UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`SANOFI-AVENTIS U.S. LLC AND
`REGENERON PHARMACEUTICALS, INC.,
`Petitioners
`v.
`
`GENENTECH, INC. AND CITY OF HOPE,
`Patent Owners
`
`U.S. Patent No. 6,331,415
`Appl. No. 07/205,419, filed June 10, 1988
`Issued: Dec. 18, 2001
`Title: Methods of Producing Immunoglobulins, Vectors
`and Transformed Host Cells for Use Therein
`
`IPR Trial No. IPR2015-01624
`_____________
`
`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.
`
`716894931
`
`

`

`TABLE OF CONTENTS
`
`Page
`
`I.
`
`II.
`
`INTRODUCTION ..........................................................................................1
`
`REQUIREMENTS FOR INTER PARTES REVIEW ...................................2
`
`A.
`
`B.
`
`Grounds for Standing (37 C.F.R. § 42.104(a)) ...................................2
`
`Identification of Challenge (37 C.F.R. § 42.104(b))............................2
`
`III. RELEVANT INFORMATION REGARDING THE '415 PATENT ............3
`
`A.
`
`B.
`
`Brief Description of the Challenged Patent .........................................3
`
`Discussion of the File History and Related Proceedings in the
`PTO.......................................................................................................7
`
`1.
`
`2.
`
`3.
`
`Prosecution of the '419 application............................................8
`
`Interference with the Boss Patent ..............................................8
`
`Ex Parte Reexamination of the '415 Patent................................9
`
`a.
`
`b.
`
`Rejections Over the Axel Patent......................................9
`
`Owners' Arguments in Response to the Rejections.......12
`
`i.
`
`ii.
`
`Owners Contrive a So-Called "Prevailing
`Mindset" before April 1983 that Only One
`Eukaryotic Protein of Interest Should Be
`Produced in a Transformed Host Cell.................12
`
`Owners Argue that the Axel Patent Does
`Not Disclose the Co-Expression of "One or
`More" Genes of Interest ......................................14
`
`C.
`
`D.
`
`Person of Ordinary Skill in the Art ....................................................15
`
`Claim Construction.............................................................................16
`
`IV. RELEVANT PRIOR ART ...........................................................................16
`
`A.
`
`Technology Background ....................................................................16
`
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`

