IPR2015-01624
`Patent Owners’ Preliminary Response
`Filed on behalf of Patent Owners Genentech, Inc. and City of Hope by:
`
`David L. Cavanaugh
`Reg. No. 36,476
`Heather M. Petruzzi
`Reg. No. 71,270
`Robert J. Gunther, Jr.
`Pro Hac Vice Application Pending
`Wilmer Cutler Pickering
`Hale and Dorr LLP
`1875 Pennsylvania Ave., NW
`Washington, DC 20006
`
`Adam R. Brausa
`Reg. No. 60,287
`Daralyn J. Durie
`Pro Hac Vice Application Pending
`Durie Tangri LLP
`217 Leidesdorff Street
`San Francisco, CA 94111
`
`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
`____________________________________________
`
`Case IPR2015-01624
`Patent 6,331,415
`____________________________________________
`
`PATENT OWNERS’ PRELIMINARY RESPONSE UNDER
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`37 C.F.R. § 42.107
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`Patent Owners’ Preliminary Response IPR2015-01624
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`TABLE OF CONTENTS
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`Page(s)
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`Introduction ......................................................................................................... 1 
`I. 
`II.  The Cabilly ‘415 Patent Claims .......................................................................... 7 
`III.  Claim Construction .......................................................................................... 9 
`IV.  Background of the Technology ..................................................................... 10 
`A.  Antibodies Are Large, Complex Multimeric Proteins .................................. 11 
`B.  As of April of 1983, Protein Production Using Recombinant DNA
`Technology Was Still in Its Infancy ..................................................................... 13 
`C.  In April of 1983, Insulin, the Only Multimeric Protein Produced Using
`Recombinant DNA Technology, Was Produced by Expressing Each Subunit in a
`Separate Host Cell ................................................................................................ 16 
`D.  The “Mindset” of a Person of Ordinary Skill in the Art at the Time of the
`Invention ............................................................................................................... 18 
`1.  Substantial Evidence Demonstrates That an Ordinarily Skilled Person
`Would Approach Production of Multimeric Proteins by Producing One Protein
`of Interest Per Host Cell in April of 1983 ......................................................... 19 
`2.  Petitioners Have Failed To Demonstrate a Countervailing “Mindset” of
`Multiple Proteins in One Host Cell as of April of 1983 ................................... 22 
`E.  The Cabilly ‘415 Patent Inventors Advanced the Art by Demonstrating That
`Recombinant Heavy And Light Chains Could Be Co-Expressed in a Single Host
`Cell to Produce Functional Antibodies ................................................................ 26 
`V.  Each Of Petitioners’ Proposed Grounds Is Deficient and Repetitive of
`Arguments Already Rejected During Reexamination ............................................. 27 
`A.  Petitioners Have Not Shown a Reasonable Likelihood That Bujard
`Anticipates Claims 1, 3-4, 9, 11-12, 15-17, 19 or 33 ........................................... 28 
`1.  Bujard (Ex. 1002) ....................................................................................... 29 
`2.  Bujard Does Not Anticipate Independent Claims 1, 15, 17, and 33 .......... 30 
`3.  Bujard Does Not Anticipate Dependent Claims 3, 4, 9, 11, 12, 16, and 19
` ……………………………………………………………………………46 
`B.  Claims 1, 3-4, 11-12, 14, 19, and 33 Are Not Obvious Over Bujard in View
`of Riggs & Itakura ................................................................................................ 47 
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`Patent Owners’ Preliminary Response IPR2015-01624
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`1.  Riggs & Itakura (Ex. 1003) ........................................................................ 47 
`2.  Petitioners Have Failed to Demonstrate a Reasonable Likelihood of
`Success .............................................................................................................. 48 
`C.  Claims 1, 2, 18, 20 and 33 Are Not Obvious Over Bujard in View of
`Southern ................................................................................................................ 50 
`1.  Southern (Ex. 1004) ................................................................................... 50 
`2.  Petitioners Have Failed to Demonstrate a Reasonable Likelihood of
`Success .............................................................................................................. 51 
`D.  Claims 1, 3-4, 11-12, 14, and 33 Are Not Obvious in View of Cohen &
`Boyer in Combination With Riggs & Itakura ...................................................... 52 
`1.  Cohen & Boyer (Ex. 1005) ........................................................................ 53 
`2.  Petitioners’ Arguments Regarding the Prior Art’s Disclosure of “Genes”
`and “Antibodies” Have Already Been Rejected ............................................... 54 
`3.  Petitioners Have Failed to Demonstrate a Reasonable Likelihood of
