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`IPR2015-01624
`Patent Owners’ Response
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`Filed on behalf of Patent Owners Genentech, Inc. and City of Hope by:
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`David L. Cavanaugh
`Reg. No. 36,476
`Heather M. Petruzzi
`Reg. No. 71,270
`Robert J. Gunther, Jr.
`Pro Hac Vice
`Wilmer Cutler Pickering
`Hale and Dorr LLP
`1875 Pennsylvania Ave., NW
`Washington, DC 20006
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`Adam R. Brausa
`Reg. No. 60,287
`Daralyn J. Durie
`Pro Hac Vice
`Durie Tangri LLP
`217 Leidesdorff Street
`San Francisco, CA 94111
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`Jeffrey P. Kushan
`Reg. No. 43,401
`Peter S. Choi
`Reg. No. 54,033
`Sidley Austin LLP
`1501 K Street, N.W.
`Washington, D.C.
`20005
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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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`____________________________________________
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`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
`____________________________________________
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`PATENT OWNERS’ RESPONSE
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`I.(cid:3)
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`II.(cid:3)
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`Patent Owners’ Response
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`TABLE OF CONTENTS
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`Page
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`INTRODUCTION ........................................................................................... 1(cid:3)
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`SUMMARY OF ARGUMENT ....................................................................... 3(cid:3)
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`III.(cid:3) TECHNOLOGY BACKGROUND ................................................................. 8(cid:3)
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`A.(cid:3)
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`B.(cid:3)
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`1.(cid:3)
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`2.(cid:3)
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`Proteins Vary In Size And Complexity. ..................................................... 8(cid:3)
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`Prior Art Antibody Production Techniques ............................................. 11(cid:3)
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`As of April 1983, polyclonal techniques were well known. ............... 11(cid:3)
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`As of April 1983, hybridoma techniques were being widely
`used to make monoclonal antibodies. ................................................. 11(cid:3)
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`C.(cid:3)
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`By April 1983, Recombinant DNA Techniques Were Not Well
`Understood And Had Only Been Used To Make Simple Proteins. ......... 12(cid:3)
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`D.(cid:3) As Of April 1983, Highly Acclaimed Scientists Were Uncertain
`Whether It Was Even Possible To Make Antibodies Using
`Recombinant DNA Techniques. ............................................................... 15(cid:3)
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`IV.(cid:3) THE CABILLY ’415 PATENT .................................................................... 19(cid:3)
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`A.(cid:3)
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`The Invention Of The Cabilly ’415 Patent ............................................... 19(cid:3)
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`B.(cid:3) Widespread Industry Recognition Of The Cabilly ’415 Invention .......... 22(cid:3)
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`V.(cid:3)
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`PROCEDURAL HISTORY .......................................................................... 23(cid:3)
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`A.(cid:3)
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`B.(cid:3)
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`C.(cid:3)
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`D.(cid:3)
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`The Panel’s Institution Decision .............................................................. 23(cid:3)
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`Prior Proceedings Involving The Cabilly ’415 Patent ............................. 23(cid:3)
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`Person Of Ordinary Skill In The Art ........................................................ 24(cid:3)
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`Claim Construction ................................................................................... 24(cid:3)
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`VI.(cid:3) ARGUMENT ................................................................................................. 24(cid:3)
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`A.(cid:3)
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`The Panel Should Reject Both Grounds Because Bujard Does Not
`Suggest Co-Expression In A Single Host Cell. ........................................ 24(cid:3)
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`1.(cid:3)
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`2.(cid:3)
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`3.(cid:3)
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`Summary of Bujard ............................................................................. 24(cid:3)
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`Bujard does not disclose any process for producing antibodies. ........ 25(cid:3)
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`Bujard does not disclose co-expressing multiple genes of
`interest in a single host cell. ................................................................ 29(cid:3)
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`a)(cid:3)
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`b)(cid:3)
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`c)(cid:3)
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`d)(cid:3)
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`Bujard’s “multimers” do not refer to a multi-chain protein,
`such as an antibody. ....................................................................... 29(cid:3)
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`“One or more structural genes” includes selectable markers,
`and is not a disclosure of the heavy and light chains of an
`antibody. ......................................................................................... 31(cid:3)
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`“A plurality of translational stop codons” efficiently
