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`Filed: September 10, 2019
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`Filed on behalf of: Eli Lilly and Company
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`______________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________________
`
`ELI LILLY AND COMPANY,
`Petitioner,
`v.
`TEVA PHARMACEUTICALS INTERNATIONAL GMBH,
`Patent Owner.
`______________________
`
`Case No. IPR2018-01425
`Patent No. 9,890,210
`______________________
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`PETITIONER’S REPLY
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`
`
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`
`
`IPR2018-01425
`Patent No. 9,890,210
`
`I.
`II.
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`B.
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`TABLE OF CONTENTS
`Introduction ................................................................................................. 1
`Teva Fails to Rebut the Prior Art’s Express Motivation to Make a
`Claimed Antibody ........................................................................................ 2
`A.
`Teva’s Motivation Arguments Are Not Directed to the Claimed
`Subject Matter.................................................................................... 4
`Teva’s Unfounded Safety Concerns Do Not Undermine
`Motivation ......................................................................................... 6
`1.
`Clinical Studies Demonstrated that the CGRP Pathway
`Could Be Safely Antagonized To Treat Migraine .................... 6
`Long-Acting Ligand Antagonists Had Desirable Benefits
`and Did Not Raise Safety Concerns ......................................... 9
`The Prior Art Would Not Have Dissuaded a POSA from
`Pursuing a Humanized Anti-CGRP Antagonist Antibody .......12
`Absolute Risk of Stroke in Migraine Patients Was Very
`Low ........................................................................................14
`Hypothetical “Spare Receptor Theory” Concerns Did Not
`Undermine Motivation ......................................................................16
`
`2.
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`3.
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`4.
`
`C.
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`Ligand Cross-Binding Did Not Undermine Motivation.....................17
`D.
`III. Teva’s Reasonable Expectation of Success Arguments Are Irrelevant ........18
`IV. Teva’s Alleged Secondary Considerations Do Not Support
`Nonobviousness ..........................................................................................20
`A.
`Teva’s Secondary Considerations Evidence Is Not
`Commensurate with the Scope of the Challenged Claims .................20
`Teva’s Secondary Considerations Lack Nexus to the Claims ............23
`Teva’s Reliance on Industry Acclaim Is Misplaced ..........................23
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`B.
`C.
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`i
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`D.
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`IPR2018-01425
`Patent No. 9,890,210
`Teva Failed to Establish Unexpected Results or Industry
`Skepticism ........................................................................................25
`Teva’s Purported Evidence of Commercial Success, Licensing,
`and Long-Felt Need Do Not Support Patentability ............................25
`Conclusion ..................................................................................................27
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`E.
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`V.
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`
`
`ii
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`
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`TABLE OF AUTHORITES
`
`IPR2018-01425
`Patent No. 9,890,210
`
`Page(s)
`
`Federal Cases
`Abbott GmbH & Co., KG v. Centocor Ortho Biotech, Inc.,
`971 F. Supp. 2d 171 (D. Mass. 2013) ................................................................. 5
`
`Alcon Research Ltd. v. Apotex Inc.,
`687 F.3d 1362 (Fed. Cir. 2012) .......................................................................... 5
`Allergan, Inc. v. Apotex Inc.,
`754 F.3d 952 (Fed. Cir. 2014) .......................................................................... 22
`Bayer Healthcare Pharm., Inc. v. Watson Pharm., Inc.,
`713 F.3d 1369 (Fed. Cir. 2013) .................................................................. 14, 24
`Cole Kepro Int’l, LLC v. VSR Indus., Inc.,
`695 F. App’x 566 (Fed. Cir. 2017) ................................................................... 26
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) .......................................................................... 16
`Genetics Inst., LLC v. Novartis Vaccines & Diagnostics, Inc.,
`655 F.3d 1291 (Fed. Cir. 2011) ........................................................................ 21
`In re Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .................................................................. 21, 23
`Kinetic Concepts, Inc. v. Smith & Nephew, Inc.,
`688 F.3d 1342 (Fed. Cir. 2012) .......................................................................... 3
`Ormco Corp. v. Align Tech., Inc.,
`463 F.3d 1299 (Fed. Cir. 2006) ........................................................................ 23
`Paint Point Med. Sys., Inc. v. Blephex, LLC,
`IPR2016-01670, Paper 44 (PTAB Feb. 28, 2018) ............................................ 26
`Par Pharm., Inc. v. TWI Pharm., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) .......................................................................... 6
`
`iii
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`IPR2018-01425
`Patent No. 9,890,210
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`S. Ala. Med. Sci. Found. v. Gnosis S.P.A.,
`808 F.3d 823 (Fed. Cir. 2015) .......................................................................... 24
`Sanofi-Aventis U.S. LLC v. Immunex Corp.,
`IPR2017-01884, Paper 96 (PTAB Feb. 14, 2019) .................................... 5, 9, 18
`Soft Gel Techs., Inc. v. Jarrow Formulas, Inc.,
`864 F.3d 1334 (Fed. Cir. 2017) .......................................................................... 2
`
`
`
`iv
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`IPR2018-01425
