IPR2016-01373
`Patent Owners’ Preliminary Response
`
`
`Adam R. Brausa
`Reg. No. 60,287
`Daralyn J. Durie
`Pro Hac Vice Filed
`Durie Tangri LLP
`217 Leidesdorff Street
`San Francisco, CA 94111
`
`
`David I. Gindler
`Pro Hac Vice Filed
`Joseph M. Lipner
`Pro Hac Vice Filed
`Irell & Manella LLP
`1800 Avenue of the
`Stars, Suite 900
`Los Angeles, CA
`90067
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`Filed on behalf of Patent Owners Genentech, Inc. and City of Hope by:
`
`David L. Cavanaugh
`Reg. No. 36,476
`Owen K. Allen
`Reg. No. 71,118
`Heather M. Petruzzi
`Reg. No. 71,270
`Robert J. Gunther, Jr.
`Pro Hac Vice Filed
`Wilmer Cutler Pickering
`Hale and Dorr LLP
`1875 Pennsylvania Ave., NW
`Washington, DC 20006
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`____________________________________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`____________________________________________
`
`MERCK SHARP & DOHME CORP.,
`Petitioner,
`
`v.
`
`GENENTECH, INC. AND CITY OF HOPE,
`Patent Owners
`____________________________________________
`
`Case IPR2016-01373
`Patent 6,331,415
`____________________________________________
`
`PATENT OWNERS’ PRELIMINARY RESPONSE
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`

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`I. 
`
`II. 
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` IPR2016-01373
`Patent Owners’ Preliminary Response
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`TABLE OF CONTENTS
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` Page
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`INTRODUCTION ........................................................................................... 1 
`
`PRIOR PROCEEDINGS ................................................................................. 5 
`
`III.  TECHNOLOGY BACKGROUND ................................................................. 8 
`
`A.  As Of April 1983, There Were Numerous Perceived Challenges To
`Producing Eukaryotic Proteins Recombinantly. ........................................ 8 
`
`B. 
`
`C. 
`
`Before April 1983, Nobody Had Reported Recombinantly
`Producing Any Multimeric Eukaryotic Protein By Co-Expression
`In A Single Host Cell. .............................................................................. 10 
`
`As Of April 1983, A Skilled Artisan Would Have Viewed
`Producing An Antibody Recombinantly As Particularly
`Challenging. .............................................................................................. 12 
`
`IV.  THE CABILLY ’415 PATENT .................................................................... 17 
`
`A. 
`
`B. 
`
`The Invention ............................................................................................ 17 
`
`Industry Recognition ................................................................................ 18 
`
`V.  MERCK’S ASSERTED REFERENCES ...................................................... 19 
`
`A.  Axel .......................................................................................................... 19 
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`B.  Mulligan Papers ........................................................................................ 21 
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`C. 
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`D. 
`
`E. 
`
`Nobel Article ............................................................................................ 24 
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`Southern .................................................................................................... 26 
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`Builder ...................................................................................................... 27 
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`VI.  PERSON OF ORDINARY SKILL ............................................................... 28 
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`Patent Owners’ Preliminary Response
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`VII.  CLAIM CONSTRUCTION .......................................................................... 28 
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`VIII.  ARGUMENT ................................................................................................. 28 
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`A. 
`
`The Board Should Deny Institution Under 35 U.S.C. § 325(d). .............. 28 
`
`B.  Merck Has Not Shown A Reasonable Likelihood Of Success On
`Any Proposed Ground. ............................................................................. 33 
`
`1. 
`
`Each proposed ground should be denied because Merck has
`presented no new arguments to overcome Axel’s previously-
`determined deficiencies. ...................................................................... 35 
`
`2. 
`
`a) 
`
`b) 
`
`a) 
`
`b) 
`
`c) 
`
`d) 
`
`Axel does not disclose co-expression of multiple different
`eukaryotic genes. ............................................................................ 35 
`
`Axel’s generic reference to “antibodies” provides no
`guidance on how to make an antibody. .......................................... 38 
`
`Ground 1: Claims 1, 3-4, 11-12, 14-17, 19, and 33 would not
`have been obvious over the Mulligan papers in combination
`with Axel. ............................................................................................ 39 
`
`A person of ordinary skill would not have combined the
`Mulligan papers with Axel. ............................................................ 45 
`
`A person of ordinary skill would have had no reasonable
`expectation of success given the uncertainties surrounding
`antibody production. ...................................................................... 46 
`
`Axel does not disclose the recovery and assembly of
`functional antibodies. ..................................................................... 48 
`
`The invention of the Cabilly ’415 patent would not have
`been obvious to try. ........................................................................ 49 
`
`3. 