`Success .............................................................................................................. 54 
`VI.  The Petition Should Be Denied Under 35 U.S.C. § 325(d) ........................... 58 
`VII.  The Grounds Presented in the Petition Are Redundant ................................. 59 
`VIII.  Conclusion ..................................................................................................... 60 
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`Patent Owners’ Preliminary Response IPR2015-01624
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`TABLE OF AUTHORITIES
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`
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`Page(s)
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`Cases
`
`Fortinet, Inc. v. Sophos Inc.,
`IPR2015-00617, Paper 9 (Aug. 13, 2015) .........................................................................50, 58
`
`Hopkins Mfg. Corp. v. Cequent Performance Prods., Inc.,
`IPR2015-00616, Paper 9 (Aug. 17, 2015) ...............................................................................40
`
`Int’l Securities Exchange, LLC v. Chicago Board Options Exchange, Inc.,
`IPR2014-00099, Paper 12 (May 22, 2014) ..............................................................................40
`
`Integrated Global Concepts, Inc. v. Advanced Messaging Techs., Inc.,
`IPR2014-01027, Paper 16 (Dec. 22, 2014) ..............................................................................59
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) .................................................................................................................48
`
`Motorola, Inc. v. Interdigital Tech. Corp.,
`121 F.3d 1461 (Fed. Cir. 1997)................................................................................................44
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`Net MoneyIN, Inc. v. VeriSign, Inc.,
`545 F.3d 1359 (Fed. Cir. 2008)..........................................................................................28, 38
`
`Nora Lighting Inc. v. Juno Mfg., LLC,
`IPR2015-00601, Paper 13 (Aug. 12, 2015) .............................................................................58
`
`Oracle Corp. v. Clouding IP, LLC,
`IPR2013-00088, Paper 13 (June 13, 2003) ..............................................................................60
`
`Therasense, Inc. v. Becton, Dickinson & Co.,
`593 F.3d 1325 (Fed. Cir. 2010)................................................................................................28
`
`Trintec Indus., Inc. v. Top-U.S.A. Corp.,
`295 F.3d 1292 (Fed. Cir. 2002)................................................................................................45
`
`Statutes and Regulations
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`35 U.S.C. § 325(d) ...............................................................................................................5, 58, 60
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`37 C.F.R. § 42.100(b) ....................................................................................................................10
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`Patent Owners’ Preliminary Response IPR2015-01624
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`I.
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`INTRODUCTION
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`In their Petition, Sanofi-Aventis U.S. LLC and Regeneron Pharmaceuticals,
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`Inc. (“Petitioners”) ask the Board to disregard the prior determinations of the
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`Patent and Trademark Office (the “Office”) that the claims of U.S. Patent No.
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`6,331,415 (the “Cabilly ‘415 patent”) define a patentable invention. The grounds
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`advanced by Petitioners, however, present arguments that were already thoroughly
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`considered, and ultimately rejected, by the Office in prior proceedings, and ignore
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`the substantial evidence considered by the Office in reaching that prior
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`determination.
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`Petitioners contend the primary prior art references it is advancing—Bujard
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`(Ex. 1002) and Cohen & Boyer (Ex. 1005)—describe or would have made obvious
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`the claimed invention, which requires production of an immunoglobulin by
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`independent expression of DNA sequences encoding the heavy and light chains in
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`a single transformed host cell. But this prior art does not show actual production
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`of an antibody, or doing so via a single transformed host cell as required by the
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`claims. If anything, the prior art advanced in the Petition is less probative on the
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`issues already considered and rejected by the Office.