`terminates translation of a single gene. .......................................... 35(cid:3)
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`There was no “prevailing mindset” that multiple eukaryotic
`genes could be co-expressed in a single host cell. ......................... 36(cid:3)
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`4.(cid:3)
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`Petitioners’ remaining arguments about Bujard lack merit. ............... 37(cid:3)
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`a)(cid:3)
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`b)(cid:3)
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`“One or more hosts for gene expression” ...................................... 37(cid:3)
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`“Prepared as a single unit or as individual subunits” ..................... 39(cid:3)
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`B.(cid:3)
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`Ground 1: Claims 1, 3-4, 11-12, 14, 19, And 33 Would Not Have
`Been Obvious Over Bujard In View Of Riggs & Itakura. ....................... 40(cid:3)
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`1.(cid:3)
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`2.(cid:3)
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`Summary of Riggs & Itakura .............................................................. 41(cid:3)
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`A person of ordinary skill in the art would have had no reason
`to combine Bujard with Riggs & Itakura. ........................................... 42(cid:3)
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`3.(cid:3)
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`4.(cid:3)
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`5.(cid:3)
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`Bujard combined with Riggs & Itakura would have led to a two
`host cell approach, not the “single host cell” invention of the
`challenged claims. ............................................................................... 43(cid:3)
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`The Cabilly ’415 invention was not obvious to try. ............................ 46(cid:3)
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`A person of ordinary skill in the art would not have had a
`reasonable expectation of success in extending Riggs &
`Itakura’s techniques to antibodies. ...................................................... 49(cid:3)
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`C.(cid:3)
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`Ground 2: Claims 1, 2, 18, 20, And 33 Would Not Have Been
`Obvious Over Bujard In View of Southern. ............................................. 51(cid:3)
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`1.(cid:3)
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`2.(cid:3)
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`3.(cid:3)
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`4.(cid:3)
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`5.(cid:3)
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`6.(cid:3)
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`Summary of Southern .......................................................................... 52(cid:3)
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`A person of ordinary skill in the art would not have combined
`Bujard with Southern. ......................................................................... 53(cid:3)
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`Southern does not disclose including multiple “genes of
`interest” in separate vectors. ................................................................ 55(cid:3)
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`Other publications confirm that a skilled artisan would not have
`applied Southern to express heavy and light chains from
`separate vectors in the same host cell. ................................................ 58(cid:3)
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`A skilled artisan would have had no reasonable expectation of
`success in combining Bujard with Southern. ...................................... 58(cid:3)
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`Southern cannot invalidate claims 1, 2, and 33. .................................. 60(cid:3)
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`D.(cid:3) Objective Indicia Of Non-Obviousness Confirm The Patentability
`Of The Challenged Claims. ...................................................................... 60(cid:3)
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`VII.(cid:3) CONCLUSION .............................................................................................. 63(cid:3)
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`TABLE OF AUTHORITIES
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`Page(s)
`
`Allergan, Inc. v. Apotex Inc.,
`754 F.3d 952 (Fed. Cir. 2014) ............................................................................ 46
`
`Allergan, Inc. v. Sandoz Inc.,
`796 F.3d 1293 (Fed. Cir. 2015) .......................................................................... 45
`
`Amgen, Inc. v. AbbVie Biotechnology Ltd.,
`IPR2015-01514, Paper 9 (Jan. 14, 2016) ............................................................ 26
`
`Apotex Inc. v. Merck Sharpe & Dohme Corp.,
`IPR2015-00419, Paper 14 (June 25, 2015) ......................................................... 26
`
`Crocs, Inc. v. International Trade Commission,
`598 F.3d 1294 (Fed. Cir. 2010) .......................................................................... 60
`
`Institut Pasteur & Universite Pierre Et Marie Curie v. Focarino,
`738 F.3d 1337 (Fed. Cir. 2013) .......................................................................... 61
`
`Kinetic Concepts, Inc. v. Smith & Nephew, Inc.,
`688 F.3d 1342 (Fed. Cir. 2012) .................................................................... 45, 63
`
`KSR International Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ...................................................................................... 41, 46
`
`Ortho-McNeil Pharmaceutical, Inc. v. Mylan Laboratories, Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) .......................................................................... 46
`
`Panduit Corp. v. Dennison Manufacturing Co.,
`810 F.2d 1561 (Fed. Cir. 1987) .......................................................................... 44
`
`Rolls-Royce, PLC v. United Technologies Corp.,
`603 F.3d 1325 (Fed. Cir. 2010) .................................................................... 47, 48
`
`In re Rosuvastatin Calcium Patent Litigation,
`703 F.3d 511 (Fed. Cir. 2012) ............................................................................ 63
`
`Spectralytics, Inc. v. Cordis Corp.,
`649 F.3d 1336 (Fed. Cir. 2011) .......................................................................... 45
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`I.
