Filed on behalf of: Eli Lilly and Company
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`Filed: August 8, 2018
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`______________________
`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
`______________________
`
`PETITION FOR INTER PARTES REVIEW
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`

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`I.
`II.
`
`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
`III. The ’210 Patent and Its Provisional Application ............................................. 4
`A.
`The Challenged Claims ......................................................................... 5
`B.
`Patent Owner Admissions in the Specification ..................................... 6
`1.
`Anti-CGRP Antagonist Antibodies and Methods of
`Making Them, Including Humanization Techniques,
`Were Known ............................................................................... 7
`Limitations of Dependent Claims Were Also Known ................ 8
`a)
`Anti-CGRP Antagonist Antibodies That Bound to
`the C-Terminus of CGRP Were Known ........................... 8
`IgG Sub-Types and Constant Regions Were
`Known ............................................................................... 9
`Prosecution of the ’210 Patent .............................................................. 9
`C.
`IV. Background and the Asserted Prior Art ......................................................... 10
`A.
`CGRP Structure, Isoforms, and Function ........................................... 10
`B.
`Anti-CGRP Antagonist Antibodies Were Well Known in the
`Art and Had Been Disclosed for Therapeutic Use in Humans ........... 11
`IgG Antibodies .................................................................................... 12
`C.
`D. Humanization of Antibodies ............................................................... 15
`E.
`The Asserted Prior Art ........................................................................ 16
`1.
`Tan 1995 ................................................................................... 16
`
`2.
`
`b)
`
`i
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`

`

`2.
`
`3.
`
`2. Wimalawansa ............................................................................ 18
`3.
`Queen ........................................................................................ 18
`Person of Ordinary Skill in the Art ................................................................ 20
`V.
`VI. Claim Construction ........................................................................................ 20
`VII. Claim 1 Is Obvious over Tan 1995, Wimalawansa, and Queen ................... 22
`A. A POSA Would Have Been Motivated to Generate a
`Humanized Anti-CGRP Antagonist Antibody of Claim 1 ................. 23
`1.
`The Prior Art Recommended the Use of Anti-CGRP
`Antagonist Antibodies, Including Humanized Antibodies,
`for Therapeutic Use in Humans ................................................ 23
`The Confirmed In Vivo Effectiveness of Prior Art Anti-
`CGRP Antagonist Antibodies Provided Additional
`Motivation to Prepare a Humanized Antibody ......................... 26
`The Prior Art Provided Additional Motivation to Prepare
`a Humanized Antibody ............................................................. 28
`A POSA Would Have Had a Reasonable Expectation of
`Successfully Making a Humanized Anti-CGRP Antagonist
`Antibody of Claim 1 ............................................................................ 30
`1.
`A POSA Would Have Had a Reasonable Expectation of
`Successfully Producing an Antibody Against Human
`CGRP ........................................................................................ 30
`A POSA Would Have Had a Reasonable Expectation of
`Successfully Producing a Humanized Anti-CGRP
`Antagonist Antibody of Claim 1 ............................................... 33
`The Prior Art Did Not Teach Away from Humanizing Anti-
`CGRP Antagonist Antibodies, as Teva Incorrectly Argued
`During Prosecution .............................................................................. 37
`The Claimed Antibodies Would Have Been Obvious ........................ 42
`D.
`VIII. The Challenged Dependent Claims Would Have Been Obvious .................. 44
`
`C.
`
`B.
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`2.
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`ii
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`