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`Specifically, in earlier reexamination proceedings, the Office considered the
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`question whether the mere appearance of the plural term “genes” along with the
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`inclusion of the word “antibody” in a laundry list of types of proteins that could be
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`produced by the recombinant DNA methods described in the Axel patent (Ex.
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`1018) would have been read by the skilled person in April of 1983 as teaching or
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`suggesting production of heavy and light chains of an immunoglobulin in a single
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`transformed host cell. The Office considered that question in the context of
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`whether claims to producing a single antibody chain read in combination with
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`Axel’s references to “genes” and “antibodies” would have led the skilled person to
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`conclude production of both heavy and light antibody chains in a single
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`transformed host cell would have been obvious in April of 1983. The Office
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`concluded, in the face of substantial evidence to the contrary, it would not.
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`Petitioners ask the Office to ignore that past determination and find that the
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`same types of simplistic textual references to “genes” and “antibodies” teach
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`production of heavy and light chains of an antibody in a single transformed host
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`cell as the claims require. Indeed, Petitioners expressly ask the Board to find that
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`the Office was incorrect in ultimately determining that the parallel use of these
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`terms in the Axel patent was insufficient, despite the substantial evidence
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`considered by the Office.
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`Doing so would be substantively and legally improper. During the
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`reexamination of the Cabilly ‘415 patent, the Office thoroughly considered and
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`ultimately rejected the precise theories of unpatentability now being advanced in
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`the Petition. The Office found probative the substantial evidence presented by
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`Patent Owners during the proceeding, evidence that Petitioners largely ignore in
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`their Petition. The Board should dismiss the Petition because it does not advance a
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`new theory of unpatentability that is not cumulative of those considered by the
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`Office during the reexamination, and because it does not present evidence showing
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`the Office’s earlier determinations were incorrect.
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`The specific grounds advanced by the Petitioners cannot justify institution of
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`trial. First, Petitioners’ anticipation grounds based on Bujard (Ex. 1003) are
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`insufficient. Bujard fails to disclose many of the elements of the Cabilly ‘415
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`Patent claims, including the requirement for (i) independent expression of the light
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`and heavy immunoglobulin chains in a single transformed host cell and (ii) the
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`production of an intact immunoglobulin. In an attempt to navigate those fatal
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`defects, the Petition asserts that general references to “genes” and “antibodies”
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`within Bujard would have been read by the skilled person as inherently describing
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`these claim elements. But that assertion fails because Petitioners cannot establish
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`the skilled person would have read the general references in Bujard to “genes” and
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`“antibodies” as necessarily describing the introduction of recombinant heavy and
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`light chain DNA sequences into a single host cell, co-expressing the heavy and
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`light chain DNA sequences as separate molecules, and producing a functional
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`antibody. Indeed, such a manner of reading Bujard conflicts with the substantial
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`evidence in the record showing the skilled person would have read such terms as
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`suggesting production of only one polypeptide per host cell in April of 1983.
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`Second, the Petition contends but falls far short of establishing that the cited
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`prior art would have made the claimed invention obvious to a person of ordinary
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`skill in the art in April of 1983. Again, Petitioners’ obviousness grounds fail to
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`rebut the substantial evidence showing that, in April of 1983, if a skilled person
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`were motivated to produce a recombinant antibody at all, such person would
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`follow the one-protein-of-interest-per-host cell method used for insulin. Such
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`method is described in, among other things, the Riggs & Itakura reference
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`specifically relied upon by Petitioners in their grounds for the contrary proposition.
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`Remarkably, Petitioners and their declarant make no effort to dispute the
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`technical underpinnings of the expert opinions considered during the
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`reexamination and advance no new historical evidence showing that the experts’
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`depiction of the mindset of the skilled person in April of 1983 was inaccurate.
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`Instead, Petitioners and their declarant advance the same linguistic arguments
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`already considered and rejected by the Office during the reexamination.
