co-express several different eukaryotic
`
`proteins. The single vector would, of course, co-express the multiple proteins of
`
`interest in a single eukaryotic host cell.
`
`Prof. Berg’s publications directly refute Owners’ arguments that the prior art
`
`“contains no suggestion to co-express multiple eukaryotic proteins of interest in a
`
`single host cell.” IPR2015-01624, Owners’ Response, 37 n.5. Significantly,
`
`researchers followed Prof. Berg’s teachings and used the pSV2 vector to co-express
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`heavy and light antibody chains together in a single eukaryotic host cell.
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`Apart from their inaccurate description of the “prevailing mindset,” Owners
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`cannot point to anything innovative in the ’415 patent. The ’415 patent simply uses
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`known recombinant DNA techniques to attempt heavy and light chain co-expression.
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`As presented in the Grounds below, the Challenged Claims are obvious in view of the
`
`prior art.
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`3
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`

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`II. OVERVIEW OF THE ’415 PATENT
`
`A.
`
`The ’415 Patent Specification
`
`The ’415 patent contains an extensive Background section detailing the prior
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`art relating to both recombinant DNA technology and immunoglobulins, all of
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`which was within the common knowledge of a POSA before April 1983. Ex.
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`1001, 1:12-4:50; Ex. 1008, ¶¶49-52; Ex. 1009, ¶39.
`
`The ’415 patent admits that “[r]ecombinant DNA technology has reached
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`sufficient sophistication that it includes a repertoire of techniques for cloning and
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`expression of gene sequences.” Ex. 1001, 4:7-9. The ’415 patent then lists the
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`known techniques, including the use of DNA cloning, expression vectors and
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`transformation of host cells, and states that this technology is “now in hand.” Id.,
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`4:9-16. The specification makes no claim to have invented new recombinant DNA
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`techniques.
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`With respect to immunoglobulins, the ’415 patent states that “[t]he basic
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`immunoglobin structural unit in vertebrate systems is now well understood.” Id.,
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`3:17-18; Ex. 1008, ¶47. This basic structure includes two identical heavy chains
`
`and two identical light chains. Ex. 1001, 3:19-22. As shown in Figure 1 of the
`
`patent, the chains are covalently joined by disulfide bonds to form a “Y” shape:
`
`4
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`

`

`Id., 3:22-38. The heavy chain and light chain are encoded by separate DNA
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`sequences. Id., 1:48-51; Ex. 1008, ¶48; Ex. 1009, ¶46.
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`The recombinant DNA approach recited in the ’415 patent for making
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`immunoglobulins follows the same basic approach for any protein made
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`recombinantly: (1) the genetic material encoding the heavy and light chains is
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`identified and isolated (Ex. 1001, 11:28-12:3, 4:9-16); (2) the DNA encoding the
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`heavy and light chains is inserted into one or more expression vectors (id., 12:4-
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`16); (3) the expression vector(s) is/are introduced into suitable host cell(s) by a
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`process called “transformation” (id., 12:23-30, 4:21-24); (4) the host cell(s)
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`transcribe and translate the DNA, a process called “expression,” to produce the
`
`5
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`

`

`heavy and light chains (id., 12:23-36, 4:24-29); and (5) the produced chains are
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`recovered from the cell culture by methods known in the art so as to recover
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`reconstituted antibody. Id., 12:17-22, 12:36-56; 4:29-32; Ex. 1008, ¶¶49-52; Ex.
`
`1009, ¶40. Indeed, the specification does not identify any aspect of using
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`recombinant DNA technology to produce immunoglobulins that is novel.
`
`Regarding the use of a single host cell, the ’415 patent states that
`
`co-expressing the heavy and light chains in a single host cell is merely a design
`
`choice, setting forth three “options” for recombinantly expressing the heavy and
`
`light chains: 1) transforming two different host cells, one with a light chain
`
`expression vector and the other with a heavy chain expression vector; 2)
`
`transforming a single host cell with two different vectors each containing the gene
`
`for the heavy or light chain; and 3) inserting the genes for the heavy and light
`
`chains in a single vector and thus a single host cell. Ex. 1001, 12:23-36; Ex. 1008,
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`¶146; Ex. 1009, ¶¶41-42. The specification does not specify a preference for any
`
`of these options. Id.
`
`B.
`
`The Challenged Claims
`
`Claims 1-4, 11-12, 14-20, and 33 are at issue in this Petition. Among the
`
`Challenged Claims, claims 1, 15, 18, and 33 are independent. Claims 1 and 33 are
`
`directed to methods of producing immunoglobulins; claim 15 is directed to a
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`vector; and claim 18 is directed to a transformed cell.
`
`6
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`

