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`Filed on behalf of: Eli Lilly and Company
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`______________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________________
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`ELI LILLY AND COMPANY
`Petitioner
`v.
`TEVA PHARMACEUTICALS INTERNATIONAL GMBH
`Patent Owner
`______________________
`
`Case No. IPR2018-01710
`Patent No. 8,586,045
`______________________
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`PETITION FOR INTER PARTES REVIEW
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`Petition for Inter Partes Review
`U.S. Patent No. 8,586,045
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`TABLE OF CONTENTS
`Introduction ...................................................................................................... 1
`Requirements for Inter Partes Review Under 37 C.F.R. § 42.104 ................. 2
`A. Grounds for Standing ............................................................................ 2
`B.
`Identification of Challenge .................................................................... 3
` The ’045 Patent and Its Provisional Application ............................................. 4
`A.
`The Challenged Claims ......................................................................... 5
`B.
`Patent Owner Admissions in the Specification ..................................... 6
`1.
`CGRP and Its Role in Migraine Was Known ............................. 7
`2.
`Anti-CGRP Antagonist Antibodies and Methods of
`Making Them, Including Humanization Techniques,
`Were Known ............................................................................... 7
`Prosecution of the ’045 Patent .............................................................. 9
`C.
` Background and Asserted Prior Art................................................................. 9
`A.
`CGRP Structure and Its Isoforms .......................................................... 9
`B. Migraine and CGRP ............................................................................ 11
`C.
`Anti-CGRP Antagonist Antibodies Were Well Known in the
`Art and Had Been Disclosed for Therapeutic Use in Humans ........... 12
`D. Humanization of Antibodies ............................................................... 13
`E.
`The Asserted Prior Art ........................................................................ 14
`1.
`Olesen ........................................................................................ 14
`2.
`Tan ............................................................................................. 16
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`2.
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`3.
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`3.
`Queen ........................................................................................ 17
`Person of Ordinary Skill in the Art ................................................................ 18
` Claim Construction ........................................................................................ 19
`A.
`“reducing incidence of or treating” ..................................................... 20
`B.
`“effective amount” .............................................................................. 21
`C.
`“anti-CGRP antagonist antibody” and “humanized
`monoclonal antibody” ......................................................................... 23
` Claim 17 Is Obvious over Olesen, Tan, and Queen ...................................... 24
`A. A POSA Would Have Been Motivated to Treat Migraine
`With a Humanized Monoclonal Anti-CGRP Antagonist
`Antibody .............................................................................................. 25
`1.
`The Prior Art Would Have Motivated a POSA to Use
`a CGRP Antagonist to Treat Migraine ..................................... 25
`A POSA Would Have Been Motivated to Use an
`Anti-CGRP Antagonist Antibody to Treat Migraine ................ 29
`A POSA Would Have Been Motivated to Use a
`Humanized Monoclonal Anti-CGRP Antagonist
`Antibody for Treating Migraine................................................ 33
`The Prior Art Provided a Reasonable Expectation of Success ........... 35
`1.
`A POSA Would Have Reasonably Expected that a
`Humanized Anti-CGRP Antagonist Antibody Would
`Successfully Reduce Incidence of or Treat Migraine ............... 37
`a)
`Blocking the CGRP Pathway Had Been
`Clinically Proven to Treat Migraine ............................... 37
`Immunoblockade with Anti-CGRP Antagonist
`Antibodies Had Been Confirmed In Vivo, and
`Was a Known “Alternative” Technique for
`Blocking the CGRP Pathway ......................................... 38
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`B.
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`b)
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`2.
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`C.
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`D.