`Patent No. 9,890,210
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`CGRP
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`FDA
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`IPR
`
`GLOSSARY
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`Calcitonin gene-related peptide
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`U.S. Food and Drug Administration
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`Inter partes review
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`Italicized text
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`Emphasis added unless otherwise indicated
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`Lilly or Petitioner Eli Lilly and Company
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`Monoclonal antibody
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`Mean arterial pressure
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`Medication-overuse headache
`
`Person of ordinary skill in the art
`
`Teva Pharmaceuticals International GmbH
`
`U.S. Patent No. 9,890,210
`
`U.S. Patent No. 6,344,438
`
`MAb
`
`MAP
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`MOH
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`POSA
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`Teva or Patent
`Owner
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`’210 patent
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`’438 patent
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`
`
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`v
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`IPR2018-01425
`Patent No. 9,890,210
`
`I.
`
`Introduction
`Teva does not challenge key elements of Lilly’s case: (1) the prior art discloses
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`every element of the challenged claims; (2) a POSA would have been motivated to
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`antagonize the CGRP pathway; (3) a POSA would have reasonably expected to
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`successfully make the claimed antibodies; and (4) Teva raises no unique arguments
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`for any dependent claim. Teva has therefore waived any argument to the contrary.
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`Instead—notwithstanding express
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`statements
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`in Wimalawansa
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`that
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`humanized anti-CGRP antibodies “should be explored” for treating various
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`diseases—Teva argues that a POSA would not have made humanized anti-CGRP
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`antibodies because of purported safety concerns regarding their use in patients. Teva
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`also argues that the “spare receptor” theory and purported cross-binding of CGRP to
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`ancillary receptors would have undermined motivation.
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`It is undisputed, however, that the ’210 patent addresses none of these alleged
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`concerns. The ’210 patent does not mention safety. It contains no pre-clinical safety
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`data and no clinical data whatsoever. It does not address the spare receptor theory
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`or CGRP cross-binding. Teva therefore seeks to hold the prior art to a higher
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`standard than its own patent, requiring proof of safety and efficacy. This constitutes
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`legal error, and infects nearly every Teva argument. Teva’s error is particularly
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`egregious because the challenged claims merely recite antibodies.
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`1
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`IPR2018-01425
`Patent No. 9,890,210
`Teva’s purported concerns are illusory. Teva relies on a handful of outdated
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`studies, but by November 2005, systemically administered CGRP antagonists had
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`repeatedly been shown to be safe and effective. Time-and-again, the art encouraged
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`making longer-acting CGRP antagonists, including humanized antibodies, for
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`therapeutic purposes. Indeed, notwithstanding Teva’s spare-receptor theory or
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`hypothetical cross-binding concerns, researchers were actively targeting CGRP for
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`treating migraine.
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`As explained below, Teva also failed to establish a showing of secondary
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`considerations for the claimed subject matter. The challenged claims are
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`unpatentable.
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`II. Teva Fails to Rebut the Prior Art’s Express Motivation to Make a
`Claimed Antibody
`Teva focuses its arguments on motivation, but the record is clear: the prior art
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`provides express motivation to make a humanized anti-CGRP antagonist antibody
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`of the challenged claims. Pet., 22-30.
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`Wimalawansa urges one to humanize anti-CGRP antagonist antibodies: “[t]he
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`role of … humanized monoclonal antibodies should be explored.” Ex. 1096, 570;
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`Pet., 18, 25; see Ex. 1303, 47:22-48:5. An express recommendation for future
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`research alone evinces motivation. Soft Gel Techs., Inc. v. Jarrow Formulas, Inc.,
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`864 F.3d 1334, 1342 (Fed. Cir. 2017).