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`B.
`
`X.
`
`A.
`Claims 2, 6, and 11 .............................................................................. 44
`Claims 3, 7, 8, and 12 .......................................................................... 47
`B.
`Claims 4, 9, and 13 .............................................................................. 49
`C.
`Claims 5, 10, 14, and 15 ...................................................................... 49
`D.
`IX. Secondary Considerations Do Not Support Nonobviousness ....................... 52
`A.
`Teva Cannot Establish Nexus to the Full Scope of the
`Challenged Claims .............................................................................. 52
`Lilly’s and Other’s Own Near-Simultaneous Development
`Precludes a Holding of Nonobviousness ............................................. 53
`The Evidence Submitted in this Petition Was Not Previously
`Considered by the Office ............................................................................... 55
`XI. Mandatory Notices Under 37 C.F.R. § 42.8 .................................................. 55
`A.
`Real Parties-in-Interest ........................................................................ 55
`B.
`Related Matters .................................................................................... 56
`C.
`Lead and Backup Counsel .................................................................... 56
`D.
`Service Information ............................................................................. 58
`XII. Payment of Fees ............................................................................................. 58
`XIII. Conclusion ..................................................................................................... 58
`CERTIFICATION OF COMPLIANCE .................................................................... 1
`CERTIFICATE OF SERVICE .................................................................................. 2
`
`
`iii
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`
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Abbott GmbH & Co., KG v. Centocor Ortho Biotech, Inc.,
`971 F. Supp. 2d 171 (D. Mass. 2013) ........................................................... 30, 36
`AbbVie Deutschland GmbH v. Janssen Biotech, Inc.,
`759 F.3d 1285 (Fed. Cir. 2014) .......................................................................... 52
`Akorn, Inc. v. Senju Pharm. Co.,
`IPR2015-01205, Paper 39 (PTAB Nov. 22, 2016) ............................................. 37
`Allergan, Inc. v. Apotex Inc.,
`754 F.3d 952 (Fed. Cir. 2014) ............................................................................ 53
`Ecolochem, Inc. v. S. Cal. Edison Co.,
`227 F.3d 1361 (Fed. Cir. 2000) .......................................................................... 53
`Geo. M. Martin Co. v. Alliance Mach. Sys. Int’l LLC,
`618 F.3d 1294 (Fed. Cir. 2010) .................................................................... 53, 54
`In re Am. Acad. of Sci. Tech Ctr.,
`367 F.3d 1359 (Fed. Cir. 2004) .......................................................................... 21
`In re Mouttet,
`686 F.3d 1322 (Fed. Cir. 2012) .................................................................... 38, 42
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ...................................................................................... 30, 41
`Paice LLC v. Ford Motor Co.,
`881 F.3d 894 (Fed. Cir. 2018) ............................................................................ 36
`PharmaStem Therapeutics, Inc. v. ViaCell, Inc.,
`491 F.3d 1342 (Fed. Cir. 2007) ...................................................................... 6, 32
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) (en banc) .......................................................... 21
`Senju Pharm. Co. v. Lupin Ltd.,
`780 F.3d 1337 (Fed. Cir. 2015) .......................................................................... 37
`
`iv
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`
`
`Statutes
`35 U.S.C. § 102(b) ..................................................................................................... 3
`35 U.S.C. § 103(a) ..................................................................................................... 3
`35 U.S.C. § 311 .......................................................................................................... 3
`35 U.S.C. § 325(d) ................................................................................................... 55
`Regulations
`37 C.F.R. § 42.8 ....................................................................................................... 55
`37 C.F.R. § 42.15(a) ................................................................................................. 58
`37 C.F.R. § 42.100(b) .............................................................................................. 20
`37 C.F.R. § 42.103(a) ............................................................................................... 58
`37 C.F.R. § 42.104 ..................................................................................................... 2
`Other Authorities
`Notice of Proposed Rulemaking (May 3, 2018) ...................................................... 21
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`
`
`v
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`
`GLOSSARY
`
`Antibody-dependent cellular cytotoxicity
`ADCC
`America Invents Act
`AIA
`Broadest reasonable interpretation
`BRI
`Complement-dependent cytotoxicity
`CDC
`Complementarity-determining region
`CDR
`Calcitonin gene-related peptide
`CGRP
`European Patent Office
`EPO
`Fragment antigen binding
`Fab
`U.S. Food and Drug Administration
`FDA
`Framework region
`FR
`Inter partes review
`IPR
`Emphasis added unless otherwise indicated
`Italicized text
`Eli Lilly and Company
`Lilly or Petitioner
`Monoclonal antibody
`MAb
`Person of ordinary skill in the art
`POSA
`provisional application U.S. Provisional App. No. 60/736,623
`Teva or Patent Owner Teva Pharmaceuticals International GmbH
`USPTO or Office
`U.S. Patent and Trademark Office
`’210 patent
`U.S. Patent No. 9,890,210
`’438 patent
`U.S. Patent No. 6,344,438
`
`vi
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`
`
`I.
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`
`
`Petition for Inter Partes Review
`U.S. Patent No. 9,890,210
`
`Introduction
`Teva’s ’210 patent broadly claims humanized monoclonal anti-CGRP
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`antagonist IgG antibodies that bind to human CGRP. The claims recite features
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`common to all IgG antibodies (e.g., heavy chains with three complementarity
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`determining regions (“CDRs”) and four framework regions (“FRs”)) and a binding
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`specificity for human CGRP possessed by many prior art antibodies.
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`Teva’s claims are obvious over the prior art. By Teva’s earliest possible filing
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`date of November 14, 2005, the prior art had already singled out anti-CGRP
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`antagonist antibodies, including humanized antibodies, for use as therapeutic agents
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`for human diseases and conditions. Multiple prior art references explicitly identified
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`anti-CGRP antagonist antibodies to treat or prevent a variety of clinical conditions.
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`Several research groups had also prepared and tested the antagonistic activity of anti-
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`CGRP antibodies in vitro and in vivo, including antibodies that specifically bound to
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`human CGRP. Thus, the prior art provided express motivation to prepare a
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`humanized anti-CGRP antagonist antibody that binds human CGRP.
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`Moreover, as Teva’s ’210 patent admits, humanization was a well-established
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`and routine procedure by 2005. Indeed, researchers had long understood that
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`humanized antibodies advantageously avoided immunogenic reactions caused by
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`administering murine or chimeric antibodies to humans. By 2005, half of the FDA-
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`1
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`