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`A POSA Would Have Had a Reasonable Expectation
`of Success in Making a Humanized Anti-CGRP
`Antagonist Antibody for Therapeutic Use in Humans ............. 40
`The Prior Art Did Not Teach Away from Using a
`Humanized Anti-CGRP Antagonist Antibody, as Teva
`Incorrectly Argued During Prosecution .............................................. 43
`The Claimed Methods for Treating Migraine Would Have
`Been Obvious ...................................................................................... 48
` The Prior Art Likewise Demonstrates the Obviousness of Claim 1 ............. 49
` The Challenged Dependent Claims Would Have Been Obvious
`Over Olesen, Tan, and Queen ........................................................................ 50
`A.
`Claims 3, 9, 19, and 24 ........................................................................ 51
`B.
`Claims 4 and 20 ................................................................................... 51
`C.
`Claim 8 ................................................................................................ 54
`D.
`Claims 10 and 25 ................................................................................. 54
`E.
`Claims 11 and 26 ................................................................................. 56
`F.
`Claims 12 and 27 ................................................................................. 57
`G.
`Claims 13 and 28 ................................................................................. 58
`H.
`Claims 14 and 29 ................................................................................. 60
`I.
`Claims 15 and 30 ................................................................................. 61
`J.
`Claims 16 and 31 ................................................................................. 61
`There Is No Objective Evidence of Nonobviousness .................................... 62
`A.
`Teva Cannot Establish Nexus to the Full Scope of the
`Challenged Claims .............................................................................. 62
`There Are No Unexpected Results ...................................................... 63
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`B.
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`C.
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`Lilly’s and Others’ Near-Simultaneous Development
`Preclude a Holding of Nonobviousness .............................................. 63
` The Evidence Submitted in this Petition Was Not Previously
`Considered by the Office ............................................................................... 65
` Mandatory Notices Under 37 C.F.R. § 42.8 .................................................. 66
`A.
`Real Parties-in-Interest ........................................................................ 66
`B.
`Related Matters .................................................................................... 66
`C.
`Lead and Backup Counsel .................................................................... 67
`D.
`Service Information ............................................................................. 68
` Payment of Fees ............................................................................................. 68
` Conclusion ..................................................................................................... 69
`CERTIFICATION OF COMPLIANCE .................................................................. 70
`CERTIFICATE OF SERVICE ................................................................................ 71
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`TABLE OF AUTHORITIES
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` Page(s)
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`Federal Cases
`Abbott GmbH & Co., KG v. Centocor Ortho Biotech, Inc.,
`971 F. Supp. 2d 171 (D. Mass. 2013) ................................................................. 42
`AbbVie Deutschland GmbH v. Janssen Biotech, Inc.,
`759 F.3d 1285 (Fed. Cir. 2014) .......................................................................... 62
`Alcon Research Ltd. v. Apotex Inc.,
`687 F.3d 1362 (Fed. Cir. 2012) .......................................................................... 22
`Allergan, Inc. v. Apotex Inc.,
`754 F.3d 952 (Fed. Cir. 2014) ...................................................................... 35, 62
`Allergan, Inc. v. Sandoz Inc.,
`726 F.3d 1286 (Fed. Cir. 2013) .......................................................................... 35
`In re Am. Acad. of Sci. Tech Ctr.,
`367 F.3d 1359 (Fed. Cir. 2004) .......................................................................... 20
`Coherus Biosciences Inc. v. AbbVie Biotechnology Ltd.,
`IPR2016-00172, Paper 9 (PTAB May 17, 2016) ............................................... 20
`Ecolochem, Inc. v. S. Cal. Edison Co.,
`227 F.3d 1361 (Fed. Cir. 2000) .......................................................................... 63
`George M. Martin Co. v. All. Mach. Sys. Int’l LLC,
`618 F.3d 1294 (Fed. Cir. 2010) .................................................................... 63, 65
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ................................................................................ 35, 48, 49
`In re Mouttet,
`686 F.3d 1322 (Fed. Cir. 2012) .................................................................... 44, 48
`Novartis Pharm. Corp. v. Actavis, Inc.,
`No. 12-cv-366, 2013 WL 6142747 (D. Del. Nov. 21, 2013) ....................... 20, 22
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`Petition for Inter Partes Review
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`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) (en banc) .......................................................... 20
`Vitronics Corp. v. Conceptronic, Inc.,
`90 F.3d 1576 (Fed. Cir. 1996) ...................................................................... 20, 21
`Regulations
`37 C.F.R. § 42.100(b) .............................................................................................. 19
`37 C.F.R. § 42.103(a) ............................................................................................... 68
`37 C.F.R. § 42.104 ..................................................................................................... 2
`37 C.F.R. § 42.15(a) ................................................................................................. 68
