`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`————————————————
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`————————————————
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner
`
`v.
`
`GENENTECH, INC. AND CITY OF HOPE,
`Patent Owners
`
`————————————————
`
`U.S. Patent No. 6,331,415
`Appl. No. 07/205,419, filed June 10, 1998
`Issued: Dec. 18, 2001
`
`Title: Methods of Producing Immunoglobulins, Vectors
`and Transformed Host Cells for Use Therein
`
`————————————————
`
`Inter Partes Review No.: IPR2016-00710
`
`————————————————
`
`
`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.
`
`

`

`
`
`
`I. 
`
`II. 
`
`
`
`TABLE OF CONTENTS
`
`INTRODUCTION ........................................................................................... 1 
`
`REQUIREMENTS FOR INTER PARTES REVIEW .................................... 3 
`
`A.  Grounds for Standing (37 C.F.R. § 42.104(a)) ..................................... 3 
`
`B. 
`
`Identification of Challenge (37 C.F.R. § 42.104(b)) ............................. 3 
`
`III.  RELEVANT INFORMATION REGARDING THE ‘415 PATENT ............. 4 
`
`A. 
`
`B. 
`
`Brief Description of the Challenged Patent .......................................... 4 
`
`Discussion of the File History and Related Proceedings
`in the PTO ............................................................................................. 8 
`
`1. 
`
`2. 
`
`3. 
`
`Prosecution of the ‘419 application ............................................ 9 
`
`Interference with the Boss Patent ............................................... 9 
`
`Ex Parte Reexamination of the ‘415 Patent .............................. 10 
`
`a. 
`
`b. 
`
`Rejections Over the Axel Patent ..................................... 10 
`
`Owners’ Arguments in Response to the Rejections ....... 14 
`
`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 .................................. 14 
`
`Owners Argue that the Axel Patent Does Not
`Disclose the Co-Expression of “One or More”
`Genes of Interest ................................................... 16 
`
`C. 
`
`D. 
`
`Person of Ordinary Skill in the Art ..................................................... 17 
`
`Claim Construction ............................................................................. 18 
`
`IV.  RELEVANT PRIOR ART ............................................................................ 18 
`
`A. 
`
`Technology Background ..................................................................... 18 
`
`
`
`

`

`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 ................................................................... 18 
`
`The Prior Art Taught Expression of Single
`Immunoglobulin Chains ............................................................ 21 
`
`The Prevailing Mindset by April 1983 Was That One or
`More Proteins of Interest Could be Made in a Single Host
`Cell ............................................................................................ 23 
`
`B. 
`
`References Underlying the Grounds for Rejection ............................. 28 
`
`1. 
`
`2. 
`
`3. 
`
`Bujard Teaches Introducing and Expressing a “Plurality
`of Genes” in Bacterial or Mammalian Host Cells and
`Identifies “Immunoglobulins” 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 .............................................................................. 31 
`
`Southern Teaches One Host Cell Transformed with Two
`Vectors ...................................................................................... 32 
`
`V. 
`
`FULL STATEMENT OF PRECISE RELIEF REQUESTED AND
`THE REASONS THEREFOR (37 C.F.R. § 42.22(a)) .................................. 34 
`
`A. 
`
`B. 
`
`C. 
`
`Explanation of Ground 1 for Unpatentability: Claims 1,
`3, 4, 11, 12, 14, 19, and 33 Are Obvious Over Bujard in
`View of Riggs & Itakura ..................................................................... 34 
`
`Explanation of Ground 2 for Unpatentability: Claims 1,
`2, 18, 20, and 33 Are Obvious Over Bujard in View of
`Southern ............................................................................................... 39 
`
`Secondary Indicia of Non-Obviousness in the Public
`Record Do Not Rebut Petitioner’s Prima Facie Case of
`Obviousness ......................................................................................... 42 
`
`VI.  MANDATORY NOTICES UNDER 37 C.F.R. § 42.8(a)(1) ........................ 44 
`
`A. 
`
`Real Party-In-Interest Under 37 C.F.R. § 42.8(b)(1) .......................... 44 
`
`
`
`ii
`
`