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`INTRODUCTION
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`Patent Owners’ Response
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`The invention at issue in this proceeding is based on one of the foundational
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`discoveries of modern biotechnology: proof that functional antibodies can be
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`produced recombinantly by co-expressing their heavy and light chains in just one
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`host cell. That revolutionary invention gave rise to the therapeutic use of
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`recombinant monoclonal antibodies, and is protected by U.S. Patent No. 6,331,415
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`(“the Cabilly ’415 patent”) (Ex. 1001). Recognizing the importance of the Cabilly
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`’415 invention, dozens of the world’s most sophisticated biotechnology companies
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`have paid well over a billion dollars in licensing royalties for the right to utilize it
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`in producing therapeutic antibodies for a wide range of diseases.
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`The antibody production methods claimed in the Cabilly ’415 patent were
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`remarkable considering the state of the art when it was filed in April 1983. By that
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`time, an established path for producing monoclonal antibodies (using “hybridoma”
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`techniques) had already been developed, and the use of hybridomas was continuing
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`to expand. But the Cabilly inventors chose not to take that proven route and
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`instead pursued antibody production using recombinant DNA techniques.
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`By the early 1980s, only a few relatively simple proteins had been produced
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`recombinantly. And while some scientists had speculated that it might be possible
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`in the future to produce antibodies recombinantly, even persons of extraordinary
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`skill (including Nobel Laureates) were uncertain whether such a technique could
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`be used to make antibodies. Indeed, Petitioners’ expert, Dr. Jefferson Foote, now
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`agrees that, as of April 1983, producing an antibody recombinantly would have
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`been a major task without any certainty of success, and that the Cabilly inventors
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`were the first to successfully perform that undertaking.
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`The Cabilly inventors’ success in producing an antibody recombinantly was
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`itself a revolutionary advance in April 1983. But even more remarkable was that
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`the Cabilly inventors achieved that result by defying conventional wisdom and co-
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`expressing the heavy and light chains in a single host cell. Dr. Foote agrees that,
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`before April 1983, no one had produced any type of multimeric eukaryotic protein
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`by recombinantly producing its constituent polypeptides in a single host cell.
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`Indeed, the only multimeric eukaryotic protein that had been produced
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`recombinantly by that time was insulin, and it was made using two separate host
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`cells—one for each polypeptide chain. And even the references Petitioners cite
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`show that highly-skilled scientists were perplexed by their inconsistent and
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`frequently unsuccessful efforts to produce even a single antibody heavy chain or
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`light chain on its own. The fact that the Cabilly inventors succeeded by pursuing a
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`path contrary to the conventional standards at the time by co-expressing both
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`heavy and light chains in a single host cell was a major breakthrough.
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`Now, decades later, Petitioners seek to rewrite this history leading up to the
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`Cabilly ’415 patent by attributing its groundbreaking invention to others. But the
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`only way to reach that result is through a hindsight-driven analysis that is contrary
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`to the disclosure of the asserted references, the state of the art, and the real-world
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`objective evidence demonstrating non-obviousness. Petitioners rely on precisely
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`such an analysis, grounded almost exclusively in assertions by Dr. Foote. But at
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`his deposition, Dr. Foote was repeatedly forced to concede facts that directly
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`conflict with his declaration assertions and that are fatal to Petitioners’ obviousness
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`arguments.
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`Petitioners cannot sustain their burden to prove obviousness based on such a
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`flawed, hindsight-driven analysis. Accordingly, Patent Owners respectfully
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`request that the Panel affirm the patentability of the challenged claims.
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`II.
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`SUMMARY OF ARGUMENT
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`In its Institution Decision, the Panel found a reasonable likelihood that
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`certain challenged claims of the Cabilly ’415 patent would have been obvious over
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`U.S. Patent No. 4,495,280 (“Bujard”) (Ex. 1002) combined with either of two
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`articles (Riggs & Itakura (Ex. 1003) or Southern (Ex. 1004)). The full record now
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`refutes those initial conclusions.