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`2
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`IPR2018-01425
`Patent No. 9,890,210
`Providing further motivation, the advantageous properties of anti-CGRP
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`antibodies were known: Tan’s MAb C4.19 and antagonized CGRP in vitro and in
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`vivo. Ex. 1021, 706-707; Ex. 1022, 568-572; Pet., 26-28; Ex. 1303, 160:2-9,
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`162:12-22. As Dr. Tan contemporaneously wrote, there is “no reason” why
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`humanized anti-CGRP antagonist antibodies should not be pursued. Ex. 1287, 247.
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`Salmon, Sveinsson, and the ’438 patent provide additional motivation,
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`disclosing and claiming anti-CGRP antagonist antibodies for treating chronic human
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`diseases. Pet., 23-24; Ex. 1010 ¶¶109-112. As Drs. Tomlinson and Ferrari
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`conceded, a POSA would have understood that administering antibodies to humans
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`for chronic use, as taught by these references, would require humanization.
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`Ex. 1301, 211:2-15; Ex. 1303, 49:1-20.
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`Teva misinterprets Kinetic Concepts, Inc. v. Smith & Nephew, Inc., 688 F.3d
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`1342, 1360 (Fed. Cir. 2012), arguing the art disclosed neither a known problem nor
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`a solution to that problem. POR, 40. Regardless, the prior art repeatedly and
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`unambiguously identified a need for new therapies, including migraine, and
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`expressly proposed humanized anti-CGRP antagonist antibodies as the solution.
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`Pet., 23-26; Ex. 1303, 205:8-12.
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`3
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`IPR2018-01425
`Patent No. 9,890,210
`A. Teva’s Motivation Arguments Are Not Directed to the Claimed
`Subject Matter
`The challenged claims lack any meaningful structural requirements,1 and are
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`broadly directed to any humanized anti-CGRP antagonist antibody having certain
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`functional properties already known in the prior art. Pet., 52-53. Attempting to
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`downplay the art’s express motivation to make such an antibody, Teva and its experts
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`seek to limit the claims to antibodies that will be safe and effective in human patients.
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`POR, 2-3; Ex. 1303, 38:22-39:10, 44:3-45:5; Ex. 2213 ¶28; Ex. 1304, 143:6-23;
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`Ex. 1301, 129:16-130:20.
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`It is undisputed, however, that Teva’s patent does not mention safety. It
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`contains no pre-clinical safety data and no clinical data whatsoever. Ex. 1303, 55:7-
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`57:19. As Teva’s expert Dr. Foord testified, the limited animal studies in Teva’s
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`patent “will never satisfy concerns about safety and efficacy.” Ex. 1300, 173:20-
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`175:6; see also Ex. 1303, 31:8-14, 54:12-23.
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`Reading safety and efficacy requirements into the claims, Teva seeks to
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`require more from the prior art than it disclosed in its patent by importing a
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`1 The “heavy chain” and “light chain” limitations are generic to all IgG antibodies
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`and do not correlate to the claimed functional properties. Pet., 5-6; Ex. 1031,
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`81:5-82:3.
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`4
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`IPR2018-01425
`Patent No. 9,890,210
`reasonable expectation of success inquiry into motivation. This is improper. Alcon
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`Research Ltd. v. Apotex Inc., 687 F.3d 1362, 1369 (Fed. Cir. 2012) (“While it is true
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`that [the prior art] does not expressly disclose that olopatadine would be safe for use
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`in human eyes, neither does the ’805 patent. The patent is not based on testing in
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`humans; instead it reports only in vitro tests”); see also Sanofi-Aventis U.S. LLC v.
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`Immunex Corp., IPR2017-01884, Paper 96 at 17 (PTAB Feb. 14, 2019).
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`The law is clear that the prospect of creating a “potential therapeutic” is
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`sufficient motivation to humanize. Immunex, IPR2017-01884, Paper 96 at 17, 19-24
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`(holding claims to humanized antibodies obvious based on motivation of creating a
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`“potential therapeutic”); Abbott GmbH & Co., KG v. Centocor Ortho Biotech, Inc.,
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`971 F. Supp. 2d 171, 185 (D. Mass. 2013) (holding claims to human antibodies
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`obvious where the antibodies merely “could be therapeutic”).