`

`B. 
`
`C. 
`
`Related Matters Under 37 C.F.R. § 42.8(b)(2) ................................... 44 
`
`Lead and Back-up Counsel and Service Information
`Under 37 C.F.R. § 42.8(b)(3), (4) ....................................................... 45 
`
`VII.  CONCLUSION .............................................................................................. 46 
`
`
`
`
`
`
`
`
`
`iii
`
`

`

`TABLE OF AUTHORITIES
`
`Cases 
`
`Cabilly v. Boss,
`55 U.S.P.Q.2d 1238 (Bd. Pat. App. & Int. 1998) ................................................. 10
`
`Callaway Golf Co. v. Acushnet Co.,
`576 F. 3d 1331 (Fed. Cir. 2009) ........................................................................... 41
`
`CBS Interactive Inc. v. Helferich Patent Licensing, LLC,
`IPR2013-00033 ..................................................................................................... 42
`
`In re Cuozzo Speed Techs., LLC,
`793 F.3d 1268 (Fed. Cir. 2015) ............................................................................ 18
`
`Iron Grip Barbell Co. v. USA Sports, Inc.,
`392 F.3d 1317 (Fed. Cir. 2004) ............................................................................ 42
`
`SIBIA Neurosciences, Inc. v. Cadus Pharm. Corp.,
`225 F.3d 1349 (Fed. Cir. 2000) ............................................................................ 42
`
`Statutes 
`
`35 U.S.C. § 120 .......................................................................................................... 4
`
`35 U.S.C. § 146 ........................................................................................................ 10
`
`35 U.S.C. § 314(a) ...................................................................................................... 1
`
`35 U.S.C. § 315(c) ...................................................................................................... 2
`
`35 U.S.C. §§ 311-319 .................................................................................................. 1
`
`Regulations 
`
`37 C.F.R. § 42.204(b) .................................................................................................. 3
`
`37 C.F.R. § 42.8(b)(2) .............................................................................................. 44
`
`
`
`
`
`
`
`
`
`iv
`
`

`

`Exhibit
`No.
`
`LIST OF EXHIBITS
`
`Description
`
`1001 U.S. Patent No. 6,331,415
`
`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, 1:327-
`341 (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
`
`‘415 patent reexamination, Office Action dated
`2/16/07
`
`Abbreviation
`
`The ‘415 patent
`
`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)
`
`1008
`
`1009
`
`1010
`
`
`
`‘415 patent reexamination, Owners’ Resp. dated
`Owners’ Resp.
`11/25/05
`(11/25/05)
`‘415 patent reexamination, Owners’ Resp. (5/21/07) Owners’ Resp.
`(5/21/07)
`
`v
`
`

`

`Exhibit
`No.
`
`Description
`
`1011
`
`‘415 patent reexamination, Office Action dated
`9/13/05
`
`1012 U.S. Patent No. 4,816,397
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`‘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
`
`1018 U.S. Patent No. 4,399,216
`
`1019 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)
`
`Abbreviation
`
`Office Action
`(9/13/05)
`
`The Boss patent
`
`-
`
`-
`
`-
`
`Office Action
`(8/16/06)
`
`Office Action
`(2/25/08)
`
`Axel, or the
`Axel patent
`
`Moore, or the
`Moore patent
`
`Rice &
`Baltimore
`
`Ochi (I)
`
`1020
`
`1021
`
`1022
`
`1023
`
`
`
`‘415 patent reexamination, Owners’ Resp. dated
`10/30/06
`
`‘415 patent reexamination, Owners’ Resp. dated
`6/6/08
`
`Owners’ Resp.
`(10/30/06)
`
`Owners’ Resp.
`(6/6/08)
`
`vi
`
`

`

`Exhibit
`No.
`
`Description
`
`1024
`
`‘415 patent reexamination, Appeal Brief
`
`Abbreviation
`
`Appeal Brief
`
`1025
`
`‘415 patent reexamination, Notice of Intent to Issue
`Ex Parte Reexamination
`
`NIRC
`
`1026
`
`‘415 reexamination, Ex Parte Reexamination
`Certificate
`1027 T.J.R. Harris, Expression of Eukaryotic Genes in E.
`Coli, in Genetic Engineering 4, 127-185 (1983)
`
`1028
`
`‘415 patent reexamination, Declaration of Dr.
`Timothy John Roy Harris under 37 C.F.R. § 1.132
`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)
`1032 European Patent Application Publication No.
`0044722 A1, published 1/27/82
`
`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
`
`
`
`vii
`
`Reexam Cert.
`
`Harris
`
`Harris Decl.
`
`Kabat
`
`Cohen
`
`Oi
`
`Kaplan
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`