`37 C.F.R. § 42.8 ....................................................................................................... 66
`Other Authorities
`Notice of Proposed Rulemaking (May 3, 2018) ...................................................... 19
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`GLOSSARY
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`America Invents Act
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`Broadest reasonable interpretation
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`Complementarity-determining region
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`Calcitonin gene-related peptide
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`Fragment antigen binding
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`U.S. Food and Drug Administration
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`Inter partes review
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`AIA
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`BRI
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`CDR
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`CGRP
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`Fab
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`FDA
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`IPR
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`Italicized text
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`Emphasis added unless otherwise indicated
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`Lilly or petitioner
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`Eli Lilly & Company
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`MAb
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`POSA
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`Monoclonal antibody
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`Person of ordinary skill in the art
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`provisional application
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`U.S. Provisional App. No. 60/736,623
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`RIA
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`SPR
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`Radioimmunoassay
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`Surface plasmon resonance
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`Teva or Patent Owner
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`Teva Pharmaceuticals International GmbH
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`USPTO or Office
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`U.S. Patent and Trademark Office
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`’045 patent
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`U.S. Patent No. 8,586,045
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`Petition for Inter Partes Review
`U.S. Patent No. 8,586,045
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`Introduction
`Teva’s ’045 patent broadly claims using any human or humanized monoclonal
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`anti-CGRP antagonist antibody for reducing incidence of or treating any vasomotor
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`symptom, including migraine. The concept of using an anti-CGRP antagonist
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`antibody for these purposes was disclosed in the prior art. The challenged claims
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`are obvious.
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`By the time Teva filed its first application in November 2005, the CGRP
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`pathway was a clinically validated target for treating migraine. A published, double-
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`blind, placebo-controlled clinical trial by Olesen firmly established that blocking the
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`CGRP pathway resulted in migraine relief in human patients. Olesen was not before
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`the USPTO during examination of the ’045 patent.
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`Anti-CGRP antagonist antibodies that bound to and blocked the biological
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`effects of CGRP were also well known in the art. These monoclonal antibodies were
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`shown to block the CGRP pathway in vivo. For example, Tan demonstrated that its
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`anti-CGRP antagonist antibodies effectively blocked CGRP in the very same in vivo
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`animal model that Teva used in its provisional application to support its original
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`claims to preventing and treating migraine. Thus, it was unsurprising that the prior
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`art had expressly recommended using humanized monoclonal anti-CGRP antagonist
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`antibodies to treat human diseases linked to CGRP, including migraine.
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`Petition for Inter Partes Review
`U.S. Patent No. 8,586,045
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`As Teva’s ’045 patent admits, humanization was a well-established and
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`routine procedure by the time Teva filed its application. Researchers had long
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`understood that humanized antibodies advantageously avoided immunogenic
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`reactions caused by administering murine antibodies to humans. By 2005, half of
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`the FDA-approved antibodies were humanized antibodies, and most antibodies in
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`phase 2 and 3 clinical trials were humanized. Queen, which was also not submitted
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`to the USPTO, represented the “gold standard” of humanization. As a result,
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`humanization does not and cannot provide any patentable weight to the challenged
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`claims.