`
`Ground 2: Claims 1, 3-4, 11-12, 14-17, 19, and 33 would not
`have been obvious over the Mulligan papers in combination
`with Axel and in further view of the Nobel article. ............................ 51 
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`4. 
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`5. 
`
`a) 
`
`b) 
`
`Ground 3: Claims 1, 3-4, 11-12, 14-17, 19, and 33 would not
`have been obvious over the Mulligan papers in combination
`with Axel in further view of Builder. .................................................. 55 
`
`Ground 4: Claims 1-2, 11-12, 14, 18-20, and 33 would not
`have been obvious over Southern in combination with Axel. ............ 56 
`
`Southern does not disclose the co-expression of antibody
`heavy and light chains in a single host cell. ................................... 56 
`
`A person of ordinary skill would not have combined
`Southern with Axel. ....................................................................... 58 
`
`c)  Merck’s remaining arguments fail for the same reasons
`addressed with respect to Ground 1. .............................................. 59 
`
`6. 
`
`Ground 5: Claims 1-2, 11-12, 14, 18-20, and 33 would not
`have been obvious over Southern in combination with Axel in
`further view of Builder. ....................................................................... 61 
`
`C. 
`
`Objective Indicia Of Non-Obviousness Confirm The Patentability
`Of The Challenged Claims. ...................................................................... 61 
`
`D.  Merck’s “Simultaneous Invention” Argument Reinforces The
`Patentability Of The Challenged Claims. ................................................. 65 
`
`E.  Merck’s Proposed Grounds Are Duplicative. .......................................... 66 
`
`IX.  CONCLUSION .............................................................................................. 67 
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`Cases
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` IPR2016-01373
`Patent Owners’ Preliminary Response
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`TABLE OF AUTHORITIES
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` Page(s)
`
`Arendi S.A.R.L. v. Apple Inc.,
`__ F.3d __, 2016 WL 4205964 (Fed. Cir. Aug. 10, 2016) ........................... 45, 58
`
`Ariosa Diagnostics, Inc. v. Illumina, Inc.,
`IPR2014-01093, Paper 14 (P.T.A.B. Jan. 8, 2015) ............................................ 55
`
`Continental Can Co. USA, Inc. v. Monsanto Co.,
`948 F.2d 1264 (Fed. Cir. 1991) .......................................................................... 63
`
`Crocs, Inc. v. International Trade Commission,
`598 F.3d 1294 (Fed. Cir. 2010) .......................................................................... 62
`
`Ecolochem, Inc. v. Southern California Edison Co.,
`227 F.3d 1361 (Fed. Cir. 2000) .......................................................................... 65
`
`Institut Pasteur & Universite Pierre et Marie Curie v. Focarino,
`738 F.3d 1337 (Fed. Cir. 2013) .......................................................................... 62
`
`Integrated Global Concepts, Inc. v. Advanced Messaging Techologies, Inc.,
`IPR2014-01028, Paper 13 (P.T.A.B. Dec. 22, 2014) ......................................... 37
`
`InTouch Technologies, Inc. v. VGO Communications, Inc.,
`751 F.3d 1327 (Fed. Cir. 2014) .......................................................................... 49
`
`Kinetic Concepts, Inc. v. Smith & Nephew, Inc.,
`688 F.3d 1342 (Fed. Cir. 2012) .......................................................................... 64
`
`KSR International Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................................ 50
`
`Monarch Knitting Machinery Corp. v. Sulzer Morat GmbH,
`139 F.3d 877 (Fed. Cir. 1998) ............................................................................ 64
`
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`Patent Owners’ Preliminary Response
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`Omron Oilfield & Marine, Inc. v. MD/Totco,
`IPR2013-00265, Paper 11 (P.T.A.B. Oct. 31, 2013) .......................................... 37
`
`Oracle Corp. v. Clouding IP, LLC,
`IPR2013-00088, Paper 13 (P.T.A.B. June 13, 2003) ......................................... 66
`
`PNC Bank, N.A. v. Secure Axcess, LLC,
`CBM2015-00039, Paper 9 (P.T.A.B. July 10, 2015) ......................................... 29
`
`Standard Oil Co. v. American Cyanamid Co.,
`774. F.2d 448, 454 (Fed. Cir. 1985) ................................................................... 65
`
`Technology Licensing Corp. v. Videotek, Inc.,
`545 F.3d 1316 (Fed. Cir. 2008) .......................................................................... 55
`
`Toyota Motor Corp. v. Cellport Systems, Inc.,
`IPR2015-01422, Paper 8 (P.T.A.B. Dec. 16, 2015) ........................................... 29
`
`Transocean Offshore Deepwater Drilling, Inc. v. Maersk Drilling USA, Inc.,
`699 F.3d 1340 (Fed. Cir. 2012) .......................................................................... 62
`
`Statutes
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`35 U.S.C.