`

`Description
`
`Abbreviation
`
`
`
`Ochi (II)
`
`Walton Expert
`Rep.
`
`Request for
`Reconsideration
`
`Feldman
`
`ReoPro®
`Prescribing
`Info.
`
`Ghrayeb Aff.
`
`Walton Decl.
`
`-
`
`Exhibit
`No.
`
`1039
`
`1040
`
`1041
`
`1042
`
`1043
`
`Milstein, Monoclonal Antibodies from Hybrid
`Myelomas, Proceedings of the Royal Society of
`London, 211:393-412 (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)
`
`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
`1047 Complaint in MedImmune v. Genentech, No. 03-
`02567 (C.D. Cal.)
`
`
`
`viii
`
`

`

`Description
`
`Exhibit
`No.
`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. 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.)
`
`Abbreviation
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`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.
`
`-
`
`
`
`ix
`
`

`

`
`
`I.
`
`
`
`INTRODUCTION
`Mylan Pharmaceuticals Inc. (“Mylan”) requests inter partes review under 35
`
`U.S.C. §§ 311-319 of claims 1-4, 11, 12, 14, 18-20, and 33 (“the challenged claims”)
`
`of U.S. Patent No. 6,331,415 (“the ‘415 patent,” Ex. 1001), which issued on
`
`December 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.
`
`In this Petition, Mylan asserts the same grounds of unpatentability upon which
`
`the Board has already instituted review of the challenged claims of the ‘415 patent in
`
`IPR2015-01624 (the “Sanofi IPR”). For the exact same reasons previously
`
`considered by the Board, on the exact same trial schedule, Mylan respectfully seeks to
`
`join the Sanofi IPR. This Petition does not add to or alter any arguments that have
`
`already been considered by the Board, and this Petition does not seek to expand the
`
`grounds of unpatentability that the Board has already instituted. Accordingly, and as
`
`explained below, there exists a reasonable likelihood that Mylan will prevail in
`
`demonstrating unpatentability of at least one of the challenged claims based on
`
`teachings set forth in the references presented in this Petition.
`
`
`
`

`

`Because this Petition is filed within one month of the institution of IPR2015-
`
`01624, and because this Petition is accompanied by a Motion for Joinder, this Petition
`
`is timely and proper under 35 U.S.C. § 315(c).
`
`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 the
`
`Bujard patent. This reference was not substantively considered by the PTO during
`
`prosecution or reexamination of the ‘415 patent. Moreover, Bujard discloses the
`
`precise teachings that Owners have previously 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 also expressly identifies immunoglobulins
`
`as being among the types of proteins that can be made in host cells by their respective
`
`methods, Bujard, in view of the Riggs & Itakura and Southern prior art references,
`
`makes obvious the challenged claims of the ‘415 patent.
`
`
`
`2
`
`

`

`II. REQUIREMENTS FOR INTER PARTES REVIEW
`A. Grounds for Standing (37 C.F.R. § 42.104(a))
`Petitioner certifies that the ‘415 patent is available for inter partes review and
`
`that Petitioner is not barred or estopped from requesting an inter partes review
`
`challenging the patent claims on the grounds identified in this Petition.
`
`Identification of Challenge (37 C.F.R. § 42.104(b))
`
`B.
`Petitioner requests that the Board cancel claims 1-4, 11, 12, 14, 18-20, and 33
`
`of the ‘415 patent on the following grounds:
`
`Ground 1. Claims 1, 3, 4, 11, 12, 14, 19, and 33 are obvious under § 103 over
`
`Bujard (Ex. 1002) in view of Riggs & Itakura (Ex. 1003); and
`
`Ground 2. Claims 1, 2, 18, 20, and 33 are obvious under § 103 over Bujard in
`
`view of Southern (Ex. 1004).
`
`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.
`
`Additional explanation and support for each ground of unpatentability is set forth in
`
`the accompanying Declaration of Jefferson Foote, Ph.D. (Ex. 1006). Solely to
`
`preserve its right to rely on expert testimony in the event that joinder is not granted or
`
`in the case that the Sanofi IPR is settled, Mylan further relies on the accompanying
`
`Declaration of Kathryn Calame, Ph.D. (Ex. 1059), in which Dr. Calame adopts the
`
`opinions set forth by Dr. Foote in connection with the Sanofi IPR.
`3
`
`
`
`