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`TABLE OF CONTENTS
`(continued)
`
`Page
`
`1.
`
`2.
`
`3.
`
`The Sophistication of Recombinant DNA Technology
`Was Advanced by April 8, 1983, and Mammalian
`Proteins Were Being Made in Host Cells Transformed
`with Foreign Genes..................................................................16
`
`The Prior Art Taught Expression of Single
`Immunoglobulin Chains...........................................................18
`
`The Prevailing Mindset by April 1983 Was That One or
`More Proteins of Interest Could be Made in a Single Host
`Cell ...........................................................................................21
`
`B.
`
`References Underlying the Grounds for Rejection............................25
`
`1.
`
`2.
`
`3.
`
`4.
`
`Bujard Teaches Introducing and Expressing a "Plurality
`of Genes" in Bacterial or Mammalian Host Cells and
`Identifies "Immunoglobulins" as a Protein of Interest ............25
`
`Cohen & Boyer Teaches Introducing and Expressing
`"One or More Genes" in Bacteria and Identifies
`"Antibodies" as a Protein of Interest........................................28
`
`Riggs & Itakura Teaches Hybridomas as a Source of
`Antibody Genes and the In Vitro Assembly of Heavy and
`Light Chains.............................................................................32
`
`Southern Teaches One Host Cell Transformed with Two
`Vectors .....................................................................................33
`
`V.
`
`FULL STATEMENT OF PRECISE RELIEF REQUESTED AND
`THE REASONS THEREFORE (37 C.F.R. § 42.22(a)) ..............................34
`
`A.
`
`Explanation of Ground 1 for Unpatentability: Bujard
`Anticipates Claims 1, 3, 4, 9, 11, 12, 15-17, 19 and 33.....................34
`
`1.
`
`Bujard Anticipates Independent Claims 1, 15, 17 and 33 .......37
`
`VI. Bujard Anticipates Dependent Claims 3, 4, 9, 11, 12, 16 and 19 ................42
`
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`TABLE OF CONTENTS
`(continued)
`
`Page
`
`A.
`
`B.
`
`C.
`
`Explanation of Ground 2 for Unpatentability: Claims 1, 3, 4,
`11, 12, 14, 19 and 33 Are Obvious Over Bujard in View of
`Riggs & Itakura ..................................................................................44
`
`Explanation of Ground 3 for Unpatentability: Claims 1, 2, 18,
`20 and 33 Are Obvious Over Bujard in View of Southern................47
`
`Explanation of Ground 4 for Unpatentability: Claims 1, 3, 4,
`11, 12, 14 and 33 Are Obvious Over Cohen & Boyer in View of
`Riggs & Itakura ..................................................................................50
`
`1.
`
`2.
`
`The Disclosures of Cohen & Boyer.........................................50
`
`Cohen & Boyer in Combination with Riggs & Itakura's
`Teachings of In Vitro Assembly of Heavy and Light
`Chains Renders Obvious Claims 1, 3, 4, 11, 12, 14 and
`33..............................................................................................54
`
`D.
`
`Secondary Indicia of Non-Obviousness in the Public Record Do
`Not Rebut Petitioners' Prima Facie Case of Obviousness .................56
`
`VII. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8(a)(1).......................58
`
`A.
`
`B.
`
`C.
`
`Real Party-In-Interest Under 37 C.F.R. § 42.8(b)(1).........................58
`
`Related Matters Under 37 C.F.R. § 42.8(b)(2) ..................................59
`
`Lead and Back-up Counsel and Service Information Under 37
`C.F.R. § 42.8(b)(3), (4) ......................................................................59
`
`VIII. CONCLUSION.............................................................................................60
`
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`TABLE OF AUTHORITIES
`
`Page
`
`Cases
`Allergan v. Apotex,
`754 F. 3d 952 (Fed. Cir. 2014) ...........................................................................34
`
`Amgen v. Hoechst Marion Roussel,
`314 F.3d 1313 (Fed. Cir. 2003) ..........................................................................36
`
`In re Antor Media Corp.,
`689 F. 3d 1282 (Fed. Cir. 2012) .........................................................................36
`
`Bristol-Myers Squibb v. Ben Venue Labs.,
`246 F.3d 1368 (Fed. Cir. 2001) ..........................................................................36
`
`Cabilly v. Boss,
`55 U.S.P.Q.2d 1238 (Bd. Pat. App. & Int. 1998) .................................................8
`
`Callaway Golf Co. v. Acushnet Co.,
`576 F. 3d 1331 (Fed. Cir. 2009) .........................................................................49
`
`CBS Interactive Inc. v. Helferich Patent Licensing, LLC,
`IPR2013-00033...................................................................................................57
`
`Continental Can Co. USA v. Monsanto,
`948 F. 2d 1264 (Fed. Cir. 1991) .........................................................................35
`
`In re Cuozzo Speed Techs., LLC,
`No. 2014-1301, 2015 WL 4097949 (Fed. Cir. Jul. 8, 2015) ..............................16
`
`Dayco Prods. v. Total Containment,
`329 F.3d 1358 (Fed. Cir. 2003) ..........................................................................34
`
`In re Donohue,
`632 F.2d 123 (C.C.P.A. 1980)............................................................................35
`
`In re Gleave,
`560 F.3d 1331 (Fed. Cir. 2009) ....................................................................35, 36
`
`In re Graves,
`69 F.3d 1147 (Fed. Cir. 1995) ............................................................................35
`
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`
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`