`
`
`
`
`
`§ 315 ................................................................................................................ 3, 29
`
`§ 325 .................................................................................................... 1, 28, 29, 31
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`Legislative Materials
`
`H.R. Rep. No. 112-98 (2011), reprinted in 2011 U.S.C.C.A.N. 67 ........................ 31
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`v
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`I.
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`INTRODUCTION
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` IPR2016-01373
`Patent Owners’ Preliminary Response
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`This proceeding involves one of the foundational inventions of modern
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`biotechnology: proof that functional antibodies can be produced recombinantly by
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`co-expressing their heavy and light chains in just one host cell. That revolutionary
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`invention gave rise to an entirely new field—the therapeutic use of recombinant
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`antibodies—and is protected by U.S. Patent No. 6,331,415 (“the Cabilly ’415
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`patent”) (Ex. 1001). Recognizing the importance of that invention, the world’s
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`most sophisticated biotechnology companies have paid well over a billion dollars
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`to license it for use in making therapeutic antibodies for a wide range of diseases.
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`The Cabilly ’415 patent has also been one of the most scrutinized patents in
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`history. It has been challenged in two reexaminations, several IPRs, and multiple
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`litigations—collectively involving hundreds of cited references. Yet, these many
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`proceedings have failed to unearth any reference before the patent’s April 1983
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`filing date disclosing the recombinant production of the different polypeptide
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`chains of any multimeric eukaryotic protein as separate molecules in a single host
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`cell—let alone a protein as large and complex as an antibody. The present petition
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`is no different and should be denied for several reasons.
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`First, the Board should decline to institute under 35 U.S.C. § 325(d). For
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`each proposed ground, Merck relies on Axel (Ex. 1006)—the only reference
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`underlying Merck’s proposed grounds that even mentions antibodies. But the
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`Patent Office previously confirmed the challenged claims over Axel, and recently
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`instituted IPR2016-00710 based on art (Bujard, Ex. 2030) that the Board has found
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`is “more specific and robust than the Axel reference.” Indeed, even Dr. Richard
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`Axel—lead inventor of the Axel patent—has supported the patentability of the
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`Cabilly invention. (Ex. 2032.) Simply put, it would be wasteful to institute based
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`on art found to be weaker than that already under consideration in IPR2016-00710.
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`Moreover, in its petition, Merck relies on Southern (Ex. 1005) for proposed
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`Grounds 4 and 5, and asserts that Southern is the culmination of the work
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`described in the Mulligan papers (Exs. 1002-03) and Nobel article (Ex. 1004)
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`underlying proposed Grounds 1-3. But the Patent Office considered Southern
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`during reexamination of the Cabilly ’415 patent—despite Merck’s claims to the
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`contrary. And the Board also is presently considering Southern in IPR2016-00710,
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`and recently declined to institute grounds relying on Southern in IPR2016-00383.
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`Because Merck does not present any new interpretation of Southern here, the
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`Board should decline to institute on any ground for this additional reason.
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`In addition, on October 11, 2016, Merck filed a separate petition (IPR2017-
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`00047) addressing the same art and grounds presented in IPR2016-00710—
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`including based on Bujard and Southern—and also requested to join IPR2016-
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`00710. If joinder is granted, the earlier final written decision in that consolidated
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`proceeding will estop Merck on any instituted ground in this proceeding under
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`35 U.S.C. § 315(e)(1). To prevent needless waste of agency and party resources,
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`the petition should be denied for this reason as well.