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`For example, during the reexamination proceedings, Patent Owners
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`submitted declarations from six different scientific experts working in the field of
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`the invention prior to April of 1983. Those declarations relied on numerous
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`scientific publications as well as the substantial personal experience of the experts
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`before April of 1983. The expert declarations accurately depicted the perspective
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`of how a skilled person would have approached the task of producing a complex
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`multimeric1 protein such as an antibody in April of 1983. Among other things, the
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`experts described the emerging nature of the genetic engineering techniques being
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`used to produce proteins at that time and identified the lack of demonstrated
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`successes in producing large, complex proteins. The experts explained this
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`perspective would have given those working in the field little confidence that a
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`multimeric protein as complex as an antibody could be produced recombinantly by
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`co-expressing both heavy and light chains as separate molecules in a single host
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`cell.
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`The experts also explained why the prior art would not have steered a skilled
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`person toward the recombinant production of antibodies through co-expression of
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`the heavy and light chains in a single host cell, let alone given them confidence
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`that such an endeavor would be successful. For example, several of the experts
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`noted that the only example of successful production of a eukaryotic multimeric
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`protein before the Cabilly ‘415 patent—the production of insulin, a far less
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`complex protein than an antibody—employed a strategy of separately producing
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`1 A multimeric protein consists of multiple polypeptides associated through non-
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`covalent interactions or disulfide bonds. Ex. 2003, McKnight Decl. II at FN 12.
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`each chain of the protein in a host cell, isolating each chain from its independent
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`culture, and then combining the separately produced insulin chains in a test tube.
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`Collectively, this evidence established that the skilled person, in April of
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`1983, would not have found a method of producing an antibody via the co-
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`transformation and co-expression steps of the Cabilly ‘415 patent claims to have
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`been obvious over prior art that is substantively indistinguishable from the prior art
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`advanced by Petitioners.
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`That conclusion is fully consistent with the contributions of the Cabilly ‘415
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`patent, which represents a groundbreaking advance in the biotechnology
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`industry—the first successful production of an active antibody by co-expression of
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`the light and heavy chains of the antibody in a single co-transformed host
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`cell. The Petition presents no evidence that at the time of the invention in April of
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`1983, any lab had achieved such a breakthrough.
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`The Cabilly ‘415 patent also has been subjected to more than thirteen years
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`of Office-related proceedings, including: (i) its original examination; (ii) an
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`interference proceeding and related section 146 litigation; and (iii) a merged ex
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`parte reexamination proceeding. It has likewise emerged unscathed from six
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`different federal court litigations. The claimed inventions of the Cabilly ‘415
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`patent have been widely adopted and extensively licensed by the biotechnology
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`industry. Between 1991 and November 2013, Patent Owners have granted a total
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`of 70 licenses under the Cabilly ‘415 patent, including at least 12 that were entered
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`into during pendency of the ex parte reexamination proceedings or afterward. See,
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`Ex. 2009, Walton Rep. at p. 22.
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`Against this record, and for these reasons explained herein, Patent Owners
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`respectfully request that the Board not institute trial on the basis of the Petition.
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`Alternatively, in view of the substantial similarity of the grounds presented in the
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`Petition to the issues addressed previously by the Office during reexamination,
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`Patent Owners request that the Board decline to institute trial under 35 U.S.C. §
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`325(d).
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`II. THE CABILLY ‘415 PATENT CLAIMS
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`The Petition challenges claims 1-4, 9, 11, 12, 14-20 and 33 of the Cabilly
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`‘415 patent. Independent claims 1 and 33 define processes, and are reproduced
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`below for convenience of the panel:
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`1. A process for producing an immunoglobulin molecule or an
`immunologically functional immunoglobulin fragment comprising at
`least the variable domains of the immunoglobulin heavy and light
`chains, in a single host cell, comprising the steps of:
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`(i) transforming said single host cell with a first DNA sequence
`encoding at least the variable domain of the immunoglobulin heavy
`chain and a second DNA sequence encoding at least the variable
`domain of the immunoglobulin light chain, and
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`(ii) independently expressing said first DNA sequence and said
`second DNA sequence so that said immunoglobulin heavy and light
`chains are produced as separate molecules in said transformed single
`host cell.