`

`Importantly, the Calame Declaration does not alter or otherwise seek to
`
`supplement the opinions offered by Dr. Foote, and Dr. Calame does not intend to offer
`
`opinions beyond those in support of the grounds of unpatentability instituted in
`
`connection with the Sanofi IPR. For at least the reasons set forth in Mylan’s Motion
`
`for Joinder, filed concurrently herewith, Mylan respectfully requests institution of trial
`
`on the unpatentability grounds detailed below and joinder with the Sanofi IPR.
`
`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
`
`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
`
`1 For purposes of
`this Petition,
`
`the claim
`
`term “immunoglobulin”
`
`is
`
`interchangeable with “antibodies,” which the ‘415 patent defines as “specific
`
`immunoglobulin polypeptides.” Ex. 1001, 1:23-24.
`
`
`
`4
`
`

`

`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.,
`
`¶ 26; Ex. 1059, Calame Decl., ¶ 16. Immunoglobulins bind to antigens to rid the
`
`body of the foreign invader. Ex. 1001, 1:26-31; Ex. 1006, Foote Decl., ¶ 26;
`
`Ex. 1059, Calame Decl., ¶ 16.
`
`
`
`Ex. 1001, Fig. 1; Ex. 1006, Foote Decl., ¶ 26; Ex. 1059, Calame Decl., ¶ 16.
`
`Most immunoglobulins are composed of two heavy chain polypeptides and
`
`two light chain polypeptides that are connected via disulfide bonds (represented
`
`above as –SS–) to form a four-chain “tetramer” with a highly specific and defined
`
`Y-shaped conformation that is required for antigen binding. Ex. 1001, Fig. 1 and
`
`
`
`5
`
`

`

`3:17-26; Ex. 1006, Foote Decl., ¶ 26; Ex. 1059, Calame Decl., ¶ 16. The heavy
`
`and light chains comprise segments referred to as the variable and constant regions.
`
`Ex. 1001, 3:42-59; Ex. 1006, Foote Decl., ¶ 27; Ex. 1059, Calame Decl., ¶ 16. The
`
`heavy chain and light chain are encoded by separate DNA sequences or “genes.”
`
`Ex. 1001, 1:48-51; Ex. 1006, Foote Decl., ¶ 27; Ex. 1059, Calame Decl., ¶ 16. The
`
`nature of immunoglobulin structure and function as described above was well
`
`known in the prior art, as is evidenced by the discussion in the “Background of the
`
`Invention” in the ‘415 patent. Ex. 1001 at 1:22-4:5; Ex. 1006, Foote Decl., ¶ 27;
`
`Ex. 1059, Calame Decl., ¶ 16.
`
`The patent identifies a prior art method of making antibodies in hybridoma
`
`cells, which results in the production of a homogeneous antibody population that
`
`specifically bind to a single antigen, so called “monoclonal” antibodies. Ex. 1001
`
`at 1:64-2:19. According to the patent, the use of recombinant DNA technology to
`
`make antibodies avoids the drawbacks of hybridoma production. Id. at 2:40-3:2.
`
`The recombinant DNA approach to making antibodies described in the
`
`patent, in short, proceeds as follows: (1) the genetic material encoding the heavy
`
`and light chains is identified and isolated (for example, from a hybridoma) (id. at
`
`11:28-12:8; Ex. 1006, Foote Decl., ¶ 29; Ex. 1059, Calame Decl., ¶ 16); (2) the
`
`heavy and light chain DNA is introduced into suitable host cells by a process
`
`called “transformation,” which may be facilitated by first inserting the DNA into
`
`
`
`6
`
`