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`Second, Merck’s petition fails on the merits. Each of Merck’s proposed
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`grounds rests on Axel. But Axel is merely directed to generic recombinant DNA
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`techniques, and only mentions the word “antibodies” in passing within a broad list
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`of other proteins—without providing any teaching specific to antibodies. Given
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`that bare disclosure, the Patent Office previously found that Axel failed to teach
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`the Cabilly ’415 invention, and Merck presents no reason for a different conclusion
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`here.
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`The Mulligan papers, Nobel article, and Southern do not cure Axel’s
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`deficiencies. None of those references mentions antibodies or discloses co-
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`expressing the different polypeptide chains of any multimeric eukaryotic protein in
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`a single host cell—and certainly not one as large and complex as an antibody.
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`Instead, Merck points to generic terms in the references such as “genes,” “genes of
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`interest,” “clusters of genes,” and “DNA segments.” Such generalized terms do
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`not teach the co-expression of antibody heavy and light chains in a single host cell,
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`as required by every challenged claim. Indeed, following Merck’s reasoning
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`would lead to the untenable conclusion that the same generalized references teach
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`the recombinant production of any protein by any means.
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`Merck also contends that the prior art disclosure of vectors with multiple
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`restriction sites teaches co-expressing the subunits of a multimeric eukaryotic
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`protein in a single host cell. But vectors with multiple restriction sites have existed
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`since at least the mid-1970s, and as of April 1983, scientists were using those
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`different sites for purposes having nothing to do with such co-expression. Merck
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`provides no explanation why a skilled artisan would have viewed the existence of
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`multiple restriction sites as suggesting co-expression, as opposed to their actual
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`established uses at the time.
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`Merck notes that the vectors described in the Mulligan papers, Nobel article,
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`and Southern were widely known. But that only reinforces the non-obviousness of
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`the challenged claims. Despite widespread knowledge and use of those vectors
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`starting in 1980, Merck has failed to identify a single instance before April 1983 in
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`which anyone (including the prolific authors of those publications and Merck’s
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`declarants in this proceeding) used the disclosed vectors—or any other vectors—to
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`co-express different polypeptide units of any multimeric eukaryotic protein, much
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`less an antibody, in a single host cell.
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`Merck’s decades-later argument that its cited art suggests co-expressing
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`antibody heavy and light chains in a single host cell is pure hindsight. That
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`conclusion is confirmed by indisputable evidence that (i) at the time of the
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`Mulligan papers and Nobel article, world-leading antibody scientists such as
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`Dr. César Milstein still were uncertain whether antibodies could even be produced
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`recombinantly; and (ii) as of April 1983, extraordinarily-skilled antibody scientists
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`such as Sir Gregory Winter remained skeptical given the perceived “uncertainty”
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`and “unpredictability” of the underlying science.
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`Merck’s hindsight-driven assertions also cannot be squared with other
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`objective evidence—including the Cabilly ’415 patent’s extraordinary licensing
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`revenues. Merck attempts to minimize the Cabilly inventors’ achievement by
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`pointing to supposed evidence of “simultaneous invention.” But the subsequent
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`success of a handful of extraordinarily skilled scientists does not demonstrate that
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`the challenged claims would have been obvious to ordinarily skilled persons.
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`II.
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`Institution should be denied.
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`PRIOR PROCEEDINGS
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`Through its original examination, reexamination, and IPRs, the Patent Office
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`has already considered the Cabilly ’415 patent at length—including in connection
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`with Axel, which underlies each proposed ground. (Ex. 2005 at 4.) Indeed, Axel
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`was the key reference considered during reexamination. Merck represents that its
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`proposed grounds rely on other art and arguments not previously considered, but
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`that is incorrect.
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`For example, Merck asserts that the Mulligan papers and Southern “were
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`never cited to or considered by the PTO during prosecution or reexamination of the
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`’415 patent.” (Paper 1 at 27, 32.) But the Patent Office considered Mulligan 1981
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`and Southern during reexamination, as shown on the face of the reexamination
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`certificate. (Ex. 1001, Reexamination Certificate at 5-6; Ex. 2006 at 10, 12.)1
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`Merck also ignores that the Board has considered proposed obviousness grounds
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`relying on Southern and refused to institute. (IPR2016-00383, Paper 16 at 27-29.)
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`The Patent Office has also already concluded that Axel does not teach co-
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`expressing antibody heavy and light chains in a single host cell. (Ex. 2005 at 4.)