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`33. A process for producing an immunoglobulin molecule or an
`immunologically functional immunoglobulin fragment comprising at
`least the variable domains of the immunoglobulin heavy and light
`chains, in a single host cell, comprising:
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`independently expressing a first DNA sequence encoding at least the
`variable domain of the immunoglobulin heavy chain and a second
`DNA sequence encoding at least the variable domain of the
`immunoglobulin light chain so that said immunoglobulin heavy and
`light chains are produced as separate molecules in said single host cell
`transformed with said first and second DNA sequences.
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`Independent claim 15 recites a single vector that contains the DNA
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`sequences for both the heavy and light chain at different insertion sites, which is
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`used to transform the single host cell, and independent claim 18 recites a host cell
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`transformed with at least two separate vectors (one that includes heavy chain DNA
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`and one that includes light chain DNA). See, Ex. 1001 at 29:22-27, 31-36.
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`During reexamination of the Cabilly ‘415 patent, Dr. Steven L. McKnight,
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`Distinguished Chair in Basic Biomedical Research and The Sam G. Winstead and
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`F. Andrew Bell Distinguished Chair in Biochemistry at the University of Texas
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`Southwestern Medical Center, described the requirements of the claims to the
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`Office as follows:
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`The ‘415 patent requires the production of an immunoglobulin
`molecule[2] . . . by expression of DNA sequences encoding both
`heavy and light immunoglobulin chain polypeptides in a single
`transformed host cell. This means that all of the following things
`must happen:
`(i) host cells must have been successfully transformed with DNA
`sequences encoding the heavy and light chain polypeptide sequences;
`(ii) the transformed host cell must independently express both
`sequences (e.g., each DNA sequence must be accurately transcribed
`into an mRNA, and each mRNA must be translated into an
`appropriate amino acid sequence corresponding to each chain); and
`(iii) the polypeptides must be assembled into an immunoglobulin
`tetramer . . . either inside or outside of the cell.
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`Ex. 2003, McKnight Decl. II at ¶4. Petitioners do not dispute that these are
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`requirements of the challenged process claims.
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`III. CLAIM CONSTRUCTION
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`In an inter partes review, the terms of the claims are to be given their
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`broadest reasonable interpretation in light of the specification as commonly
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`2 The Cabilly ‘415 patent claims recite “immunoglobulins.” Petitioners argue that
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`the term “immunoglobulin” is interchangeable with “antibody.” Paper 1 at 4 n.1.
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`For purposes of this Response, Patent Owners also use the terms interchangeably.
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`understood by those of ordinary skill in the art.3 See, 37 C.F.R. § 42.100(b).
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`Petitioners take the position that they “do not believe any special meanings apply
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`to the claim terms in the ‘415 Patent.” Paper 1 at 16. For purposes of this
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`Preliminary Response, Patent Owners do not dispute Petitioners’ position.
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`IV. BACKGROUND OF THE TECHNOLOGY
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`The technology background of the Cabilly ‘415 patent has been discussed at
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`length both before the Office and in District Court litigations involving the Cabilly
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`‘415 patent. From those earlier proceedings, the following pertinent facts have
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`been established, which the Petition does not dispute:
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`
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`3 For the limited purpose of this Preliminary Response, Patent Owners deem it
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`unnecessary to contest the level of ordinary skill in the art. The level of ordinary
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`skill in the art identified by Petitioners, Paper 1 at 15, is consistent with that
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`identified during reexamination and litigation. See, e.g., Ex. 2001, Fiddes Rep. at
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`¶37 (“Ph.D. in molecular biology or related discipline, such as biochemistry,
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`microbiology or cell biology plus two to three years post-doctoral training and
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`experience (whether in academia or industry) in the application of recombinant
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`DNA technology to protein production”).