`

`TABLE OF AUTHORITIES
`(continued)
`
`Page
`
`Hybritech v. Monoclonal Antibodies,
`802 F.2d 1367 (Fed. Cir. 1986) ..........................................................................36
`
`Iron Grip Barbell Co. v. USA Sports, Inc.,
`392 F.3d 1317 (Fed. Cir. 2004) ..........................................................................57
`
`King Pharms. v. Eon Labs,
`616 F.3d 1267 (Fed. Cir. 2010) ..........................................................................35
`
`Schering Corp. v. Geneva Pharmaceuticals,
`339 F. 3d 1373 (Fed. Cir. 2003) .........................................................................35
`
`SIBIA Neurosciences, Inc. v. Cadus Pharm. Corp.,
`225 F.3d 1349 (Fed. Cir. 2000) ..........................................................................57
`
`Standard Haven Prods. v. Gencor Indus.,
`953 F.2d 1360 (Fed. Cir. 1991) ..........................................................................35
`
`Vas-Cath v. Mahurkar,
`935 F.2d 1555 (Fed. Cir. 1991) ..........................................................................36
`
`In re Wiggins,
`488 F.2d 538 (C.C.P.A. 1973)............................................................................36
`
`Statutes
`
`35 U.S.C. § 120..........................................................................................................3
`
`35 U.S.C. § 146......................................................................................................7, 9
`
`35 U.S.C. § 311-319...................................................................................................1
`
`35 U.S.C. § 314(a) .....................................................................................................1
`
`Other Authorities
`
`37 C.F.R. § 42.8(a)(1)..............................................................................................58
`
`37 C.F.R. § 42.8(b)(1)..............................................................................................58
`
`37 C.F.R. § 42.8(b)(2)..............................................................................................59
`
`37 C.F.R. § 42.8(b)(3), (4).......................................................................................59
`
`716894931
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`

`

`TABLE OF AUTHORITIES
`(continued)
`
`Page
`37 C.F.R. § 42.104(a).................................................................................................2
`
`37 C.F.R. § 42.104(b) ................................................................................................2
`
`37 C.F.R. § 42.204(b) ................................................................................................3
`
`716894931
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`

`

`PETITION EXHIBIT LIST
`
`Exhibit
`No.
`
`1001
`
`1002
`
`1003
`
`1004
`
`Description
`
`U.S. Patent No. 6,331,415
`
`U.S. Patent No. 4,495,280
`
`Riggs and Itakura, Synthetic DNA and
`Medicine, American Journal of Human
`Genetics, 31:531-538 (1979)
`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, 1:327-341 (1982)
`
`1005
`
`U.S. Patent No. 4,237,224
`
`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
`
`Abbreviation
`
`The '415 patent
`
`Bujard, or the Bujard
`Patent
`
`Riggs & Itakura
`
`Southern
`
`Cohen & Boyer, or the
`Cohen & Boyer patent
`
`Foote Decl.
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`U.S. Patent No. 4,816,657
`
`The Cabilly I patent
`
`'415 patent reexamination, Office Action
`dated 2/16/07
`
`Office Action (2/16/07)
`
`'415 patent reexamination, Owners'
`Resp. dated 11/25/05
`
`'415 patent reexamination, Owners'
`Resp. (5/21/07)
`
`Owners' Resp. (11/25/05)
`
`Owners' Resp. (5/21/07)
`
`'415 patent reexamination, Office Action
`dated 9/13/05
`
`Office Action (9/13/05)
`
`716894931
`
`EXHIBIT LIST - 1
`
`

`

`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`U.S. Patent No. 4,816,397
`
`The Boss patent
`
`'415 patent file history, paper no. 17
`
`'415 patent file history, paper no. 14
`
`'415 patent file history, paper no. 18
`
`-
`
`-
`
`-
`
`'415 patent reexamination, Office Action
`dated 8/16/06
`
`'415 patent reexamination, Office Action
`dated 2/25/08
`
`Office Action (8/16/06)
`
`Office Action (2/25/08)
`
`U.S. Patent No. 4,399,216
`
`Axel, or the Axel patent
`
`U.S. Patent No. 5,840,545
`
`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)
`
`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, Owners'
`Resp. dated 10/30/06
`
`'415 patent reexamination, Owners'
`Resp. dated 6/6/08
`
`Moore, or the Moore
`patent
`
`Rice & Baltimore
`
`Ochi (I)
`
`Owners' Resp. (10/30/06)
`
`Owners' Resp. (6/6/08)
`
`'415 patent reexamination, Appeal Brief
`
`Appeal Brief
`
`'415 patent reexamination, Notice of
`Intent to Issue Ex Parte Reexamination
`
`NIRC
`
`716894931
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`EXHIBIT LIST - 2
`
`