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`That conclusion was supported by declarations from several distinguished experts,
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`who explained that the process described in Axel would have only been suitable to
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`express a single gene together with a selectable marker. (Ex. 2007, Harris Decl.
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`¶¶ 20-30; Ex. 2008, McKnight Decl. ¶¶ 65-78; Ex. 2009, Botchan Decl. ¶¶ 48-62.)
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`It also was confirmed by Dr. Axel’s declaration filed in support of the patentability
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`of the Cabilly invention. (Ex. 2032.)2
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`1 Mulligan 1980 was not cited, but its disclosure is similar to Mulligan 1981.
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`Indeed, Merck’s petition addresses both references collectively. (Paper 1 at 27-
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`30.)
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`2
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`Dr. Axel supported the patentability of U.S. Patent No. 7,923,211, which is a
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`continuation of the Cabilly ’415 patent and also involves co-expressing antibody
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`heavy and light chains in a single host cell.
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`Merck portrays its obviousness arguments as different from the double-
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`patenting challenge raised during reexamination. (Paper 1 at 23.) But Merck’s
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`petition rests on the same interpretation of Axel that the Patent Office previously
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`rejected. (Compare Paper 1 at 39 (“[T]he Axel patent teaches the co-
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`transformation and co-expression of genes coding for eukaryotic proteins in a
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`eukaryotic host cell.”), with Ex. 2005 at 4 (“Axel et al did not teach co-expression
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`of two foreign DNA sequences ....”).)
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`The same is true for Builder (Ex. 1007), which Merck cites in Grounds 3 and
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`5. The Patent Office considered Builder during reexamination and squarely held it
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`“did not teach assembly of immunoglobulin tetramer” (Ex. 2005 at 6)—the very
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`teaching Merck attributes to Builder here (Paper 1 at 50).
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`Similarly, Merck relies upon the Mulligan papers for their disclosure of
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`vectors with multiple restriction sites and passing reference to “one or more
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`additional DNA segments.” (Paper 1 at 40.) But that generic reference to a
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`plurality of “DNA segments” is no different from other references previously
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`addressed by the Patent Office (e.g., Axel) referring to “genes,” “genes of interest,”
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`and other similarly generic terms.
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`The Patent Office did not previously consider the Nobel article. But Merck
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`admits that reference merely describes Dr. Paul Berg’s “work developing the pSV2
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`vector,” which is the subject of the previously-considered Mulligan 1981 and
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`Southern references. (Paper 1 at 31; id. at 48-49 (“[T]he Nobel Article is by the
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`same lead author as the Mulligan Papers and describes the same research as the
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`Mulligan Papers, including the development of the pSV2 vector.”).)
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`III. TECHNOLOGY BACKGROUND
`A. As Of April 1983, There Were Numerous Perceived Challenges
`To Producing Eukaryotic Proteins Recombinantly.
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`Merck characterizes the task of producing a eukaryotic protein from
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`recombinant DNA as known and predictable as of April 1983.3 But those
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`assertions are contrary to the actual state of the art. For instance, an article that
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`Dr. Timothy Harris published in April 1983—i.e., the same month the Cabilly ’415
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`patent was filed—confirms the technology was still nascent: “[I]t is clear that not
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`all the rules governing the expression of cloned genes have been elaborated and
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`those rules that do exist are still largely empirical.” (Ex. 2010 at 129.)
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`As the Harris article explained, there still were many perceived challenges
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`with producing eukaryotic proteins recombinantly, including (i) the presence of
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`introns (non-coding sequences) in eukaryotic genes; (ii) the different regulatory
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`3
`Prokaryotes are simple organisms, like bacteria, that lack a membrane-bound
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`nucleus and maintain their genetic material as circular DNA in the cytoplasm.
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`Eukaryotes are higher organisms that contain a nuclear membrane and distinct
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`chromosomes with their genetic material. (Ex. 2014 at 11-12, 15, 20, Table 1-1.)
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`signals found in eukaryotic DNA; (iii) the different codon usage in eukaryotic
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`genes; and (iv) factors “not well defined” affecting protein folding, solubility, and
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`post-translational modifications. (Id. at 131-33, 173.)