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`As explained below and in the Expert Declarations of Dr. Andrew Charles, a
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`neurologist and long-time CGRP researcher who specializes in the treatment of
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`migraine, and Dr. Alain Vasserot, an antibody engineer with expertise in antibody
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`humanization, the challenged claims of the ’045 patent would have been obvious
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`over Olesen, Tan, and Queen. Lilly therefore requests inter partes review of claims
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`1, 3, 4, 8-17, 19, 20, and 24-31 of the ’045 patent.
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` Requirements for Inter Partes Review Under 37 C.F.R. § 42.104
`A. Grounds for Standing
`Petitioner certifies that the ’045 patent is available for IPR based on Teva’s
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`assertions to the Office that it is entitled to claim priority to a pre-AIA effective filing
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`date of November 14, 2005, and that Petitioner is not barred or estopped from
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`Petition for Inter Partes Review
`U.S. Patent No. 8,586,045
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`requesting review on the ground identified. (Ex. 1206, 3; Ex. 1207, 5-6 (listing
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`priority chain and declining to designate as a transition application); Ex. 1001,
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`1:7-14, title page, item (60).)1
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`Identification of Challenge
`B.
`Lilly respectfully requests review under 35 U.S.C. § 311 of claims 1, 3, 4,
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`8-17, 19, 20, and 24-31 of the ’045 patent. Lilly requests that the Board find these
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`claims unpatentable as obvious under 35 U.S.C. § 103(a) in view of the following
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`combination of references:
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`Reference 1: Olesen, J. et al., New Engl. J. Med. 350:1104-1110 (2004)
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`(“Olesen”) (Ex. 1025), published on March 11, 2004.
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`Reference 2: Tan, K.K.C. et al., Clin. Sci. 89:565-573 (1995) (“Tan”)
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`(Ex. 1022), published on December 1, 1995.
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`Reference 3: U.S. Patent No. 6,180,370 (“Queen”) (Ex. 1023) issued on
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`January 30, 2001.
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`1 Citations refer to the original page numbering of each exhibit except for
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`references that do not have any pagination in their original form. Citations to such
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`references refer to the stamped-on page numbers.
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`Olesen, Tan, and Queen are each prior art under 35 U.S.C. § 102(b).
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` The ’045 Patent and Its Provisional Application
`The ’045 patent is entitled “Methods of Using Anti-CGRP Antagonist
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`Antibodies.” (Ex. 1001, title page, item (54).) It states that the alleged invention
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`relates to “methods for preventing or treating CGRP associated disorders such as
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`vasomotor symptoms, including headaches (e.g., migraine, cluster headache, and
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`tension headache) and hot flushes, by administering an anti-CGRP antagonist
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`antibody.” (Ex. 1001, Abstract.) The ’045 patent discloses a single humanized
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`antagonist antibody (G1) and its purported derivatives. (E.g., id., Abstract, Example
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`4.) The ’045 patent does not include any clinical or other human data.
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`The ’045 patent belongs to a family of fifteen patents and applications, all of
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`which purport to claim priority to U.S. Provisional Application No. 60/736,623, filed
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`on November 14, 2005. (Ex. 1014 ¶80.) The provisional application, like the ’045
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`patent, identifies only one humanized anti-CGRP antagonist antibody, G1, as well
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`as its variants with minor sequence differences. (E.g., Ex. 1019, Example 4;
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`Ex. 1001, Abstract, Example 4.) The only in vivo data disclosed in the provisional
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`application was generated using a well-known assay—the rat saphenous nerve
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`assay—used in the prior art for the specific purpose of evaluating anti-CGRP
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`antagonist antibodies. (Compare Ex. 1019, [0244] (citing Ex. 1052), with Ex. 1022,
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`572 (citing Ex. 1052 as reference 9); Ex. 1014 ¶¶86-87.)
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`When filing its PCT application a year later, Teva only added additional
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`animal study results, not clinical data, to the disclosure of its provisional application.
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`(Ex. 1020, 66-68 (adding Examples 6-8).)