`

`All of the Challenged Claims relate to expressing DNA encoding the heavy
`
`and light chains in a single host cell. The challenged method claims require that a
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`single host cell “independently” express the heavy chain and light chain so that the
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`heavy and light chains “are produced as separate molecules.” Ex. 1001, 28:48-49;
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`30:40; Ex. 1009, ¶¶43, 48. The method claims also require assembly of the
`
`separate heavy and light chains into an immunoglobulin tetramer. Ex. 1001, 28:36;
`
`Ex. 1008, ¶55; Ex. 1009, ¶46; Ex. 1011, 46. This can occur either via in vitro
`
`assembly, in which the cell is lysed and the separate chains are assembled by
`
`chemical means or via in vivo assembly, in which the host cell uses its natural
`
`cellular machinery to assemble and secrete a complete immunoglobulin. Ex. 1001,
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`12:50-55; Ex. 1008, ¶55; Ex. 1009, ¶46; Ex. 1012, 29, n.8.
`
`C.
`
`Construction Of The Challenged Claims
`
`Petitioner submits that, for purposes of this IPR, no construction of any claim
`
`term is needed. Petitioner proposes that the claim terms take on their ordinary and
`
`customary meaning that the terms would have to a POSA in April 1983.
`
`D.
`
`The Prosecution History Of The ’415 Patent
`
`The application that issued as the ’415 patent did not initially include any
`
`claims having limitations directed to expressing the heavy and light chains in a
`
`single host cell. During prosecution, Owners provoked an interference with U.S.
`
`Patent No. 4,816,397 (“the Boss patent”), by copying the Boss patent’s claims
`
`7
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`

`

`reciting that limitation. Ex. 1013, 6-7. The copying of those claims was the first
`
`time that Owners added claim limitations directed to co-expression in a single host
`
`cell. Id.
`
`1.
`
`Interference With The Boss Patent
`
`On February 28, 1991, the PTO declared an interference between claims 1-
`
`18 of the Boss patent and the substantially identical claims 101-120 in the ’419
`
`application. Ex. 1014. The PTO awarded priority to Boss, holding that Owners
`
`had not established an actual reduction to practice before the Boss patent’s British
`
`priority date. Cabilly v. Boss, 55 U.S.P.Q.2d 1238 (Bd. Pat. App. & Int. 1998).
`
`Genentech filed an action under 35 U.S.C. § 146, and, following a confidential
`
`settlement of the § 146 action, priority of invention was ultimately awarded to
`
`Owners. Ex. 1015.
`
`2.
`
`Ex Parte Reexamination Of The ’415 Patent
`
`Rejections Over The Axel Patent
`a.
`In 2005, the PTO received separate requests seeking ex parte reexamination
`
`of the ’415 patent that were merged into a single proceeding. During the
`
`reexamination, the PTO repeatedly rejected the claims of the ’415 patent on
`
`obviousness-type double patenting grounds (“ODP”) based on the claims of the
`
`’415 patent’s parent, the Cabilly ’567 patent (Ex. 1016), in combination with
`
`various prior art references, including
`
`the Axel patent, Rice & Baltimore (Ex.
`
`1017), and Ochi I (Ex. 1018). Exs. 1010, 1019, 1020, and 1021.
`
`8
`
`

`

`The ODP rejections that relied on the Axel patent were based on the
`
`Examiner’s
`
`interpretations
`
`that Axel discloses
`
`the co-transformation and
`
`co-expression of heavy and light chains in a single host cell and thus makes up the
`
`“missing” teaching in the Cabilly ’567 patent to produce both the heavy and light
`
`chains in one host cell. Ex. 1019, 5; Ex. 1021, 28-30; Ex. 1010, 51. The Examiner
`
`maintained these positions throughout the reexamination, and ultimately issued a
`
`Final Office Action on that basis, among others. Ex. 1021, 29-30.
`
`b.
`
`Owners’ Arguments In Response To The Rejections
`
`i.
`
`Owners Concoct Their “Prevailing Mindset”
`Argument
`
`To overcome these rejections, Owners argued that POSAs would not have
`
`thought to co-express both the heavy and light chains in a single host cell because
`
`the “prevailing mindset” among POSAs in April 1983 was that only one
`
`“polypeptide of interest” should be expressed per host cell. Ex. 1023, 8.
`
`According to Owners, no prior art reference, including the Axel patent, taught
`
`co-expressing two different proteins of interest in a single host cell, and thus a
`
`POSA would have expressed the heavy and light chains in separate host cells. Id.
`
`Owners submitted seven Rule 132 expert declarations regarding the alleged
`
`“prevailing mindset.” Ex. 1024, 85-87. According to Owners’ declarants, the
`
`“prevailing mindset” would have led a POSA “to break down a complex project,
`
`such as production of a multimeric eukaryotic protein, into more manageable steps
`
`9
`
`

`

`(e.g., produce each constituent polypeptide of the multimer in a separate host
`
`cell).”3 Ex. 1023, 6-7.
`
`In making these arguments, Owners repeatedly took advantage of the one-
`
`sided nature of the ex parte reexamination process, arguing that the PTO must
`
`accept the veracity of Owners’ declarations: “The Examiner committed serious
`
`legal error by repeatedly substituting his own interpretations of the cited references
`
`for the well-reasoned opinions of qualified experts….
`
` Relevant § 1.132
`
`declaration evidence from a qualified expert is entitled to particular deference by
`
`the Office.” Ex. 1024, 86.
`
`As discussed below, Owners’ one-sided declarations do not accurately
`
`reflect the thinking of a POSA in 1983. Numerous prior art references taught
`
`co-expressing more than one “protein of interest” in a single host cell, and by
`
`1983, vectors had been designed with the specific goal of enabling the encoding of
`
`multiple genes of interest on a single vector for co-expression of several proteins of
`
`interest in a single host cell.
`
`ii.
`
`Owners Attempt to Re-Interpret the Meaning
`of “Antibody” in the Axel Patent
`
`Owners also challenged the ODP rejections in view of the Axel patent