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`Given these obstacles, only a few relatively small and simple eukaryotic
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`proteins had been produced recombinantly by April 1983—as reflected in Harris’s
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`Table 2, which provided “an up to date summary of the higher eukaryotic proteins
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`that have been expressed in E. coli.” (Id. at 163-69, Table 2; Ex. 2007, Harris
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`Decl. ¶ 16 (describing listed proteins as “relatively small polypeptides with simple
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`tertiary structures”).) In the now-terminated IPR2015-01624 proceeding, both
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`parties’ technical experts (Drs. Jefferson Foote and John Fiddes) confirmed that
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`Harris had accurately described the uncertainties facing skilled artisans attempting
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`to produce eukaryotic proteins recombinantly in April 1983. (Ex. 2011, Foote
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`Dep. 76-79, 134-49; Ex. 2012, Fiddes Decl. ¶¶ 57, 72; see Ex. 2013, Silverstein
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`Dep. 28 (Axel co-inventor admitting he “had a lot of trouble” with recombinant
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`DNA techniques in early 1980s).)
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`Despite responding to other arguments that Patent Owners raised in that
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`prior IPR proceeding, Merck says nothing about Harris—including why Dr. Harris
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`would have described these perceived challenges and uncertainties as still existing
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`in April 1983, if Merck’s cited art had supposedly resolved them years earlier.
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`B.
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`Before April 1983, Nobody Had Reported Recombinantly
`Producing Any Multimeric Eukaryotic Protein By Co-Expression
`In A Single Host Cell.
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`Before the Cabilly ’415 invention, skilled artisans viewed recombinantly
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`producing a multimeric eukaryotic protein (i.e., one consisting of multiple
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`polypeptide chains) as especially challenging. At that time, only one multimeric
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`eukaryotic protein (insulin) was reported to have been produced recombinantly.
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`(Ex. 2010 at 163-69, Table 2.) That insulin work involved either producing
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`preproinsulin (a single polypeptide) or expressing the A and B chains in different
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`host cells (i.e., one polypeptide per host cell) and joining them afterward. (Ex.
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`1067; Ex. 2012, Fiddes Decl. ¶¶ 81-91; Ex. 2011, Foote Dep. 103, 109-11; Ex.
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`2015, Harris Decl. II ¶ 14.)
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`This insulin work reflected a basic reality of prior art recombinant
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`eukaryotic protein techniques: all used one host cell per polypeptide. Indeed,
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`despite numerous proceedings challenging the Cabilly ’415 patent, the record is
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`devoid of a single example in which anyone produced a multimeric eukaryotic
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`protein recombinantly via co-expression in a single host cell before April 1983.
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`And numerous experts have consistently confirmed that, even today, they are
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`unaware of anyone who did so before the Cabilly inventors. (Ex. 2011, Foote Dep.
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`114-15; Ex. 2012, Fiddes Decl. ¶¶ 127-28; Ex. 2015, Harris Decl. II ¶¶ 15-16; Ex.
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`2016, McKnight Decl. II ¶ 5; Ex. 2017, Rice Decl. ¶ 15.)
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`The present petition is no different. Merck points to pre-April 1983
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`experiments involving aspartate transcarbamoylase (“ATCase”). (Paper 1 at 19-
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`20.) ATCase, however, is a prokaryotic protein, and the genes encoding its two
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`polypeptide chains exist within a contiguous DNA sequence (i.e., an operon). (Ex.
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`1050 at 4023.)4 Co-expressing two prokaryotic genes that are naturally expressed
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`from a single contiguous piece of DNA under the control of the same promoter
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`provides no teaching or expectation that two different eukaryotic genes from
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`different locations in the genome (e.g., the genes encoding for antibody heavy and
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`light chains) could be recombinantly expressed in a single host cell. (Ex. 2012,
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`Fiddes Decl. ¶ 184.)
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`Merck asserts that there was a “prevailing mindset” that “recombinant DNA
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`technology could be used to produce multiple proteins of interest in a single host
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`cell” and that “a single host cell was the preferred choice for producing the heavy
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`and light chains of an immunoglobulin.” (Paper 1 at 16, 38.) But there can hardly
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`be a “prevailing mindset” or “preferred choice” for an approach that no one had
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`previously used. It would not have been obvious for a person of ordinary skill in
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`Operons are naturally-occurring sequences of prokaryotic genes under the
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`control of a single operator/promoter region. They are unrelated to whether
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`multiple eukaryotic genes could be co-expressed. (Ex. 2012, Fiddes Decl. ¶ 184.)