`

`1026
`
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`1038
`
`1039
`
`Certificate
`
`'415 reexamination, Ex Parte
`Reexamination Certificate
`
`T.J.R. Harris, Expression of Eukaryotic
`Genes in E. Coli, in Genetic Engineering
`4, 127-185 (1983)
`
`'415 patent reexamination, Declaration
`of Dr. Timothy John Roy Harris under
`37 C.F.R. § 1.132
`
`Kabat et al., Sequences of Proteins of
`Immunological Interest (1983) (excerpt)
`
`Cohen, Recombinant DNA: Fact and
`Fiction, Science, 195:654-657 (1977)
`
`Oi et al., Immunoglobulin Gene
`Expression in Transformed Lymphoid
`Cells, Proceedings of the National
`Academy of Sciences USA, 80:825-829
`(1983)
`
`European Patent Application Publication
`No. 0044722 A1, published 1/27/82
`
`U.S. Patent No. 4,487,835
`
`U.S. Patent No. 4,371,614
`
`U.S. Patent No. 4,762,785
`
`U.S. Patent No. 4,476,227
`
`U.S. Patent No. 4,362,867
`
`U.S. Patent No. 4,396,601
`
`Reexam Cert.
`
`Harris
`
`Harris Decl.
`
`Kabat
`
`Cohen
`
`Oi
`
`Kaplan
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`Milstein, Monoclonal Antibodies from
`Hybrid Myelomas, Proceedings of the
`Royal Society of London, 211:393-412
`
`Milstein
`
`716894931
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`EXHIBIT LIST - 3
`
`

`

`(1981)
`
`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)
`
`MedImmune, Inc. v. Genentech, Inc., No.
`03-02567 (C.D. Cal. Aug. 17, 2007),
`Expert Report of E. Fintan Walton
`
`'415 patent reexamination, Request for
`Reconsideration and/or Petition Under
`37 C.F.R. § 1.183 dated 5/15/09
`
`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)
`
`1040
`
`1041
`
`1042
`
`1043
`
`Ochi (II)
`
`Walton Expert Rep.
`
`Request for
`Reconsideration
`
`Feldman
`
`1044
`
`ReoPro® Prescribing Information
`
`ReoPro® Prescribing Info.
`
`Genentech v. Centocor, No. 94-01379
`(N.D. Cal.), Affidavit of John Ghrayeb,
`Ph.D.
`
`'415 patent reexamination, Declaration
`of Dr. E. Fintan Walton under 37 C.F.R.
`§ 1.132
`
`Complaint in MedImmune v. Genentech,
`No. 03-02567 (C.D. Cal.)
`
`Stipulation and order of dismissal in
`MedImmune v. Genentech, No. 03-02567
`(C.D. Cal.)
`
`EXHIBIT LIST - 4
`
`1045
`
`1046
`
`1047
`
`1048
`
`716894931
`
`Ghrayeb Aff.
`
`Walton Decl.
`
`-
`
`-
`
`

`

`1049
`
`1050
`
`1051
`
`1052
`
`1053
`
`1054
`
`1055
`
`1056
`
`1057
`
`1058
`
`Complaint in Centocor v. Genentech,
`No. 08-CV-3573 (C.D. Cal.)
`
`Order of dismissal in Centocor v.
`Genentech, No. 08-CV-3573 (C.D. Cal.)
`
`Complaint in Glaxo Group Ltd. v.
`Genentech, No. 10-02764 (C.D. Cal.)
`
`Order of dismissal in Glaxo Group Ltd.
`v. Genentech, No. 10-02764 (C.D. Cal.)
`
`Complaint in Human Genome Sciences
`v. Genentech, No. 11-CV-6519 (C.D.
`Cal.)
`
`Order of dismissal in Human Genome
`Sciences v. Genentech, No. 11-CV-6519
`(C.D. Cal.)
`
`Complaint in Eli Lilly and ImClone
`Systems LLC v. Genentech, No. 13-CV-
`7248 (C.D. Cal.)
`
`Stipulation of dismissal in Eli Lilly and
`ImClone Systems LLC v. Genentech, No.
`13-CV-7248 (C.D. Cal.)
`
`Complaint in Bristol-Myers Squibb v.
`Genentech, No. 13-CV-5400 (C.D. Cal.)
`
`Stipulation of dismissal in Bristol-Myers
`Squibb v. Genentech, No. 13-CV-5400
`(C.D. Cal.)
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`716894931
`
`EXHIBIT LIST - 5
`
`