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`That standard is consistent with the evidence here. Dr. Vasserot testified that
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`a POSA would have been motivated to humanize a murine antibody when it “had
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`been shown to exhibit functional properties that could be useful in treating a
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`disease.” Ex. 1011 ¶¶79-81; Pet., 28-30. He testified that “[w]e have started projects
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`with less data than [Tan.]” Ex. 2191, 100:8-15, 97:15-100:1. Teva’s own expert
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`admitted that he and his colleagues “humanized antibodies all the time.” Ex. 1301,
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`55:5-6. Further, Teva’s experts conceded that a POSA would have found it
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`appropriate to use humanized antibodies throughout drug development, including
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`5
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`IPR2018-01425
`Patent No. 9,890,210
`binding assays, in vitro testing, and animal studies. Id., 208:3-12; Ex. 1303, 54:25-
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`55:6; Ex. 1304, 145:23-146:3.
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`To establish motivation, all the law requires is a “suitable option from which
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`the prior art did not teach away.” Par Pharm., Inc. v. TWI Pharm., Inc., 773 F.3d
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`1186, 1197-98 (Fed. Cir. 2014) (emphasis in original). As explained below, Teva’s
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`overblown safety concerns would not have undermined the express motivation to
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`pursue humanized anti-CGRP antagonist antibodies for therapeutic use.
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`B.
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`Teva’s Unfounded Safety Concerns Do Not Undermine
`Motivation
`Contrary to Teva’s unfounded safety allegations (POR, 21), the prior art
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`repeatedly demonstrated that blocking the CGRP pathway was both safe and
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`effective for treating migraine.
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`1.
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`Clinical Studies Demonstrated that the CGRP Pathway Could
`Be Safely Antagonized To Treat Migraine
`By November 2005, the prior art had established that antagonizing the CGRP
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`pathway was understood to be safe and effective. Ex. 1326 §IV, ¶¶76-77; Ex. 1303,
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`70:13-75:11, 84:13-22; Ex. 1304, 91:6-10; Exs. 1291, 1292 (depleting CGRP to
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`prevent cluster headache and treat migraine).
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`Sumatriptan, FDA-approved since the early 1990s, was a safe and effective
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`migraine-specific treatment that inhibited CGRP. Ex. 1326 ¶¶11, 44; Ex. 1303,
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`18:7-19:3, 211:2-9; Ex. 1282, 1519-1520. Indeed, by 2005, inhibiting CGRP release
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`6
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`IPR2018-01425
`Patent No. 9,890,210
`was understood as one of “the most important contribution[s]” to sumatriptan’s anti-
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`migraine effects. Ex. 1303, 23:22-24:22; Ex. 1304, 90:10-15. Despite “transient”
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`blood pressure increases observed in some patients, sumatriptan was considered
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`“very safe” when prescribed to appropriate patients. Ex. 1326 ¶44; Ex. 1282, 1521;
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`Ex. 1308, 1673. Consistent with the well-recognized safety of sumatriptan, Teva’s
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`clinician experts advocated daily triptan administration for up to a year for
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`preventative migraine treatment. Ex. 1294, Abstract, 487; Ex. 1295, Abstract, 1405;
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`Ex. 1326 ¶12.
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`In 2004, Olesen again confirmed that antagonizing the CGRP pathway
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`produced no serious side effects and no cardiovascular events. Ex. 1025, 1109;
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`Ex. 1326 ¶¶33-34; Pet., 25-26; Ex. 1303, 84:13-22. Contradicting Teva’s argument
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`that “Olesen says nothing about cerebrovascular safety” (POR, 28), Olesen states
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`that BIBN4096BS “had no constrictor effect on the middle cerebral, radial, or
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`superficial temporal artery or on regional cerebral blood flow, blood pressure, or
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`heart rate.” Ex. 1025, 1108.2 Moreover, Olesen reported that BIBN4096BS further
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`improved over triptans as the “first migraine-specific medication that is not a
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`2 Teva incorrectly asserts that Dr. Charles failed to consider safety concerns.
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`POR, 33. Dr. Charles considered Olesen, Tan, Iovino, Andrew, and Wong, all of
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`which reveal an absence of safety concerns. Ex. 1010, Appendix B.
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`7
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`IPR2018-01425
`Patent No. 9,890,210
`vasoconstrictor.” Id.; Ex. 2010, 2561 (BIBN4096BS is “devoid of vasoconstrictive
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`actions in humans”).
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`Similarly, Iovino and Petersen reported “a very favourable safety profile” for
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`BIBN4096BS in human volunteers. Ex. 1042, Abstract (reporting no “clinically
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`relevant, drug-induced changes” in blood pressure, pulse rate, blood flow, or vital
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`signs); Ex. 2019, Abstract (reporting “no effect of CGRP-receptor blockade on the
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`cerebral or systemic circulation in humans”); Ex. 1326 ¶¶35-38; Ex. 1303, 84:23-
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`85:7, 87:1-11, 90:22-92:20.