`

`an expression vector2 that acts as a vehicle to introduce the foreign DNA into the
`
`host cell (Ex. 1001, 12:9-30; Ex. 1006, Foote Decl., ¶ 29; Ex. 1059, Calame Decl.,
`
`¶ 16); and (3) the host cells transcribe and translate the heavy and light chain DNA,
`
`a process called “expression,” to produce the heavy and light chain polypeptides
`
`(Ex. 1001, 12:31-33, 4:24-29; Ex. 1006, Foote Decl., ¶ 29; Ex. 1059, Calame
`
`Decl., ¶ 16). Host cells may either be microorganisms (for example, prokaryotic
`
`cells, such as bacteria) or cell lines from multicellular eukaryotic organisms,
`
`including mammalian cells. Ex. 1001, 8:41-56, 9:56-10:18.
`
`The challenged claims of the ‘415 patent cover various aspects and
`
`components of the above-described recombinant production of immunoglobulins.
`
`All of the challenged claims (whether process or composition) require two genes:
`
`a first DNA sequence encoding the heavy chain and a second DNA sequence
`
`encoding the light chain. All of the challenged process claims require that the host
`
`cell express both DNA sequences to produce both heavy chain and light chain
`
`polypeptides (referred to as “co-expression” in the ‘415 patent and during
`
`reexamination3). Ex. 1009, Owners’ Resp. (11/25/05), at 46. The heavy and light
`
`
`2 Vectors that express inserted DNA sequences are called “expression vectors” in
`
`the patent, a term that is used interchangeably with “plasmid.” Ex. 1001, 8:16-22.
`
`3 Ex. 1001, 12:50-51; Ex. 1008, Office Action (2/16/07), at 19.
`
`
`
`7
`
`

`

`chain polypeptides are produced as “separate molecules” by virtue of their
`
`“independent expression.” Ex. 1001, claims 1, 33; Ex. 1022, Owners’ Resp.
`
`(10/30/06), at 30 (“[T]he ‘415 patent requires that the transformed cell produce the
`
`immunoglobulin heavy and light chain polypeptides encoded by the two DNA
`
`sequences as separate molecules. This result stems from the requirement for
`
`independent expression of the introduced DNA sequences . . . .”)
`
` Furthermore, the process claims also require assembly of the separate heavy
`
`and light chain polypeptides into an immunoglobulin tetramer. Ex. 1001, claim 1
`
`(“A process for producing an immunoglobulin molecule”); Ex. 1009, Owners’
`
`Resp. (11/25/05), at 46. This can occur inside of the host cell through its natural
`
`cellular machinery (“in vivo” assembly), which could then secrete the assembled
`
`immunoglobulin; or, if the host cell is unable to assemble the chains in vivo, the
`
`cell may be lysed and the separate chains assembled by chemical means (“in vitro”
`
`assembly). Ex. 1001, 12:50-55, claims 9 and 10; Ex. 1010, Owners’ Resp.
`
`(5/21/07), at 29, n.8.
`
`B. Discussion of the File History and Related Proceedings in the PTO
`The ‘415 patent and the ‘419 application have had an extended and
`
`extensive 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 prosecution, the ‘415 patent was involved in a decade-long interference
`
`
`
`8
`
`

`

`proceeding (and related 35 U.S.C. § 146 action) with U.S. Patent No. 4,816,397,
`
`issued to Boss et al. (Ex. 1012). After the interference was resolved, prosecution
`
`of the ‘415 patent continued until it issued. The ‘415 patent was later the subject
`
`of an ex parte reexamination for four years, from May 13, 2005, to May 19, 2009.
`
`Prosecution of the ‘419 application
`
`1.
`The prosecution of the ‘419 application consisted largely of a series of
`
`restriction requirements by the PTO and claim cancellations and elections by
`
`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
`
`Disclosure Statement filed on September 18, 1991, Genentech characterized the
`
`Rice & Baltimore (Ex. 1020) prior art reference as “distinguishable from the
`
`instant claims in that the cells are not transformed with exogenous DNA encoding
`
`both of the heavy and light chains.” Ex. 1013, ‘415 patent file history, paper no.
`
`17, at 2 (emphasis in original).
`
`Interference with the Boss Patent
`
`2.
`On February 28, 1991, the Board of Patent Appeals and Interferences
`
`declared an interference between claims 1-18 of the Boss patent and then-pending
`
`claims 101-120 in the ‘419 application, which were copied from the Boss patent.
`
`Ex. 1014, ‘415 patent file history, paper no. 14. The count was defined to be claim
`
`1 of the Boss patent, which was identical to claim 101 of the ‘419 application (and
`
`
`
`9
`
`