`

`I. INTRODUCTION
`
`Sanofi-aventis U.S. LLC and Regeneron Pharmaceuticals, Inc. (collectively,
`
`"Petitioners") request inter partes review under 35 U.S.C. § 311-319 of claims 1-4,
`
`9, 11, 12, 14-20 and 33 of U.S. Patent No. 6,331,415 ("the '415 patent," Ex. 1001),
`
`which issued on Dec. 18, 2001 to inventors Cabilly et al. and is assigned to
`
`Genentech, Inc. and City of Hope ("Owners"). A petition for inter partes review
`
`must demonstrate "a reasonable likelihood that the petitioner would prevail with
`
`respect to at least one of the claims challenged in the petition." 35 U.S.C. § 314(a).
`
`This petition meets this threshold for the reasons outlined below.
`
`The challenged claims of the '415 patent purport to cover recombinant DNA
`
`processes and associated compositions for making immunoglobulins (or
`
`antibodies) in "host" cells that are genetically engineered to contain the two DNA
`
`sequences encoding the heavy and light chain polypeptides necessary for the cell to
`
`make an immunoglobulin. The generally applicable techniques employed by the
`
`'415 patent inventors were already disclosed and commonly used in the prior art,
`
`including Petitioners' prior art references: the Bujard patent, and the seminal Cohen
`
`& Boyer patent, one of the foundational platform technologies in the field of
`
`recombinant DNA. Neither of these references were substantively considered by
`
`the PTO during prosecution or reexamination of the '415 patent. Moreover, Bujard
`
`and Cohen & Boyer disclose the precise teachings that Owners have previously
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`

`argued were missing from the prior art: the introduction of "a plurality of" or "one
`
`or more" DNA sequences into a host cell—language which necessarily
`
`accommodates two DNA sequences, including the heavy and light chain
`
`sequences. Because Bujard and Cohen & Boyer also expressly identify
`
`immunoglobulins as being among the types of proteins that can be made in host
`
`cells by their respective methods, Bujard and Cohen & Boyer anticipate—or at
`
`least make obvious in view of the Riggs & Itakura and Southern prior art
`
`references—the challenged claims of the '415 patent.
`
`II. REQUIREMENTS FOR INTER PARTES REVIEW
`
`A. Grounds for Standing (37 C.F.R. § 42.104(a))
`Petitioners certify that the '415 patent is available for inter partes review and
`
`that Petitioners are not barred or estopped from requesting an inter partes review
`
`challenging the patent claims on the grounds identified in this petition.
`
`B. Identification of Challenge (37 C.F.R. § 42.104(b))
`
`Petitioners request that the Board cancel claims 1-4, 9, 11, 12, 14-20 and 33
`
`("the challenged claims") of the '415 patent on the following grounds:
`
`Grounds Based on the Bujard Patent:
`All of the Challenged Claims Are Covered by Grounds 1-3
`
`Ground 1. Claims 1, 3, 4, 9, 11, 12, 15, 16, 17, 19 and 33 are anticipated
`
`under § 102(e) by Bujard (Ex. 1002);
`
`Ground 2. Claims 1, 3, 4, 11, 12, 14, 19 and 33 are obvious under § 103
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`

`over Bujard in view of Riggs & Itakura (Ex. 1003); and
`
`Ground 3. Claims 1, 2, 18, 20 and 33 are obvious under § 103 over Bujard
`
`in view of Southern (Ex. 1004).
`
`Grounds Based on the Cohen & Boyer Patent:
`A Subset of the Challenged Claims Are Covered by Ground 4
`Ground 4. Claims 1, 3, 4, 11, 12, 14 and 33 are obvious under § 103 over
`
`Cohen & Boyer (Ex. 1005) in view of Riggs & Itakura.
`
`Pursuant to 37 C.F.R. § 42.204(b), a detailed explanation of the precise relief
`
`requested for each challenged claim including where each element is found in the
`
`prior art and the relevance of the prior art reference is provided in Section V
`
`below, including claim charts. Additional explanation and support for each ground
`
`of rejection is set forth in the accompanying Declaration of Jefferson Foote, Ph.D.
`
`(Ex. 1006).
`
`III. RELEVANT INFORMATION REGARDING THE '415 PATENT
`
`A. Brief Description of the Challenged Patent
`
`The '415 patent issued on December 18, 2001, from Application No.
`
`07/205,419 ("the '419 application"), filed on June 10, 1988. The '419 application
`
`has an earliest effective filing date under 35 U.S.C. § 120 of April 8, 1983, by
`
`virtue of a priority claim to Application No. 06/483,457, which issued as U.S.
`
`Patent No. 4,816,567 ("the Cabilly I patent," Ex. 1007). A reexamination
`
`certificate for the '415 patent issued on May 19, 2009, based on two separate
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`