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`In 2005, in view of these studies, both of Teva’s clinician experts
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`independently praised “CGRP antagonists” as promising antimigraine drugs.
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`Ex. 1290, 657 (advocating “CGRP antagonists” as “promising, new antimigraine
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`drugs without vascular side effects”); Ex. 1297, S119 (recommending “antagonising
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`the effect of CGRP” for acute and preventive migraine therapies).
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`Contrary to Teva’s incorrect arguments (POR, 20-21), safety lessons from
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`antagonizing the CGRP pathway with sumatriptan and BIBN4096BS were pertinent
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`for therapeutics that directly target CGRP. By 2005, the prior art expressly
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`recognized
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`that
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`targeting CGRP and
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`its receptor were “alternative” and
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`“complementary” techniques for antagonizing the CGRP pathway. Ex. 1022, 566,
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`571; Ex. 1033, 95; Ex. 1010 ¶115; Ex. 1325 ¶¶35-39. Indeed, the prior art
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`recognized that “inhibition of CGRP or antagonism of CGRP receptors could be a
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`8
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`IPR2018-01425
`Patent No. 9,890,210
`viable therapeutic target” for treating migraine—and researchers were already
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`targeting both CGRP and its receptor. Ex. 1040, 182; Ex. 1326 ¶¶37, 15-17.
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`For example, citing Wimalawansa, researchers had developed prior art
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`αCGRP ligand antagonists—e.g., aptamers that bound CGRP—for treating
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`migraine. Ex. 1082, Abstract, 2 (ref. 19). Upon anti-CGRP aptamer administration,
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`researchers reported that “[b]asal blood flow and systemic arterial pressure were
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`unchanged.” Ex. 1240, 923; Ex. 1325 ¶¶38, 54. The prior art explained that
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`“aptamers can be thought of as … analogs to antibodies,” and recognized their
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`relatively longer half-life. Ex. 1309, Abstract; Ex. 1240, 923; Ex. 1082, Abstract, 7;
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`Ex. 1325 ¶51. Thus, the prior art demonstrated that longer acting anti-CGRP drugs
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`were desirable and indicated as safe. Ex. 1326 ¶¶5-17, 41-51; Ex. 1325 ¶¶48-55.
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`Accordingly, by 2005 purported theoretical safety concerns of targeting the
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`CGRP pathway would not have undermined the clear motivation to develop a
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`humanized anti-CGRP antagonist antibody. Immunex, IPR2017-01884, Paper 96 at
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`17, 19-24 (rejecting patentee’s “theoretical” side effect arguments against a
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`motivation to humanize).
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`2.
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`Long-Acting Ligand Antagonists Had Desirable Benefits and
`Did Not Raise Safety Concerns
`Teva contends that the relatively long half-lives of antibodies would have been
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`expected to exacerbate any potential CGRP-blocking side effects. POR, 28-29. To
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`9
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`IPR2018-01425
`Patent No. 9,890,210
`the contrary, a POSA would have viewed anti-CGRP drugs with longer half-lives as
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`desirable for preventative migraine treatments, without posing safety concerns.
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`Ex. 1326 ¶¶5-17, 46-50; Ex. 1325 ¶¶48-55; Pet., 28-30. As explained above, the art
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`was developing “analogs” to antibodies known as aptamers targeting CGRP for
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`treating migraine. These compounds did not affect basal blood flow or systemic
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`arterial pressure. Ex. 1240, 923.
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`Teva nevertheless argues that the transient and mild increase in blood pressure
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`observed in Tan would raise safety concerns. POR, 23-25. But as Lilly’s expert Dr.
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`Balthasar explains,3 a POSA would have understood that the minor blood-pressure
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`increase in Tan’s anesthetized rats normalized within 10 to 15 minutes of
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`administering MAb C4.19, and “had no relationship to the half-life” of the antibody.
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`Ex. 1325 ¶¶56-60; Ex. 1022, 568. Teva also greatly exaggerates Tan’s blood-
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`pressure effects, alleging a “13-fold” increase whereas Dr. Foord admitted it was
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`only “1.1-fold.” Compare POR, 24 with Ex. 1300, 129:21-130:4.