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`
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`approved antibodies were humanized antibodies, and most antibodies in phase 2 and
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`
`
`Petition for Inter Partes Review
`U.S. Patent No. 9,890,210
`
`3 clinical trials were humanized.
`
`As explained below and in the Expert Declarations of Dr. Andrew Charles, a
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`neurologist who specializes in the treatment of migraine and long-time CGRP
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`researcher, and Dr. Alain Vasserot, an antibody engineer with expertise in antibody
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`humanization, there is a reasonable likelihood that Petitioner will prevail on all
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`challenged claims, and that the prior art renders the claims obvious by at least a
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`preponderance of the evidence. (Ex. 1010 ¶¶1-17; Ex. 1011 ¶¶1-15.) Notably, in
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`parallel proceedings at the EPO, Teva did not appeal the EPO’s revocation of broad
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`antibody claims similar to those challenged here. Similarly, in parallel UK
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`proceedings, Teva abandoned broad antibody and composition claims challenged by
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`Lilly to pursue only claims to the prevention and treatment of headaches.
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`Accordingly, Lilly requests inter partes review of claims 1-15 of the ’210 patent.
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`II. Requirements for Inter Partes Review Under 37 C.F.R. § 42.104
`A. Grounds for Standing
`Petitioner certifies that the ’210 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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`requesting review on the ground identified. (Ex. 1186, 4-6 (listing priority chain and
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`2
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`