`reexamination requests filed on May 13 and December 23, 2005.
`
`The '415 patent is directed to processes and related compositions for making
`
`immunoglobulins1 (or fragments thereof) in host cells using recombinant DNA
`
`technology. Ex. 1001, 1:14-21, 3:53-67. Immunoglobulins are proteins (or
`
`"polypeptides") having a globular conformation that are produced by and secreted
`
`from cells of the immune system of vertebrates in response to the presence in the
`
`body of a foreign substance, called an "antigen," often a foreign protein or a
`
`foreign cell (such as a bacterium). Id. at
`
`1:23-37; 16:38-39; Ex. 1006, Foote Decl.,
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`¶ 26. Immunoglobulins bind to antigens to
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`rid the body of the foreign invader. Ex.
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`1001, 1:26-31; Ex. 1006, Foote Decl.,
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`¶ 26. Most immunoglobulins are
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`composed of two heavy chain
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`polypeptides and two light chain polypeptides that are connected via disulfide
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`bonds (represented above as –SS–) to form a four-chain "tetramer" with a highly
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`specific and defined Y-shaped conformation that is required for antigen binding.
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`1 For purposes of this Petition, the claim term "immunoglobulin" is interchangeable
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`with "antibodies," which the '415 patent defines as "specific immunoglobulin
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`polypeptides." Ex. 1001, 1:23-24.
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`Ex. 1001, Fig. 1 and 3:17-26; Ex. 1006, Foote Decl., ¶ 26. The heavy and light
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`chains comprise segments referred to as the variable and constant regions. Ex.
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`1001, 3:42-59; Ex. 1006, Foote Decl., ¶ 27. The heavy chain and light chain are
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`encoded by separate DNA sequences or "genes." Ex. 1001, 1:48-51; Ex. 1006,
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`Foote Decl., ¶ 27. The nature of immunoglobulin structure and function as
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`described above was well known in the prior art, as is evidenced by the discussion
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`in the "Background of the Invention" in the '415 patent. Ex. 1001 at 1:22-4:5; Ex.
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`1006, Foote Decl., ¶ 27.
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`The patent identifies a prior art method of making antibodies in hybridoma
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`cells, which results in the production of a homogeneous antibody population that
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`specifically bind to a single antigen, so called "monoclonal" antibodies. Ex. 1001
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`at 1:64-2:19. According to the patent, the use of recombinant DNA technology to
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`make antibodies avoids the drawbacks of hybridoma production. Id. at 2:40-3:2.
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`The recombinant DNA approach to making antibodies described in the
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`patent, in short, proceeds as follows: (1) the genetic material encoding the heavy
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`and light chains is identified and isolated (for example, from a hybridoma) (id. at
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`11:28-12:8; Ex. 1006, Foote Decl., ¶ 29); (2) the heavy and light chain DNA is
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`introduced into suitable host cells by a process called "transformation," which may
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`be facilitated by first inserting the DNA into an expression vector2 that acts as a
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`vehicle to introduce the foreign DNA into the host cell (Ex. 1001, 12:9-30; Ex.
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`1006, Foote Decl., ¶ 29); and (3) the host cells transcribe and translate the heavy
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`and light chain DNA, a process called "expression," to produce the heavy and light
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`chain polypeptides (Ex. 1001, 12:31-33, 4:24-29; Ex. 1006, Foote Decl., ¶ 29).
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`Host cells may either be microorganisms (for example, prokaryotic cells, such as
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`bacteria) or cell lines from multicellular eukaryotic organisms, including
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`mammalian cells. Ex. 1001 at 8:41-56, 9:56-10:18.
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`The challenged claims of the '415 patent cover various aspects and
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`components of the above-described recombinant production of immunoglobulins.
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`All of the challenged claims (whether process or composition) require two genes: a
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`first DNA sequence encoding the heavy chain and a second DNA sequence