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`A POSA would not have viewed Tan’s minor, transient blood-pressure
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`increase in anesthetized rats as a safety concern. Ex. 1326 ¶¶41-45; see Ex. 1303,
`
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`3 In contrast to Dr. Balthasar’s antibody-pharmacology expertise, Dr. Foord
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`admitted his grasp of immunology was “tenuous.” Ex. 1300, 33:8-11. Dr. Ferrari
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`likewise has a deficient understanding of antibodies. Ex. 1303, 69:10-16.
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`10
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`IPR2018-01425
`Patent No. 9,890,210
`25:11-17 (transient blood-pressure increase for sumatriptan was not “a major
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`concern”). Indeed, Teva omits that a similar blood pressure increase was observed
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`with the CGRP-receptor antagonist CGRP8-37, but that did not deter development of
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`BIBN4096BS or other receptor antagonists. Ex. 1022, 569; Ex. 1025, 1109.
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`Similarly, Teva omits that Tjen-A-Looi observed a stronger blood pressure increase
`
`with CGRP8-37 than an anti-CGRP antisera, which similarly did not deter
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`development of CGRP-receptor antagonists. Ex. 2084, H687 (disclosing testing
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`under non-physiologic, hypoxic conditions); Ex. 1325 ¶¶66-70.
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`Teva incorrectly attempts to undermine Tan’s disclosures by characterizing it
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`as a “basic research paper” and citing purported personal knowledge of its authors.
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`Ex. 2213 ¶70; POR, 42. But in describing his own work, Dr. Tan wrote in 1994 that
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`there was “no reason” why humanized anti-CGRP monoclonal antibodies should not
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`be investigated and used as “therapeutic agents” for migraine and other diseases.
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`Ex. 1287, 247 (similarly discussing human anti-CGRP MAbs as an “exciting
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`possibility” for administration “in man”). Dr. Tan’s contemporaneous statements
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`were written with first-hand knowledge of the blood pressure results focused on by
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`Teva and directly contradict Teva’s litigation-driven position.
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`Other prior art further confirms that anti-CGRP antagonist antibodies did not
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`have any chronic blood-pressure or vascular effects. Ex. 1325 ¶¶61-65; Ex. 1326
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`¶¶43-53. For instance, Wong conducted in vivo blood pressure testing on the same
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`11
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`IPR2018-01425
`Patent No. 9,890,210
`antibody (4901) that Teva evaluated in its specification and concluded that it “had
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`no significant effect on MAP [mean arterial pressure] and heart rate.” Ex. 1033, 101;
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`Ex. 1001, 52:53. Similarly, Andrew evaluated immunized animals with “high levels
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`of circulating antibodies to rat CGRP” after 10-15 weeks and confirmed that “they
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`did not show any signs of physical or behavioural abnormality.” Ex. 1055, 88, 93.
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`Salmon and other researchers disabled αCGRP production entirely in knockout
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`mice, and rather than experiencing any safety concerns, they claimed therapeutic
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`uses of anti-CGRP antagonist antibodies. Ex. 1027, ¶[0069], claims 8, 9; Ex. 1026,
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`claim 2; Ex. 1288, Abstract. Teva and its experts disregard this compelling evidence
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`of safety entirely.
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`3.
`
`The Prior Art Would Not Have Dissuaded a POSA from
`Pursuing a Humanized Anti-CGRP Antagonist Antibody
`Ignoring more recent prior art (supra §§II.B.1-2 and below), Teva cites several
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`early studies, largely published before Wimalawansa proposed exploring humanized
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`anti-CGRP antibodies, to support its hypothetical safety arguments. POR, 21-22;
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`Ex. 2213 ¶¶27-47. But Teva’s cited studies do not indicate that antagonizing
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`endogenous CGRP—as an anti-CGRP antagonist antibody would have been
`
`expected to do—would have had any effect on cardiovascular or cerebrovascular
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`safety. Ex. 1326 ¶¶18-25; Ex. 1303, 108:25-133:7.
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`12
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`IPR2018-01425
`Patent No. 9,890,210
`For example, Teva relies on early studies reporting the effects of administering
`
`exogenous CGRP (Exs. 2058, 2079, 2139), which increases CGRP levels instead of
`
`antagonizing endogenous CGRP. Ex. 1326 ¶21. Teva also relies on early studies
`
`attempting to discern CGRP’s biological effects without the benefit of a specific
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`antagonist, making it impossible to separate the effects of CGRP from other
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`vasopeptides. Id. ¶¶22-23; Exs. 2150, 2151, 2154, 2070, 2089, 2209. In the one
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`study that used CGRP8-37 (a receptor antagonist) under physiological conditions, no
`
`vascular changes were observed. Ex. 2152, 165; Ex. 1326 ¶24; Ex. 1303, 111:23-
`
`119:13.