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`A. The Challenged Claims
`Independent claim 17 recites “[a] method of reducing incidence of or treating
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`headache in a human, comprising administering to the human an effective amount
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`of an anti-CGRP antagonist antibody, wherein said anti-CGRP antagonist antibody
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`is a human monoclonal antibody or a humanized monoclonal antibody.” (Ex. 1001,
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`claim 17; Ex. 1014 ¶82; Ex. 1015 ¶69.)
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`Independent claim 1, the only other independent claim, is even broader.
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`Rather than specifying “headache,” it encompasses any vasomotor symptom.
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`(Ex. 1001, claim 1; Ex. 1014 ¶83; Ex. 1015 ¶70.) It is also directed to any
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`“individual” (all mammals such as rats, Ex. 1001 at 19:4-7) rather than specifying a
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`“human.” (Ex. 1001, claim 1; Ex. 1014 ¶83; Ex. 1015 ¶70.)
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`The challenged dependent claims further require:
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`• reducing incidence of or treating a subset of vasomotor symptoms or
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`headache, including migraine (claims 3, 9, 19, and 24);
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`• a binding affinity of 50 nM or less as measured by surface plasmon
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`resonance at 37 °C (claims 4 and 20);
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`• a human individual (claim 8);
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`• binding to a particular fragment or epitope (claims 10 and 25);
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`• an Fc region with an impaired effector function (claims 11 and 26);
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`• various routes of administration (claims 12 and 27);
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`• a heavy chain constant region derived from a human IgG2 constant region
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`(claims 13 and 28);
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`• a formulation (claims 14 and 29);
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`• a humanized monoclonal antibody (claims 15 and 30); and
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`• a dose of at least about 3 µg/kg (claims 16 and 31).
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`(Ex. 1001, claims 3, 4, 8-16, 19, 20, and 24-31; Ex. 1015 ¶71.)
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`Patent Owner Admissions in the Specification
`B.
`The ’045 patent discloses that many of the claimed limitations were known in
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`the art. “Admissions in the specification regarding the prior art are binding on the
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`patentee for the purposes of a later inquiry into obviousness.” PharmaStem
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`Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1362 (Fed. Cir. 2007).
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`CGRP and Its Role in Migraine Was Known
`1.
`The ’045 patent acknowledges that “CGRP is a potent vasodilator that has
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`been implicated in the pathology of other vasomotor symptoms, such as all forms of
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`vascular headache, including migraines (with or without aura) and cluster
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`headache.” (Ex. 1001, 2:3-7.) The ’045 patent further acknowledges that “[p]ossible
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`CGRP involvement in migraine has been the basis for the development and testing
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`of a number of compounds” that block the CGRP pathway. (Id., 2:14-23.)
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`2.
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`Anti-CGRP Antagonist Antibodies and Methods of Making
`Them, Including Humanization Techniques, Were Known
`The ’045 patent states that “[a]nti-CGRP antagonist antibodies are known in
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`the art,” including those described by Tan. (Id., 25:59-63 (citing Tan (Ex. 1022)).)
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`It confirms that anti-CGRP antibodies were commercially available, such as
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`antibody #4901 from Sigma Aldrich. (Id.; Ex. 1051, 350.) The ’045 patent also
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`expressly discloses that the claimed anti-CGRP antagonistic antibodies may be made
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`using prior art methods:
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`The anti-CGRP antagonist antibodies may be made by any method
`known in the art. The route and schedule of immunization of the host
`animal are generally in keeping with established and conventional
`techniques for antibody stimulation and production, as further
`described herein.
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`(Ex. 1001, 27:41-45, 31:27-31 (“Anti-CGRP antagonist antibodies and polypeptides
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`derived from antibodies can be identified or characterized using methods known in
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`the art . . . .”); 27:45-47 (“General techniques for production of human and mouse
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`antibodies are known in the art and are described herein.”).)