`

`which issued as claim 1 of the ‘415 patent). Id. at 4. The BPAI decided priority in
`
`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
`
`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,
`
`2001, following 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.
`
`3.
`
`Ex Parte Reexamination of the ‘415 Patent
`a.
`Over the course of reexamination, the PTO rejected the claims of the ‘415
`
`Rejections Over the Axel Patent
`
`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 &
`
`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
`
`obviousness. The OTDP rejections were in part based on (1) the claims of the
`
`Cabilly I patent, which were directed to chimeric4 heavy or light chains produced
`
`
`4 A “chimeric” chain has variable regions derived from one species of mammal,
`
`
`
`
`
`10
`
`

`

`using recombinant DNA technology, in combination with (2) Axel, Rice &
`
`Baltimore or 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.
`
`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:
`
`“DNA I,” which coded for a “desired proteinaceous material”5
`
`that
`
`is
`
`
`with constant portions derived from another species. See Ex. 1007, Cabilly I
`
`patent, 6:54-59 and claim 1.
`
`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,
`
`
`
`
`
`11
`
`

`

`“heterologous” to the host cell;6 and “DNA II,” which coded for a protein that
`
`would act as a “selectable marker.”7 Id. at Fig. 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; Fig. 1), the respective proteins encoded by DNA I and II would be
`
`independently expressed as separate molecules. Ex. 1006, Foote Decl., ¶ 39;
`
`Ex. 1059, Calame Decl., ¶ 16. The Axel patent identified “antibodies” as one of
`
`the preferred “proteinaceous materials” that could be made by the disclosed
`
`methods. Ex. 1018, Axel, 3:31-36, 2:61-66. In the first Office Action, the PTO
`
`
`Owners’ Response (5/21/07), at 49; Ex. 1006, Foote Decl., ¶ 39, n.2; Ex. 1059,
`
`Calame Decl., ¶ 16.
`
`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. 1059, Calame Decl., ¶ 16; 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,
`
`Owners’ Response (11/25/05), at 34; Ex. 1006, Foote Decl., ¶ 39, n.4; Ex. 1059,
`
`Calame Decl., ¶ 16.
`
`
`
`12
`
`

`

`characterized Axel as “demonstrat[ing] the predictability of expression of multiple
`
`heterologous proteins in a single host cell [and the] desirability of expressing
`
`immunoglobulins in mammalian host cells, and as intact (assembled) proteins.”
`
`Ex. 1011, Office Action (9/13/05), at 5.
`
`The Examiner eventually entered a Final Office Action rejecting the claims
`
`in part over Axel, stating that the “Axel Abstract and definitions suggest
`
`cotransforming more than one desired gene for making proteinaceous materials
`
`which include multimeric proteins.”8 Ex. 1017, Office Action (2/25/08), at 29; see
`
`also id. at 30 (“The Axel reference clearly encompasses one or more genes which
`
`encode one or more proteins.”). Moreover, the Examiner also found that Axel
`
`“teaches co-expression of two different proteins encoded by foreign DNA I and
`
`foreign DNA II in a single eukaryotic host cell.” Id. at 28 (emphasis added).
`
`Because the proteins disclosed in the Axel patent included “multimeric proteins
`
`
`8 A “multimeric” protein is a protein that is composed of more than one distinct
`
`polypeptide constituents or subunits. Ex. 1009, Owners’ Response (11/25/05), at
`
`37. An immunoglobulin is a multimeric protein because it is composed of four
`
`distinct polypeptide subunits: two heavy chains and two light chains. Ex. 1022,
`
`Owners’ Response