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`Bujard: Bujard is the primary reference underlying both instituted grounds,
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`but discloses nothing about how to make an antibody. Indeed, Bujard’s only
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`mention of antibodies is in a large, generic list of “proteins of interest”—which Dr.
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`Foote originally cited as evidence that the Bujard inventors supposedly intended to
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`suggest making antibodies in a single host cell. But the record now shows that
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`same list of proteins (including antibodies) appears in dozens of unrelated
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`applications that Bujard’s prosecuting attorney had filed for others starting in 1975.
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`When confronted with that evidence, Dr. Foote admitted that Bujard’s list was
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`likely just recycled from those earlier applications. Petitioners can hardly infer any
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`key insight concerning antibody production from a list that has nothing to do with
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`Bujard’s invention.
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`The Panel pointed to isolated statements in Bujard referring to “a plurality of
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`genes, including multimers” and “one or more structural genes” as suggesting the
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`co-expression of antibody heavy and light chains in a single host cell. But that is
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`not how Bujard uses those terms, and certainly not how a skilled artisan would
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`have interpreted them in April 1983. Indeed, the only evidence supporting the
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`Panel’s initial interpretation of “multimers” was Dr. Foote’s opinion that the term
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`always refers to “a protein with more than one subunit.” But Dr. Foote now
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`concedes that his only citation for that assertion was a source from 2016, and that
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`other references now in the record—including from the Bujard inventors—use the
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`same term to refer to repeating copies of the same gene, just as it was used in
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`Bujard.
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`Nor did Bujard use the phrase “one or more structural genes” to refer to co-
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`expression of genes that encode different proteins of interest. Dr. Foote now
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`agrees that Bujard expressly defines a “structural gene” as including markers, and
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`that Bujard does not include any embodiment involving two genes encoding for
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`different proteins of interest.
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`Simply put, Bujard does not disclose or suggest co-expressing the heavy and
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`light chains in a single host cell. Had Bujard made that groundbreaking discovery,
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`the patent would have no doubt touted and claimed it—but it did not. And the
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`scientific literature would have cited Bujard for that remarkable advance—but
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`Bujard has never been cited for that purpose. The record also now includes
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`testimony from Dr. Reiner Gentz, who worked in Dr. Bujard’s lab in the early
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`1980s and co-authored the scientific paper corresponding to the Bujard patent. Dr.
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`Gentz is not aware of anyone in Dr. Bujard’s lab who contemplated using their
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`DNA constructs to co-express different eukaryotic proteins of interest in a single
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`host cell.
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`That testimony is confirmed by what became of the Bujard patent: it was
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`allowed to expire only four years after it issued for failure to pay maintenance fees.
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`That is hardly a result one would expect for a patent that supposedly renders
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`obvious one of the foundational inventions of modern biotechnology, and it
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`underscores how divorced Petitioners’ arguments are from the reality of what
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`Bujard actually discloses and how a skilled artisan in April 1983 would have
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`understood it.
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`Ground 1: Petitioners’ arguments based on an obviousness combination
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`with Riggs & Itakura does not cure the elements missing from Bujard, and only
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`highlights the non-obviousness of the challenged claims. Riggs & Itakura is a
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`review article describing the production of insulin from recombinant DNA, and
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`does not disclose any details that would have led to the Cabilly ’415 invention.
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`The technique that Riggs & Itakura describes for insulin undisputedly could not be
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`used to produce antibody polypeptides; different techniques would have to be
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`developed and used, as Dr. Foote admits. And even if its teachings had been
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`considered together with Bujard, Riggs & Itakura would have led a skilled artisan
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`away from co-expression; it describes producing insulin using two separate host
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`cells, one for each polypeptide subunit. Petitioners’ implausible theory that a
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`skilled artisan would have ignored the central teaching of Riggs & Itakura and
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`pursued the opposite approach to arrive at the Cabilly ’415 invention rests on
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`hindsight.
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`The Panel also concluded that the claimed invention would have been
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`obvious to try based upon the combination of Bujard with Riggs & Itakura. But all
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`of the prerequisites for that conclusion are absent here: (1) Bujard does not present
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`a finite number of options to pursue—it presents “millions,” as Dr. Foote admits;
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`(2) it was not predictable at the time that a recombinant DNA technique to make an
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`antibody would have led to success—as Dr. Foote also admits; and (3) the single
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`host cell approach claimed in the Cabilly ’415 patent was not an identified solution
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`that anyone had used before—which Dr. Foote now concedes as well.