`

`
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`declining to designate as a transition application); Ex. 1001, 1:8-29, title page, item
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`
`
`Petition for Inter Partes Review
`U.S. Patent No. 9,890,210
`
`(60).)1
`
`Identification of Challenge
`B.
`Lilly respectfully requests review under 35 U.S.C. § 311 of claims 1-15 of
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`the ’210 patent. In the sole ground presented in this Petition, Lilly requests that the
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`Board find these claims unpatentable as obvious under 35 U.S.C. § 103(a) in view
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`of the following combination of references:
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`Reference 1: K.K.C. Tan et al., Clin. Sci. 89:565-573 (1995) (“Tan 1995”)
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`(Ex. 1022), published on December 1, 1995. Tan 1995 is prior art to the ’210 patent
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`under 35 U.S.C. § 102(b).
`
`Reference 2: S.J. Wimalawansa, Endocrine Reviews 17(5):533-585 (1996)
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`(“Wimalawansa”) (Ex. 1096), published in 1996. Wimalawansa is prior art to the
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`’210 patent under 35 U.S.C. § 102(b).
`
`Reference 3: U.S. Patent No. 6,180,370 (“Queen”) (Ex. 1023), issued on
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`January 30, 2001. Queen is prior art to the ’210 patent under 35 U.S.C. § 102(b).
`
`
`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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`3
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`
`
`III. The ’210 Patent and Its Provisional Application
`The ’210 patent is entitled “Antagonist Antibodies Directed Against
`
`
`
`Petition for Inter Partes Review
`U.S. Patent No. 9,890,210
`
`Calcitonin Gene-Related Peptide.” (Ex. 1001, title page, item (54).) It states that
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`the alleged invention “relates to the use of anti-CGRP antagonist antibodies for the
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`prevention, amelioration, or treatment of vasomotor symptoms, such as CGRP
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`related headaches (e.g., migraine) and hot flushes.” (Id., 1:33-36; Ex. 1010 ¶81.)
`
`The ’210 patent discloses a sole humanized antagonist antibody (G1) and its
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`purported derivatives. (E.g., Ex. 1001, Abstract, Example 4.) The ’210 patent does
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`not include any clinical or other human data.
`
`The ’210 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 (“the
`
`provisional application”), filed on November 14, 2005. (Ex. 1010 ¶82.) Lilly has
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`also filed IPR petitions for related U.S. Patent Nos. 8,597,649; 9,266,951; 9,340,614;
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`9,346,881; and 9,890,211. These patents are similarly directed to anti-CGRP
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`antagonist antibodies.
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`The provisional application, like the ’210 patent, identifies only one
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`humanized anti-CGRP antagonist antibody, G1, as well as its variants with minor
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`sequence differences. (E.g., Ex. 1019, Example 4; Ex. 1001, Abstract, Example 4.)
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`The only in vivo data disclosed in the provisional application was generated using a
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`well-known assay—the rat saphenous nerve assay—used in the prior art for the
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`4
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`

`
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`specific purpose of evaluating anti-CGRP antagonist antibodies. (Compare
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`
`
`Petition for Inter Partes Review
`U.S. Patent No. 9,890,210
`
`Ex. 1019, ¶[0244] (citing Ex. 1052), with Ex. 1022, 572 (citing Ex. 1052 as
`
`reference 9); Ex. 1010 ¶¶90-91.) When filing its PCT application a year later, Teva
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`only added additional animal study results, and not any clinical data, to the
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`disclosure of its provisional application. (Ex. 1020, 66-68 (adding Examples 6-8).)
`
`A. The Challenged Claims
`Claim 1 of the ’210 patent, the only independent claim, recites:
`
`A humanized monoclonal anti-Calcitonin Gene-
`Related Peptide (CGRP) antagonist antibody, comprising:
`two human IgG heavy chains, each heavy chain
`comprising three complementarity determining regions
`(CDRs) and four framework regions, wherein portions of
`the two heavy chains together form an Fc region; and
`two light chains, each light chain comprising three
`CDRs and four framework regions;
`wherein the CDRs impart to the antibody specific
`binding to a CGRP consisting of amino acid residues 1 to
`37 of SEQ ID NO:15 or SEQ ID NO: 43.
`(Ex. 1001, claim 1; Ex. 1010 ¶¶83-84; Ex. 1011 ¶¶59.) The recited sequence IDs
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`correspond to human αCGRP and βCGRP, respectively. (Ex. 1010 ¶85; Ex. 1011
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`¶60; Ex. 1001, cols. 53-56 (Table 4 designates human αCGRP and βCGRP as SEQ
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`ID NOS:15 and 43).) The recited “heavy chain” and “light chain” limitations are
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`5
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`