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`A. Antibodies Are Large, Complex Multimeric Proteins
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`As shown in Figure 1 of the Cabilly ‘415 patent (Ex. 1001), an antibody is a
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`multimeric protein composed of
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`four polypeptide chains.
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`Naturally occurring antibodies
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`consist of two identical “heavy”
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`chains (or “H” chains) and two
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`identical “light” chains (or “L”
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`chains) that form what is
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`schematically depicted as a Y-
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`shaped molecule. Ex 1001 at 3:17-27; Ex. 2005, Harris Decl. II at ¶17.
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`A disulfide bond joins each L chain to a respective H chain, forming the
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`“arms” of the Y, and three disulfide bonds join the two H chains at the top of the
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`“stalk” of the Y. Id. The heavy and light chains are so-called because they differ
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`in molecular weight. Ex. 2001, Fiddes Rep. at ¶42.
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`Antibodies are large, complex molecules. For example, each heavy chain of
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`an antibody of the immunoglobulin G (“IgG”) isotype contains about 447 amino
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`acids and has a molecular weight of about 50,000 Daltons. Ex. 2001, Fiddes Rep.
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`at ¶42. Each light chain of an IgG isotype antibody contains about 214 amino
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`acids and has a molecular weight of about 25,000 Daltons. Id. The molecular
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`weight of an IgG antibody made up of two heavy and two light chains is thus about
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`150,000 Daltons. Id.
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`Before April of 1983, scientists could create antibodies to an antigen by
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`immunizing an animal (e.g., a rat, mouse, or rabbit) with the antigen. See
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`generally, Ex. 1001 at 1:42-2:19. This technique generated a mixture of antibodies
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`with each antibody in the mixture binding to a unique epitope on the antigen. Id.
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`These antibodies are called polyclonal antibodies because they are produced by
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`multiple different cell lines in the animal in response to the foreign antigen. Id.
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`The therapeutic usefulness of polyclonal antibodies is limited to some degree,
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`however, because, by definition, these antibodies have varying specificities (i.e.,
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`they bind to a variety of locations on an antigen). Ex. 1001 at 1:61-63.
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`Today, it is understood that many therapeutic applications require antibodies
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`specific to the same part of a single antigen, i.e., monoclonal antibodies. Ex. 1001
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`at 1:63-2:11. As the name suggests, monoclonal antibodies are produced by a
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`single cell line, have the same amino acid sequence, and have the same specificity
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`to a given antigen, i.e., they all bind to the same part of the antigen, called an
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`epitope. Id. The production of monoclonal antibodies was significantly advanced
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`by the development of hybridoma techniques in 1975 by Georges Kohler and
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`Cesar Milstein. A “hybridoma” results from the fusion of a cancer cell with an
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`antibody-producing B-cell, which has the advantage of that the fused cell is
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`“immortalized” by the inclusion of the cancer cell. Ex. 2013, Kohler and Milstein.
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`As a result, the hybridoma can be grown in cell culture and the antibody naturally
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`produced by the fused B-cell can be produced. Id.
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`By April of 1983, the hybridoma technique was being used, but was limited.
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`Specifically, the antibodies that were produced were what the animal being
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`immunized would generate in response to immunization with the antigen. Ex.
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`1001 at 2:62-66. It was not possible to know, a priori, the sequence of the
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`antibody or what its particular binding properties would be. Id. A significant
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`need, thus, existed in 1983 for an alternative way to produce antibodies. Id. at
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`2:40-3:2.
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`B. As of April of 1983, Protein Production Using Recombinant DNA
`Technology Was Still in Its Infancy
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`One of skill in the art would have faced various uncertainties if he or she
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`endeavored to try to recombinantly express any protein in April of 1983. This is
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`because, as Dr. McKnight explained, as of April of 1983, “many of the biological
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`mechanisms that controlled expression of foreign DNA and assembly of proteins
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`were not well understood.” Ex. 2003, McKnight Decl. II at ¶6. By April of 1983,
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`only a few proteins with known therapeutic value had been recombinantly
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`produced, and each success was considered a major scientific breakthrough. See,
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`e.g., Ex. 2005, Harris Decl. II at ¶12-13. Indeed, Dr. Timothy John Roy Harris,
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`Chief Executive Officer of Novasite Pharmaceuticals, shared his then-
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`contemporaneous perspective on producing proteins using recombinant DNA
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`techniques in April of 1983:
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`By early April of 1983, I was aware that a number of groups had
`successfully expressed polypeptides using recombinant techniques.