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`Ground 2: The combination of Bujard with Southern fares no better.
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`Southern does not mention antibodies at all; it simply describes a new selectable
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`marker for use in eukaryotic cells. As Dr. Foote admits, Bujard’s bacterial
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`expression constructs would not be compatible in the host expression systems
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`addressed in Southern, and vice versa. Petitioners rely on Southern for its
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`supposed mention of two vectors used to express different genes of interest. But
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`Southern’s only discussion of a two-vector approach relates to unspecified
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`experiments supposedly “in progress” (but never reported) for testing markers (not
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`genes of interest). In fact, Southern does not disclose any embodiment involving
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`even one gene of interest. Thus, a skilled artisan in April 1983 would have viewed
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`the challenged claims as a significant and non-obvious advance over Southern.
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`Objective Indicia: Although not addressed in the Panel’s Institution
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`Decision, the record now includes substantial evidence of objective indicia of non-
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`obviousness: (1) the biotechnology industry has widely embraced the validity of
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`the Cabilly ’415 patent by taking numerous licenses at rates above industry
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`averages, amounting to licensing revenues well over a billion dollars; (2) using the
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`Cabilly ’415 patent invention, Genentech and others have made many
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`commercially successful products; and (3) at a time when leading scientists were
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`skeptical that the many challenges to producing an antibody from recombinant
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`DNA could be overcome, the Cabilly inventors not only succeeded, but did so in
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`an unexpected way—by co-expressing the heavy and light chains in a single host
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`cell. This objective evidence weighs heavily against a hindsight-based finding of
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`obviousness.
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`III. TECHNOLOGY BACKGROUND
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`A.
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`Proteins Vary In Size And Complexity.
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`There are a vast number of proteins, which vary in size and complexity.
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`Monomeric proteins consist of a single polypeptide chain, while multimeric
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`proteins are more complex structures that consist of multiple polypeptide chains
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`held together by covalent and/or non-covalent interactions. To perform their
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`intended biological function, a protein’s polypeptide chains must fold and
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`assemble into a particular three-dimensional shape. (Ex. 2019, Fiddes Decl. ¶¶ 24-
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`34.)
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`There are a wide variety of multimeric eukaryotic proteins. A simple
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`example is insulin, which has an A chain (21 amino acids) and a B chain (30 amino
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`acids) linked by two disulfide bonds (and a third intrachain bond):
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`(Id. ¶¶ 35-37; Ex. 2020, Foote Dep. 83, 116-18; Ex. 1003 at 532.)
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`This proceeding involves antibodies (also called immunoglobulins), which
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`are larger and far more complex than insulin. Antibodies play a critical role in the
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`body’s immune system by binding to “antigens”—foreign substances that provoke
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`an immune response. Each antibody consists of at least four chains—typically,
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`two identical heavy chains, and two identical light chains that assemble into a “Y”-
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`shape, as shown in Figure 1 from the Cabilly ’415 patent:
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`(Ex. 1001, 3:17-26, Fig. 1; Ex. 2019, Fiddes Decl. ¶¶ 38-42; Ex. 2020, Foote Dep.
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`86.) The larger size and complexity of an antibody (right) as compared to insulin
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`(left) is illustrated in the molecular models below:
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`(Ex. 2019, Fiddes Decl. ¶¶ 43-45.) An antibody of the immunoglobulin G (“IgG”)
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`isotype1 contains more than 1300 amino acids and has a molecular weight of about
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`150,000 Daltons, while insulin contains only 51 amino acids and weighs just 5,800
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`Daltons. (Id. ¶ 39; Ex. 2020, Foote Dep. 105-06.)
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`1 There are five classes of antibodies (IgG, IgD, IgE, IgA, and IgM), and each is
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`further divided into multiple different isotypes. (Ex. 2019, Fiddes Decl. ¶ 38.)
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`B.
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`Prior Art Antibody Production Techniques
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`1.
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`As of April 1983, polyclonal techniques were well known.
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`For decades before the Cabilly ’415 patent, antibodies could be produced by
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`immunizing an animal (e.g., mouse, rabbit) with an antigen, which generates a
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`polyclonal mixture of antibodies with different binding characteristics. By April
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`1983, polyclonal antibodies were widely used. (Ex. 1001, 1:45-63; Ex. 2019,
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`Fiddes Decl. ¶¶ 46-47.)