`
`Teva also ignored more recent prior-art studies demonstrating that blocking
`
`the effects of endogenous CGRP with specific antagonists does not worsen ischemic
`
`events. Ex. 1326 ¶¶26-32. For instance, a 1998 publication reported that blocking
`
`endogenous CGRP did not worsen myocardial ischemia in pigs. Ex. 1283, 498
`
`(“locally released CGRP does not function as a cardioprotective agent”); Ex. 1303,
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`134:23-136:17. A 2001 study investigating BIBN4096BS in ischemic rats reported
`
`that CGRP antagonism produced no effect on infarct size. Ex. 1284, Abstract;
`
`Ex. 1303, 140:5-7, 142:2-7. Similarly, a 2003 study antagonizing CGRP in dogs
`
`with chronic heart failure reported that “endogenous α-CGRP does not appear to
`
`play a major role in the regulation of cardiac and peripheral vascular dynamics in
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`the late stage of heart failure.” Ex. 1285, Abstract; Ex. 1303, 142:24-143:22.
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`13
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`Another 2003 publication involving repeated administration of BIBN4096BS
`
`concluded that CGRP played no major role in cardiovascular regulation. Ex. 1318,
`
`76.
`
`Teva even overlooked a 2004 publication from Dr. Ferrari’s Ph.D. advisor, Dr.
`
`Saxena, studying global and regional cardio- and cerebro-vascular effects of
`
`antagonizing the CGRP pathway with BIBN4096BS. Ex. 1263, Abstract; Ex. 1303,
`
`97:10-98:2. No undesired effects were observed, even at high doses, leading the
`
`investigators to conclude that “endogenous CGRP does not play an important role in
`
`regulating systemic and regional haemodynamics.” Ex. 1263, 296; Ex. 1303, 102:9-
`
`106:19. Summarizing the pre-clinical and clinical data, Dr. Saxena wrote later in
`
`2004 that “[a]n important advantage of CGRP antagonists over the triptans [for
`
`migraine treatment] can be their use in patients with coronary artery disease.”
`
`Ex. 1031, 326; Ex. 1326 ¶¶39-40.
`
`Absolute Risk of Stroke in Migraine Patients Was Very Low
`4.
`Teva alleges that migraine is a risk factor for stroke. POR, 25-26. But these
`
`arguments directed to specific subpopulations of migraine patients are legally
`
`irrelevant. Bayer Healthcare Pharm., Inc. v. Watson Pharm., Inc., 713 F.3d 1369,
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`1376 (Fed. Cir. 2013) (rejecting patient sub-population arguments where “the [drug]
`
`product claims at issue do not distinguish between target patient populations”).
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`14
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`IPR2018-01425
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`Teva’s arguments are also irrelevant for most migraine patients. Ex. 1326
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`¶¶57-62. For example, over two-thirds of migraine patients experience migraine
`
`without aura, for which no correlation between migraine and stroke was known to
`
`exist. Ex. 1040, 177; Ex. 1303, 193:3-10. Moreover, while an increased relative
`
`risk was observed among young women compared to the general populace, “the
`
`absolute risk of stroke in young women with migraine is low: 18 per 100,000 per
`
`year.” Ex. 2157, 535; Ex. 1303, 190:3-193:12. A similarly low absolute risk of
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`myocardial ischemia among young women was also known as of 2005. Ex. 1315,
`
`Abstract; Ex. 2157, 536 (from a vascular standpoint, migraine is “mostly benign”).
`
`Thus, there is no significant overlap between migraine patients and individuals at
`
`high risk of stroke or myocardial infarction.
`
`Even if there had been potential safety concerns, they would not—and in fact
`
`did not—discourage researchers from pursuing anti-CGRP therapies. Anti-migraine
`
`treatments could be contraindicated in patients with particular risk factors, as had
`
`been done with sumatriptan and ergots. Ex. 1326 ¶¶63-64; Ex. 1282, 1520;
`
`Ex. 1290, 564-565. Teva offers no reason why anti-CGRP antagonist antibodies
`
`would have been viewed differently, especially when the safety profile of CGRP-
`
`antagonists was deemed favorable in the prior art.