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`
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`generic to IgG antibodies and do not provide meaningful structure that correlates
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`
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`Petition for Inter Partes Review
`U.S. Patent No. 9,890,210
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`with the recited function of specific binding to CGRP. (Ex. 1011 ¶61.)
`
`Dependent claims 2, 6, and 11 further recite IgG1, IgG2, or IgG4 heavy chain
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`constant regions. (Ex. 1001, claims 2, 6, 11; Ex. 1010 ¶86; Ex. 1011 ¶64.) The
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`challenged claims that further depend from claims 2, 6, and 11 additionally require:
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`• CDRs imparting to the antibody specific binding to a fragment
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`comprising CGRP8-37 of human αCGRP (claims 3, 7, and 12);
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`• CDRs imparting to the antibody specific binding to a fragment
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`comprising CGRP33-37 of human αCGRP (claim 8);
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`• CDRs of the humanized monoclonal antibody derived from mouse, rat,
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`or rabbit CDRs (claims 4, 9, and 13); and
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`• a mutation in an oligosaccharide attachment amino acid residue that is
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`part of an N-glycosylation recognition sequence in the constant region
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`(claims 5, 10, 14, and 15).
`
`(Ex. 1001, claims 3-5, 7-10, 12-15; Ex. 1010 ¶¶87-88; Ex. 1011 ¶65.)
`
`Patent Owner Admissions in the Specification
`B.
`The ’210 patent itself expressly discloses that multiple claim limitations were
`
`known in the art. “Admissions in the specification regarding the prior art are binding
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`on the 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).
`
`6
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`
`
`Petition for Inter Partes Review
`U.S. Patent No. 9,890,210
`
`1.
`
`Anti-CGRP Antagonist Antibodies and Methods of Making
`Them, Including Humanization Techniques, Were Known
`The ’210 patent states that “[a]nti-CGRP antagonist antibodies are known in
`
`the art.” (Ex. 1001, 26:28-32 (citing Ex. 1022).) It confirms that anti-CGRP
`
`antibodies were commercially available, such as antibody #4901 from Sigma
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`Aldrich. (Id.; Ex. 1051, 350.) The ’210 patent also expressly discloses that the
`
`claimed anti-CGRP antagonistic antibodies may be made using prior art methods:
`
`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.
`
`(Ex. 1001, 28:10-14, 32:4-8 (“Anti-CGRP antagonist antibodies and polypeptides
`
`derived from antibodies can be identified or characterized using methods known in
`
`the art . . . .”), 28:15-16 (“General techniques for production of human and mouse
`
`antibodies are known in the art and are described herein.”).)
`
`
`
`The ’210 patent states that preparing humanized and human antibodies from
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`non-human antibodies, such as murine antibodies, was “known” and “conventional.”
`
`(Id., 28:10-16, 32:4-8, 32:51-52, 36:24-25, 38:8-12; see also id., cols. 28-30;
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`Ex. 1011 ¶66.) According to the ’210 patent, the prior art taught methods to
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`humanize a monoclonal antibody:
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`7
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`Petition for Inter Partes Review
`U.S. Patent No. 9,890,210
`
`(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.
`
`(Ex. 1001, 29:27-36 (citing Queen (Ex. 1023) and other prior art patents); Ex. 1011
`
`¶67.)
`
`
`
`The ’210 patent also states that humanized anti-CGRP antagonist antibodies
`
`“are designed to minimize unwanted immunological response toward rodent anti-
`
`human antibody molecules.” (Ex. 1001, 29:54-59.)
`
`Limitations of Dependent Claims Were Also Known
`2.
`The ’210 patent also acknowledges that many of the limitations recited in its
`
`dependent claims were known, conventional, or routine.
`
`a)
`
`Anti-CGRP Antagonist Antibodies That Bound to the
`C-Terminus of CGRP Were Known
`The ’210 patent confirms that prior art anti-CGRP antagonist antibody #4901
`
`binds to the C-terminal fragment of CGRP (e.g., amino acids 8-37 and 33-37), just
`
`as the literature had earlier reported. (Ex. 1001, 26:28-32 (identifying #4901 as
`
`commercially available from Sigma), 52:4-11 (“The data indicate that these anti-
`
`CGRP antibodies generally bind to the C-terminal end of CGRP.”), Fig. 1; see
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`8
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`