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`2.
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`As of April 1983, hybridoma techniques were being widely
`used to make monoclonal antibodies.
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`Many diagnostic and therapeutic applications require compositions that
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`contain only one type of antibody with uniform binding characteristics, called
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`“monoclonal” antibodies. Such monoclonal antibodies may be produced using
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`“hybridoma” techniques, which involve fusing an antibody-producing B cell with a
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`cancer cell. (Ex. 2019, Fiddes Decl. ¶¶ 48-50.)
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`Dr. César Milstein developed the first hybridoma technique in 1975 (for
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`which he won the Nobel Prize). By April 1983, hybridomas were being used
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`extensively to produce monoclonal antibodies, and these uses were “expanding
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`very rapidly,” with “many commercial companies beginning to market them.”
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`(Ex. 1039, Milstein at 407; Ex. 2019, Fiddes Decl. ¶ 50; Ex. 2020, Foote Dep. 37,
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`48-49 (hybridomas were a “very big” deal in the early 1980s due to “significant
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`achievements”); Ex. 1001, 1:64-2:11.)
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`C.
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`By April 1983, Recombinant DNA Techniques Were Not Well
`Understood And Had Only Been Used To Make Simple Proteins.
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`Recombinant DNA techniques allow for the production and isolation of a
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`protein of interest in a foreign, i.e., “heterologous,” host organism, usually a cell or
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`“host cell.” Among other things, recombinant techniques allow scientists to
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`introduce a new gene into a host cell that does not naturally contain that gene, and
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`then to use the inserted (or “cloned”) gene and cellular machinery of the host to
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`produce a desired protein. (Ex. 2019, Fiddes Decl. ¶¶ 51-56.)
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`By April 1983, many of the biological mechanisms controlling the
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`expression of foreign DNA and assembly of the resulting proteins were poorly
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`understood. Indeed, Dr. Foote agrees that, as of April 1983, it was “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. 2020, Foote Dep. 135;
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`Ex. 1027, Harris at 129.) Dr. Foote also admits that efforts at that time to use
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`recombinant DNA to produce proteins remained fraught with problems. (Ex.
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`2020, Foote Dep. 136-46 (discussing problems, including from unknown behavior
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`of “intervening sequences,” “post-translational modifications,” and “inclusion
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`bodies”); Ex. 1027, Harris at 131, 156, 173 (“Further work is clearly needed
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`towards gaining an understanding of the conformation of eukaryotic proteins
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`during their synthesis by E. coli.”).)
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`Because of these obstacles and the nascent state of the field, only a small
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`number of relatively simple proteins had been recombinantly-produced by April
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`1983—as reflected in an article published that very month, which provided “an up
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`to date summary of the higher eukaryotic proteins that have been expressed in E.
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`coli.” (Ex. 1027, Harris at 163-69, Table 2.) As the author of that article, Dr.
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`Timothy Harris, has explained, the proteins produced recombinantly at that time
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`were limited to “relatively small polypeptides with simple tertiary structures.” (Ex.
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`2004, Harris Decl. ¶ 16; Ex. 2020, Foote Dep. 76-79; Ex. 2019, Fiddes Decl. ¶ 57.)
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`The Harris article itself identifies a number of the perceived problems with
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`producing eukaryotic proteins recombinantly in prokaryotic hosts as of April 1983,
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`such as (1) the presence of introns (non-coding sequences) in eukaryotic genes; (2)
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`the different regulatory signals found in eukaryotic DNA; (3) the different codon
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`usage in eukaryotic genes; and (4) factors “not well defined” affecting protein
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`folding, solubility, and post-translational modifications. (Ex. 1027, Harris at 131-
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`133, 156, 173.) Dr. Foote agrees with Harris’s summary of the many challenges
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`that existed with recombinant DNA techniques as of April 1983 (Ex. 2020, Foote
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`Dep. 136-46), which explains why the only reported recombinantly-produced
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`eukaryotic proteins at that time were relatively simple (Ex. 2019, Fiddes Decl.
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`¶¶ 58-74).