`
`In sum, even if the Board determines that safety should be considered in
`
`evaluating motivation, the hypothetical concerns alleged by Teva neither teach away
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`15
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`IPR2018-01425
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`nor undermine the express prior-art motivation to explore humanized anti-CGRP
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`antagonist antibodies for therapeutic use. Galderma Labs., L.P. v. Tolmar, Inc., 737
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`F.3d 731, 738 (Fed. Cir. 2013) (to teach away, a reference must “criticize, discredit,
`
`or otherwise discourage investigation”).
`
`C. Hypothetical “Spare Receptor Theory” Concerns Did Not
`Undermine Motivation
`Teva incorrectly asserts that a POSA would lack motivation to block the
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`CGRP ligand based on Teva’s theory that “in the CGRP receptor system, less than
`
`1% of [CGRP] receptors needed to be bound by ligand to elicit a full response.”
`
`POR, 31. As with safety, Teva’s patent does not address the spare receptor theory.
`
`Teva’s hypothetical is also contradicted by the prior art, which indicated the
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`spare receptor theory does not apply. Ex. 1325 ¶¶40-47. Indeed, during cross-
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`examination, Dr. Foord conceded that Shekyzade (Ex. 2065), far from disclosing
`
`that 1% CGRP receptor occupancy elicits a full biological response, instead
`
`discloses that 27% CGRP receptor occupancy is required to generate a half-maximal
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`response. Ex. 1300, 68:19-69:8. Thus, a POSA would have understood that a large
`
`percentage of CGRP receptors would need to be bound to elicit a full biological
`
`response, contrary to Teva’s hypothetical. Ex. 1325 ¶42.
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`The prior-art clinical evidence also contradicts Teva’s spare receptor theory.
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`Ex. 1326 ¶¶65-69. Successfully treating migraine does not require antagonizing
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`16
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`99.999% of CGRP ligands to effectively abolish all CGRP activity, as Teva contends.
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`POR, 31. Rather, only elevated or inappropriate levels of CGRP were recognized
`
`as a cause of migraine, while normalizing CGRP levels was accompanied by
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`subsidence of migraine headache. E.g., Ex. 1044, Abstract; Ex. 1096, 567; Pet., 25.
`
`By 2005, researchers had already targeted the CGRP ligand to treat migraine,
`
`further confirming that Teva’s hypothetical “spare receptor” theory did not, in fact,
`
`deter targeting CGRP. Ex. 1326 ¶¶17, 69; Pet., 23-26.
`
`D. Ligand Cross-Binding Did Not Undermine Motivation
`Teva also contends that targeting the CGRP ligand and inhibiting its ability to
`
`bind to calcitonin, adrenomedullin, and amylin receptors would have been
`
`undesirable. POR, 30. Safety concerns resulting from ligand cross-binding are not
`
`addressed in Teva’s patent. Regardless, Teva is incorrect.
`
`As Dr. Foord admitted, “by 2005 it was unclear what physiological activities
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`were mediated by CGRP binding at these [other] receptors.” Ex. 2231 ¶34. His own
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`table of binding potency for various ligands at these ancillary receptors illustrates
`
`that CGRP is a secondary or worse binding ligand to non-CGRP receptors. Id.;
`
`Ex. 2059, 63. Mere speculation about theoretical physiological effects from CGRP’s
`
`poor binding to other receptors would not have deterred development of a humanized
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`anti-CGRP antagonist antibody. Ex. 1326 ¶¶70-75.
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`17
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`To the extent it is deemed relevant at all, cross-binding would have
`
`encouraged targeting CGRP as opposed to its receptor. Ex. 1326 ¶73. For example,
`
`adrenomedullin was reported
`
`to bind CGRP receptors, eliciting similar
`
`cardiovascular responses as CGRP, but without having any implicated role in
`
`migraine. Ex. 2003, 912-914, 919-921. Under Teva’s cardiovascular safety theory,
`
`blocking the CGRP receptor would have been viewed as a potentially riskier
`
`approach because it would reduce both CGRP’s and adrenomedullin’s purported
`
`cardiovascular effects. By contrast, antagonizing CGRP directly would still permit
`
`adrenomedullin to bind the CGRP receptor. Thus, ligand cross-binding favors
`
`targeting CGRP rather than its receptor, and indeed researchers were actively
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`targeting CGRP with aptamers and anti-CGRP antagonist antibodies. Ex. 1326 ¶74.
`
`III. Teva’s Reasonable Expectation of Success Arguments Are Irrelevant
`Teva misconstrues the legal inquiry by arguing that a reasonable expectation
`
`of success is required for drug-developmen
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