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`The ’045 patent states that preparing humanized and human antibodies from
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`non-human antibodies, such as murine antibodies, was “known” and “conventional.”
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`(Id., 27:41-47, 31:27-31, 32:7-8, 35:46-47; see also id., cols. 28-30; Ex. 1015 ¶72.)
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`According to the ’045 patent, the prior art taught methods to humanize a monoclonal
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`antibody:
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`(1) determining the nucleotide and predicted amino acid sequence of
`the starting antibody light and heavy variable domains[;] (2) designing
`the humanized antibody, i.e., deciding which antibody framework
`region to use during the humanizing process[;] (3) the actual
`humanizing methodologies/techniques[;] and (4) the transfection and
`expression of the humanized antibody.
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`(Ex. 1001, 28:55-64 (citing Queen (Ex. 1023) and other prior art patents); Ex. 1015
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`¶73.)
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`The ’045 patent acknowledges that humanized anti-CGRP antagonist
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`antibodies “are designed to minimize unwanted immunological response toward
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`rodent anti-human antibody molecules.” (Ex. 1001, 29:15-20.)
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`Petition for Inter Partes Review
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`Prosecution of the ’045 Patent
`C.
`During prosecution, the Office did not raise any art-based rejections against
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`the pending claims. But certain key documents, including Olesen (Ex. 1025) and
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`Queen (Ex. 1023), had not been submitted.
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`The Office rejected the pending claims as lacking enablement. (Ex. 1213,
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`4-5.) In response, Teva argued that the enablement requirement was met because,
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`inter alia, four murine anti-CGRP antibodies (including Antibody #4901,
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`commercially available at the time of filing) inhibited skin vasodilation in a rat
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`saphenous nerve model and other models. (Ex. 1143, 10; Ex. 1001, 25:59-63;
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`Ex. 1051, 350.) Teva also admitted that skin vasodilation, like migraine, is a
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`vasomotor symptom. (Ex. 1143, 10; Ex. 1001, 3:37-45.)
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` Background and Asserted Prior Art
`A. CGRP Structure and Its Isoforms
`By 2005, the neuropeptide CGRP had been identified and extensively studied.
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`(Ex. 1014 ¶¶16-23.) Human CGRP is expressed in two closely related isoforms,
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`αCGRP and βCGRP, both 37 amino acids in length. (Id. ¶16; Ex. 1032, 275;
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`Ex. 1096, 534.) Human αCGRP and βCGRP differ by only three amino acids.
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`(Ex. 1014 ¶16; Ex. 1032, 275; Ex. 1096, 534.) Rat CGRP is also expressed in α and
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`β isoforms, and they differ by only one amino acid. (Ex. 1014 ¶16; Ex. 1032, 275;
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`Ex. 1096, 534.) CGRP shows significant sequence identity across species: human
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`αCGRP and βCGRP differ from their rat counterparts by only four and three
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`Petition for Inter Partes Review
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`variations, respectively. (Ex. 1014 ¶16; Ex. 1033, 93-94; Ex. 1096, 534.) Whereas
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`human βCGRP is predominantly expressed in the enteric nervous system and
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`pituitary gland, αCGRP was known to be expressed in sensory neurons, suggesting
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`that αCGRP had an important role in migraine. (Ex. 1014 ¶21; Ex. 1031, 317.)
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`CGRP has powerful vasodilatory effects that, by 2005, had been directly
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`linked to various human diseases, including migraine. (Ex. 1014 ¶¶26-38, 112; Ex.
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`1026, 7:5-12, 7:19-24, 10:25-30; Ex. 1027, [0002]-[0003]; Ex. 1025, 1105; Ex.
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`1040, 182-83; Ex. 1096, 533, 567-570.)