`These experiments generally involved expression of genes encoding
`relatively small polypeptides with simple tertiary structures (e.g.,
`monomeric or dimeric proteins). The state of the art in this time
`frame is reflected in a review paper I authored [Ex. 1027].
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`Ex. 2004, Harris Decl. at ¶16; see also, Ex. 2003, McKnight Decl. II at ¶7.
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`The Petition cites Dr. Harris’s review article, Paper 1 at 18, but fails to
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`address the fact that each and every one of the examples listed in the paper as
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`having been produced through recombinant DNA techniques involved a protein
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`that was significantly less complex than an antibody. As Dr. Harris explained, “all
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`but one of the[] examples [in Ex. 1027] concerned production of relatively simple
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`monomeric proteins. The exception was insulin . . . .” Ex. 2005, Harris Decl. II at
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`¶14; see also, Ex. 2001, Fiddes Rep. at ¶¶43-46.
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`Insulin is a relatively simple multimeric protein. It is made up of two
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`polypeptide chains linked by two inter-chain disulfide bonds, with one of the two
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`chains containing one intrachain disulfide bond. Ex. 2003, McKnight Decl. II at
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`¶10. The insulin A chain has 21 amino acids and the insulin B chain has 30 amino
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`acids, Ex. 2003, McKnight Decl. II at ¶10, and, as a result, the assembled insulin
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`Patent Owners’ Preliminary Response IPR2015-01624
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`protein has a significantly lower molecular weight than an antibody. Ex. 2001,
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`Fiddes Rep. at ¶52. By comparison, antibody light chains have between 210 and
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`220 residues and heavy chains have between 455 and 550 residues, an assembled
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`antibody weighs approximately 150 kD, and an antibody is a complex tetramer that
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`links four discrete polypeptides together via multiple disulfide bonds and non-
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`covalent interactions. Ex. 2003, McKnight Decl. II at ¶10; Ex. 2001, Fiddes Rep.
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`at ¶¶42, 49.
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`Like Dr. McKnight, Dr. Harris explained during the reexamination that the
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`complexity of a tetrameric antibody compared to the few monomeric recombinant
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`proteins, or the lone dimeric recombinant protein that had been produced as of
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`April of 1983, would have impacted the mindset of a person of ordinary skill in the
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`art in April of 1983, particularly with respect to how the person would have
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`approached producing each protein using recombinant DNA techniques:
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`“Based on [the] known structural characteristics of the tetrameric
`immunoglobulin molecule, I believe a person of ordinary skill in the
`art, in early April of 1983, would have expected that the production of
`an immunoglobulin tetramer using recombinant DNA techniques
`would have been a significantly more challenging undertaking than
`the types of projects described in my review article . . . .”
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`Patent Owners’ Preliminary Response IPR2015-01624
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`Ex. 2005, Harris Decl. II at ¶18.; see also, id. at ¶16 (in April of 1983 “I . . . was
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`not aware of any published reports . . . of production of a multimeric protein of the
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`size (~150 kD) or structural complexity of an immunoglobulin tetramer”).
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`C.
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`In April of 1983, Insulin, the Only Multimeric Protein Produced
`Using Recombinant DNA Technology, Was Produced by
`Expressing Each Subunit in a Separate Host Cell
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`As of April of 1983, the only successful report of a multimeric eukaryotic
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`protein produced using recombinant DNA techniques was insulin. See, Ex. 2001,
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`Fiddes Rep. at ¶48. Neither of the approaches taken for doing so inv