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`April 1983 to select a single-host-cell-approach to produce an antibody when that
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`technique had never been used to make any multimeric eukaryotic protein before.
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`C. As Of April 1983, A Skilled Artisan Would Have Viewed
`Producing An Antibody Recombinantly As Particularly
`Challenging.
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`A typical antibody consists of four polypeptide chains (two light chains and
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`two heavy chains) joined together in a “Y”-shape:
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`(Ex. 1001, Fig. 1.) Antibodies are significantly larger and more complex than
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`other eukaryotic proteins made recombinantly as of April 1983. (Ex. 2011, Foote
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`Dep. 107 (admitting no eukaryotic protein listed in Harris is as large as an
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`assembled antibody).) For example, the immunoglobulin G (“IgG”) isotype
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`contains more than 1,300 amino acids, has a molecular weight of about 150,000
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`Daltons, and is joined together by 12 intra-chain and 4 inter-chain disulfide bonds.
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`(Ex. 2012, Fiddes Decl. ¶¶ 39-45; Ex. 2011, Foote Dep. 86, 105-06.)
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`By contrast, insulin—the only multimeric eukaryotic protein produced
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`recombinantly before April 1983—contains only 51 amino acids, has a molecular
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`weight of about 5,800 Daltons, and is joined together by 2 inter-chain disulfide
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`bonds and 1 intra-chain disulfide bond. (Ex. 2012, Fiddes Decl. ¶¶ 35-37; Ex.
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`2011, Foote Dep. 83, 116-18.) The larger size and complexity of an antibody
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`(right) as compared to insulin (left) is illustrated in the molecular models below:
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`(Ex. 2012, Fiddes Decl. ¶¶ 43-45.)
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`As of April 1983, a person of ordinary skill would have viewed extending
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`the recombinant techniques enabling insulin production to antibodies as a
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`significant and unpredictable undertaking. Indeed, leading scientists expressed
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`great uncertainty at the time as to whether antibodies could be recombinantly
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`produced. For example, in March 1981, an article reported then-recent comments
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`from Dr. César Milstein—a future Nobel laureate and leading antibody scientist.
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`Dr. Milstein speculated that antibodies might someday be produced using
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`recombinant DNA techniques. (Ex. 2018 at 409-10.) However, he acknowledged
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`that “there are very serious problems to be solved before such a scheme is carried
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`out” and that “[t]he way to proceed from here is clouded by uncertainties and
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`multiple possibilities.” (Id. at 410.)
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`Merck ignores these observations from Dr. Milstein because they cannot be
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`squared with Merck’s hindsight-driven and unsupported storyline that Axel, the
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`Mulligan papers, and the Nobel article all had already solved the same “very
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`serious problems” and “uncertainties” that Dr. Milstein identified as still existing at
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`the time.
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`The years leading up to the Cabilly ’415 patent confirmed the many
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`challenges forecast by Dr. Milstein. During that period, leading antibody scientists
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`encountered numerous uncertainties and unexplained results when attempting to
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`recombinantly express just a single antibody chain:
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` In 1982, Falkner & Zachau could not explain why they had failed to
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`express antibody light chain, speculating that “something may be missing
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`from our systems” or “some as yet undefined factors provided in tissue-
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`specific differentiation events may have a role.” (Ex. 2019 at 288.)
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` In December 1982, Dr. David Baltimore, a Nobel laureate, observed that
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`“relatively little is known about the molecular mechanisms that control
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`[antibody] gene expression.” (Ex. 1017 at 7862.)
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` In February 1983, Dr. Berg (co-author of the Mulligan papers and sole
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`author of the Nobel article) and his co-authors published the Oi paper, in
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`which these highly accomplished researchers could not explain why two
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`cell lines failed to produce any detectable light chain from recombinant
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`DNA. (Ex. 1045 at 827.)
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` In March 1983, Ochi reported introducing the gene encoding for antibody
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`light chain into cells already producing heavy chains, and could not
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`explain why nearly all cell lines had no detectable antibody production or
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`the observed “variability in gene expression.” (Ex. 1018 at 341-42.)
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`This uncertainty and unpredictability continued through April 1983.
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`Indeed, even Sir Gregory Winter—a world-leading antibody scientist—confirmed
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`that he was “uncertain in the spring of 1983 about how to express recombinant
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`antibodies,” and that he