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`Researchers had also investigated the biological functions of CGRP by using
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`monoclonal antibodies that bound to CGRP and prevented it from binding to its
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`receptors. (Ex. 1014 ¶¶50-61.) This is known as “immunoblockade.” (Ex. 1022,
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`566; Ex. 1014 ¶50.) By 2005, immunoblockade with monoclonal anti-CGRP
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`antibodies was shown to inhibit the effects of CGRP in vivo and was recognized as
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`an alternative to blocking CGRP with receptor antagonists because of its “inherent
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`advantages of defined specificity, known affinity, reproducibility, and unlimited
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`availability.” (Ex. 1014 ¶¶50, 61; Ex. 1022, 572.)
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`U.S. Patent No. 8,586,045
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`B. Migraine and CGRP
`Migraine is a chronic, and often debilitating disease. (Ex. 1014 ¶24; Ex. 1040,
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`176.) During migraine attacks, changes in nerve activity in the trigeminal region of
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`the head, which lies outside the blood brain barrier (“BBB”), lead to a painful,
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`reflexive vasodilatation of cranial blood vessels. (Ex. 1031, 322; Ex. 1089, 258.)
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`Well before Teva filed its provisional application, CGRP had been identified
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`as a key substance involved in provoking migraine. Upon stimulation, the trigeminal
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`nerve releases CGRP in an antidromic manner (i.e., in the opposite direction of the
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`normal nerve fiber conduction). (Ex. 1014 ¶27; Ex. 1035, 290.) This results in pain
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`and further nerve activation. (Ex. 1014 ¶¶25, 27; Ex. 1035, 290.)
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`By the early 2000s, it was understood that: (1) levels of CGRP—but not other
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`neuropeptides—are significantly elevated in migraine patients compared to those
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`without migraine; (2) plasma CGRP concentrations and migraine headache strongly
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`correlate; (3) baseline CGRP levels are considerably higher during migraine; and (4)
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`the changes in plasma CGRP levels during migraine attacks significantly correlate
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`with headache intensity. (Ex. 1043, 185; Ex. 1044, 48; Ex. 1045, 467; Ex. 1040,
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`182-83; Ex. 1014 ¶¶28, 35.) Further, administering CGRP to migraine patients
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`induced not only an immediate headache, but also a delayed headache bearing most
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`of the characteristics of migraine. (Ex. 1047, 56, 59; Ex. 1014 ¶¶29, 35.)
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`These clinical findings and observations led to the consensus that CGRP
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`played a causative role in migraine, making it an attractive target for treatment of
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`migraine. (See Ex. 1031, 316; Ex. 1040, 182; Ex. 1041, 1073; Ex. 1014 ¶¶26, 38.)
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`Indeed, as discussed in § IV.E.1 below, the prior art had even shown that migraine
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`could be treated—in human patients—by blocking the CGRP pathway.
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`C. Anti-CGRP Antagonist Antibodies Were Well Known in the Art
`and Had Been Disclosed for Therapeutic Use in Humans
`By 2005, several publications had described anti-CGRP antagonist antibodies
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`and methods of making them. (Ex. 1021; Ex. 1022; Ex. 1032; Ex. 1033; Ex. 1055.)
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`These well-established prior art methods generally involved immunizing mice with
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`αCGRP, collecting serum, screening for antibodies that exhibit anti-CGRP activity,
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`culturing hybridoma cells, and producing the monoclonal antibodies in bulk. (See,
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`e.g., Ex. 1033, 95-96; Ex. 1021, 704; Ex. 1015 ¶¶27-29.) Anti-CGRP antagonist
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`antibodies had been prepared against both human and rat αCGRP. (Ex. 1021, 704;
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`Ex. 1033, 95-96, 102; Ex. 1055, 88.)
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`The prior art specifically identified anti-CGRP antagonist antibodies,
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`including humanized antibodies, to treat human diseases such as migraine. (See
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`infra §§ VII.A.1-2.)