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`encoding the light chain. All of the challenged process claims require that the host
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`cell express both DNA sequences to produce both heavy chain and light chain
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`polypeptides (referred to as "co-expression" in the '415 patent and during the
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`reexamination3). Ex. 1009, Owners' Resp. (11/25/05), at 46. The heavy and light
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`chain polypeptides are produced as "separate molecules" by virtue of their
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`2 Vectors that express inserted DNA sequences are called "expression vectors" in
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`the patent, a term that is used interchangeably with "plasmid." Ex. 1001, 8:16-22.
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`3 Ex. 1001, 12:50-51; Ex. 1008, Office Action (2/16/07), at 19.
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`"independent expression." Ex. 1001, claims 1, 33; Ex. 1022, Owners' Resp.
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`(10/30/06), at 30 ("[T]he '415 patent requires that the transformed cell produce the
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`immunoglobulin heavy and light chain polypeptides encoded by the two DNA
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`sequences as separate molecules. This result stems from the requirement for
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`independent expression of the introduced DNA sequences...")
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`Furthermore, the process claims also require assembly of the separate heavy
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`and light chain polypeptides into an immunoglobulin tetramer. Ex. 1001, claim 1
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`("A process for producing an immunoglobulin molecule…"); Ex. 1009, Owners'
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`Resp. (11/25/05), at 46. This can occur inside of the host cell through its natural
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`cellular machinery ("in vivo" assembly), which could then secrete the assembled
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`immunoglobulin; or, if the host cell is unable to assemble the chains in vivo, the
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`cell may be lysed and the separate chains assembled by chemical means ("in vitro"
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`assembly). Ex. 1001, 12:50-55, claims 9 and 10; Ex. 1010, Owners' Resp.
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`(5/21/07), at 29, n. 8.
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`B. Discussion of the File History and Related Proceedings in the PTO
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`The '415 patent and the '419 application have had an extended and extensive
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`history in the PTO. The '415 patent issued nearly thirteen-and-a-half years after its
`
`filing date and more than eighteen years after its priority filing date. During
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`prosecution, the '415 patent was involved in a decade-long interference proceeding
`
`(and related 35 U.S.C. § 146 action) with U.S. Patent No. 4,816,397, issued to
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`Boss et al. (Ex. 1012). After the interference was resolved, prosecution of the '415
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`patent continued until it issued. The '415 patent was later the subject of an ex parte
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`reexamination for four years, from May 13, 2005 to May 19, 2009.
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`1. Prosecution of the '419 application
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`The prosecution of the '419 application consisted largely of a series of
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`restriction requirements by the PTO and claim cancellations and elections by
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`Owners. See generally Ex. 1009, Owners' Resp. (11/25/05), at 8-10, 12-13. There
`
`were no prior art rejections of the pending claims. However, in an Information
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`Disclosure Statement filed on September 18, 1991, Genentech characterized the
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`Rice & Baltimore (Ex. 1020) prior art reference as "distinguishable from the
`
`instant claims in that the cells are not transformed with exogenous DNA encoding
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`both of the heavy and light chains." Ex. 1013, '415 patent file history, paper no. 17,
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`at 2 (emphasis in original).
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`2. Interference with the Boss Patent
`
`On February 28, 1991, the Board of Patent Appeals and Interferences
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`declared an interference between claims 1-18 of the Boss patent and then-pending
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`claims 101-120 in the '419 application, which were copied from the Boss patent.
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`Ex. 1014, '415 patent file history, paper no. 14. The count was defined to be claim
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`1 of the Boss patent, which was identical to claim 101 of the' 419 application (and