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`Using recombinant DNA to produce a multimeric protein was especially
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`challenging. By April 1983, only one multimeric eukaryotic protein (insulin) was
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`reported to have been produced recombinantly. That recombinant work with
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`insulin involved either producing preproinsulin (a single polypeptide), or
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`separately expressing the A and B chains in two different host cells and joining the
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`polypeptide subunits afterward. (Ex. 2019, Fiddes Decl. ¶¶ 81-91; Ex. 2020, Foote
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`Dep. 103, 109-11; Ex. 2005, Harris Decl. II ¶ 14.)
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`This insulin work reflected a basic reality of recombinant eukaryotic protein
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`techniques back in 1983: all used one host cell per polypeptide. Indeed, Dr. Foote
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`admits that the record is devoid of evidence that anyone had co-expressed the
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`subunits of any multimeric eukaryotic protein in the same host cell before the
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`Cabilly inventors. (Ex. 2020, Foote Dep. 114-15; id. at 111-12 (“all of the
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`examples described in [Harris] involved production of one polypeptide in one
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`transformed host cell”).) That critical admission is reinforced by other evidence
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`that multiple persons of extraordinary skill—all of whom also are unaware of
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`anyone who had independently expressed the multiple subunits of a eukaryotic
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`protein in a single host cell before April 1983. (Ex. 2019, Fiddes Decl. ¶¶ 127-28;
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`Ex. 2005, Harris Decl. II ¶¶ 15-16; Ex. 2003, McKnight Decl. II ¶ 5; Ex. 2006,
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`Rice Decl. ¶ 15.)
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`It is not surprising that no one as of April 1983 had reported producing more
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`than one polypeptide of a eukaryotic multimeric protein in a single host cell. Co-
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`expressing multiple polypeptides in a single host cell is a far more complicated
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`task in almost every way compared to the prior art multiple host cell approach. For
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`example, before April 1983, it would have been (i) more difficult to engineer
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`expression constructs for use in a single host cell; (ii) uncertain that separate genes
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`of interest would even co-express; and (iii) unclear whether the desired
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`polypeptides would be produced in the correct ratios. (Ex. 2019, Fiddes Decl. ¶¶
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`129-37; Ex. 2021, Gentz Decl. ¶¶ 27-30.)
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`D.
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`As Of April 1983, Highly Acclaimed Scientists Were Uncertain
`Whether It Was Even Possible To Make Antibodies Using
`Recombinant DNA Techniques.
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`By the early 1980s, a handful of scientists had begun to theorize that it might
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`be possible in the future to produce antibodies recombinantly. But the
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`uncertainties with producing antibodies recombinantly were even greater than with
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`other proteins—for example, because antibodies were believed to require certain
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`chaperone proteins to coordinate the timing, expression, and proper assembly of
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`heavy and light chains. (Ex. 2019, Fiddes Decl. ¶¶ 95, 136.) As such, even by
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`April 1983, highly-respected scientists still had serious doubts whether antibodies
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`could ever be produced recombinantly, and nobody had suggested that antibodies
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`could be produced by co-expressing the heavy and light chains in a single host cell.
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`For example, in March 1981, an article reported then-recent comments from
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`Dr. Milstein—inventor of the hybridoma technique, future Nobel Laureate, and
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`one of the most prominent scientists in the antibody field at the time. In his closing
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`remarks, Dr. Milstein speculated about the future—noting he could “imagine the
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`next stage is to move away from the animals,” and that it was “perhaps not too
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`premature to start thinking along those lines.” He did not offer any specific
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`solution; rather, he just said that “[s]omehow the DNA fragments will have to go
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`into cells capable of transcribing and translating the information with adequate
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`efficiency.” (Ex. 1039, Milstein at 409-10 (emphases added); Ex. 2020, Foote
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`Dep. 47-60 (agreeing Milstein’s comments are “directed towards possible things
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`that might be done in the future, nothing that [Dr. Milstein] or his colleagues, or
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`anyone that he knows, has currently done”).)
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`In fact, Dr. Milstein conceded that his wishful idea might not work: “we
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`have to face the possibility that bacteria might not be able to handle properly the
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`separated heavy and light chains so that correct assembly becomes possible.” He
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`said that because the basic science presented “very serious problems,” was “not so
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`well established,” and was “clouded by uncertainties and multiple possibilities.”
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`(Ex. 1039, Milstein at 410.) Dr. Foote admits that he has no basis to dispute this
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`description of the uncertain state of the art. (Ex