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`U.S. Patent No. 8,586,045
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`D. Humanization of Antibodies
`Before Teva filed its provisional application, researchers understood that
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`administering non-human antibodies to human patients resulted in immunogenicity
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`that could eliminate the therapeutic effects of an antibody drug, or worse, cause
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`harmful effects in patients. (Ex. 1015 ¶¶30-33; Ex. 1023, 1:44-57.) Consequently,
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`researchers developed therapeutic antibodies that were more “human.” (Ex. 1015
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`¶¶34-36; see also id. ¶¶37-53.)
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`One prominent method was to humanize antibodies by grafting CDRs from a
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`non-human antibody into a human IgG antibody scaffold. (Ex. 1015 ¶39.) This
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`technique was first introduced nearly twenty years before Teva’s earliest filing date,
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`and was thereafter refined by the work of Queen and others. (Id. ¶40; Ex. 1101, 522;
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`Ex. 1075, 10029; Ex. 1023, 2:61-3:32.) By 2005, antibody humanization was
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`considered a “clinically well-validated technology.” (Ex. 1015 ¶41; Ex. 1073, 120;
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`Ex. 1056, 1077.) Moreover, the FDA had approved many humanized antibodies,
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`and most monoclonal antibodies in phase 2 and phase 3 trials were humanized.
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`(Ex. 1056, 1077; Ex. 1073, 120.) IgG antibodies were the preferred scaffold for
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`humanized antibodies. (Ex. 1015 ¶¶21, 98.)
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`U.S. Patent No. 8,586,045
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`E.
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`The Asserted Prior Art
`1. Olesen
`Olesen, a 2004 publication in The New England Journal of Medicine, reported
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`that blocking the CGRP pathway in human patients effectively treated migraine.
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`(Ex. 1014 ¶¶67-68.)
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`Olesen confirms that by 2004, researchers understood that CGRP played an
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`important role in initiating and mediating migraine attacks, making the CGRP
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`pathway a prime target for treating migraine in the clinic. (Ex. 1025, 1105.) Olesen
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`attributes these extensive pre-clinical findings as the basis for its clinical study in
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`human patients to evaluate the efficacy of BIBN4096BS, a known CGRP-receptor
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`antagonist, that had been shown to “potently block[] the effect of CGRP.” (Id.)
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`Patients in the Olesen study experiencing acute migraine attacks received an
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`intravenous infusion of either BIBN4096BS or placebo. (Ex. 1025, 1106; Ex. 1014
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`¶32.) The primary study endpoint was a reduction of severe or moderate headache
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`at baseline to mild or no headache at two hours after dosing. (Ex. 1025, 1106; Ex.
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`1014 ¶32.) Secondary endpoints included the rates of response at different time
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`points after administration; the rates of sustained response over a 24-hour period; the
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`relief of other migraine-associated symptoms; side effects; and clinical laboratory
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`values. (Ex. 1025, 1106-07; Ex. 1014 ¶32.)
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`Two hours after treatment with BIBN4096BS, 66% of patients exhibited a
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`positive response compared to only 27% of patients on placebo. (Ex. 1025, 1107-
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`08; Ex. 1014 ¶33.) BIBN4096BS was also superior to placebo for the tested
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`secondary endpoints. For example, the rate of migraine recurrence was only 20% of
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`patients for the BIBN4096BS groups, whereas the rate was 46% for those receiving
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`placebo. (Ex. 1025, 1108; Ex. 1014 ¶33.) Based on these results, Olesen concluded
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`that BIBN4096BS was effective in treating migraine attacks up to six hours after
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`onset. (Ex. 1025, 1108.) Although BIBN4096BS was a CGRP-receptor antagonist,
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`Olesen announced that “proof-of-concept was thus established” for treatment more
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`generally—blocking the CGRP pathway with a CGRP antagonist. (Id., 1108-09;
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`Ex. 1014 ¶34.)
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`In a symposium held shortly after the publication of Olesen, the authors
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`further emphasized the general applicability of