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`which issued as claim 1 of the '415 patent). Id. at 4. The BPAI decided priority in
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`favor of the senior party, Boss, holding that the inventors of the '415 patent had not
`
`established an actual reduction to practice before the Boss patent's British priority
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`date. Cabilly v. Boss, 55 U.S.P.Q.2d 1238 (Bd. Pat. App. & Int. 1998). Priority of
`
`invention was ultimately awarded to the inventors of the '415 patent on March 16,
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`2001, following the settlement by the parties of an action instituted by Genentech
`
`under 35 U.S.C. § 146. Ex. 1015, '415 patent file history, paper no. 18.
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`3. Ex Parte Reexamination of the '415 Patent
`
`a. Rejections Over the Axel Patent
`
`Over the course of the reexamination, the PTO rejected the claims of the
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`'415 patent in each of four office actions. See Exs. 1011, 1016, 1008 and 1017, '415
`
`patent reexamination, Office Actions dated 9/13/2005, 8/16/2006, 2/16/2007, and
`
`2/25/2008. Among the prior art relied upon by the PTO were U.S. Patent Nos.
`
`4,399,216 ("Axel," Ex. 1018) and 5,840,545 ("Moore," Ex. 1019), Rice &
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`Baltimore (Ex. 1020), and Ochi (I) (Ex. 1021). The PTO rejected the claims on a
`
`variety of grounds, including obviousness-type double patenting, anticipation and
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`obviousness.
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`The ODP rejections were in part based on (1) the claims of the Cabilly I
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`patent, which were directed to chimeric4 heavy or light chains produced using
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`recombinant DNA technology, in combination with (2) Axel, Rice & Baltimore or
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`Ochi (I), alone or in combination with Moore. E.g., Ex. 1008, Office Action
`
`(2/16/07), at 26-42. The obviousness rejections were based in part on the Moore
`
`patent either alone or in combination with the Axel patent. Id. at 12-14.
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`The PTO rejections relying on Axel were based on the Examiner's
`
`interpretation of Axel as disclosing the co-expression of heavy and light chains in a
`
`single host cell transformed with the respective DNA sequences. The invention of
`
`the Axel patent concerned "the introduction and expression of genetic
`
`informational material, i.e., DNA which includes genes coding for proteinaceous
`
`materials… into eucaryotic cells…. Such genetic intervention is commonly
`
`referred to as genetic engineering and in certain aspects involves the use of
`
`recombinant DNA technology." Ex. 1018, Axel, 1:12-21. Axel disclosed the
`
`transformation of eukaryotic (mammalian) host cells using a two-DNA system:
`
`
`4 A "chimeric" chain has variable regions derived from one species of mammal,
`
`with constant portions derived from another species. See Ex. 1007, Cabilly I
`
`patent, 6:54-59 and claim 1.
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`"DNA I," which coded for a "desired proteinaceous material"5 that is
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`"heterologous" to the host cell;6 and "DNA II," which coded for a protein that
`
`would act as a "selectable marker."7 Id. at Figure 1, 3:20-26, 8:56-62. Because
`
`DNA I and DNA II are present in a single vector "physically unlinked" to each
`
`other (id. at 9:61-10:1; Figure 1), the respective proteins encoded by DNA I and II
`
`would be independently expressed as separate molecules. Ex. 1006, Foote Decl., ¶
`
`39. The Axel patent identified "antibodies" as one of the preferred "proteinaceous
`
`materials" that could be made by the disclosed methods. Id. at 3:31-36, 2:61-66. In
`
`the first Office Action, the PTO characterized Axel as "demonstrat[ing] the
`
`predictability of expression of multiple heterologous proteins in a single host cell
`
`5 A "desired proteinaceous material," or "protein of interest," is the protein that is
`
`sought to be isolated from the host cell after its production by the cell. Ex. 1010,
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`Owners' Response (5/21/07), at 49; Ex. 1006, Foote Decl., ¶ 39, n. 2.
`
`6 A "heterologous" protein is a protein produced in a cell that does not normally
`
`make that protein or that is foreign to the cell, e.g., by genetically engineering the
`
`cell. Ex. 1006, Foote Decl., ¶ 39, n. 3; Ex. 1001, 4:9-12, 4:33-41.
`
`7 The function of a "selectable marker" is to permit scientists to identify which host
`
`cells have been transformed. Because it is not intended to be isolated or studied, it
`
`is not, strictly speaking, a protein "of interest" or a "desired" protein. Ex. 1009,
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`Owners' Response (11/25/05), at 34; Ex. 1006, Foote Decl., ¶ 39, n. 4.
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`[and the] desirability of expressing immunoglobulins in mammalian host cells, and
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`as intact (assembled) proteins." Ex. 1011, Office Action (9/13/05), at 5.
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`The Examiner eventually entered a Final Office Action rejecting the claims
`
`in part over Axel, stating that the "Axel Abstract and definitions suggest co-
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`tr