`

`
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`Ex. 1033, 104, 102 (“The monoclonal antibody recognizes an epitome [sic] in the
`
`
`
`Petition for Inter Partes Review
`U.S. Patent No. 9,890,210
`
`10 amino acid C-terminal region of the rat α-CGRP.”).)
`
`IgG Sub-Types and Constant Regions Were Known
`b)
`The ’210 patent states that anti-CGRP antagonist antibodies may include a
`
`heavy chain constant region derived from human IgG1, IgG2, or IgG4 constant
`
`regions, and that such regions were known in the art. (Ex. 1001, 5:25-45, 12:64-65
`
`(“The subunit structures and three-dimensional configurations of different classes of
`
`immunoglobulins are well known.”); Ex. 1011 ¶68; see also id. ¶69.)
`
`Prosecution of the ’210 Patent
`C.
`During prosecution, the Office rejected the pending claims based on
`
`obviousness-type double patenting over a series of related patents:
`
`• U.S. Patent No. 8,007,794
`
`• U.S. Patent No. 8,597,649
`
`• U.S. Patent No. 9,266,951
`
`• U.S. Patent No. 9,346,881
`
`• U.S. Patent No. 9,340,614
`
`• U.S. Appl. No. 15/588,461 (issued as U.S. Patent No. 9,890,211).
`
`(Ex. 1187, 3-6.) Teva did not substantively dispute these obviousness rejections but
`
`instead filed terminal disclaimers. (Ex. 1188, 5-6; Ex. 1189.)
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`9
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`

`

`Petition for Inter Partes Review
`U.S. Patent No. 9,890,210
`
`
`
`
`
`IV. Background and the Asserted Prior Art
`A. CGRP Structure, Isoforms, and Function
`By 2005, the neuropeptide CGRP had been identified and extensively studied.
`
`(Ex. 1010 ¶¶18-25.) Human CGRP is expressed in two closely related isoforms,
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`αCGRP and βCGRP, both 37 amino acids in length. (Id. ¶18; Ex. 1032, 275;
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`Ex. 1096, 534.) Human αCGRP and βCGRP differ by only three amino acids.
`
`(Ex. 1010 ¶18; 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. 1010 ¶18; Ex. 1032, 275;
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`Ex. 1096, 534.) CGRP shows significant homology across species: human αCGRP
`
`and βCGRP differ from their rat counterparts by only four and three variations,
`
`respectively. (Ex. 1010 ¶18; Ex. 1033, 93-94; Ex. 1096, 534.) Whereas human
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`βCGRP is predominantly expressed in the enteric nervous system and pituitary
`
`gland, αCGRP was known to be expressed in sensory neurons, suggesting that
`
`αCGRP had an important role in diseases such as migraine. (Ex. 1010 ¶23; Ex. 1031,
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`317 (citing Ex. 1096).)
`
`CGRP has powerful vasodilatory effects that, by 2005, had been directly
`
`linked to various human diseases, including migraine, neurogenic pain, and
`
`psoriasis. (Ex. 1010 ¶¶35-47; Ex. 1026, 7:5-12, 7:19-24, 10:25-30, claims 2, 7;
`
`Ex. 1025, 1105; Ex. 1040, 182-83; Ex. 1096, 533, 567-70.) Moreover, in 2004,
`
`Olesen reported successful human clinical trials demonstrating proof of concept that
`
`10
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`blocking the CGRP pathway leads to migraine relief. (Ex. 1010 ¶¶40-43; Ex. 1025,
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`
`
`Petition for Inter Partes Review
`U.S. Patent No. 9,890,210
`
`1104, 1108-09.)
`
`Researchers had also investigated the biological functions of CGRP by using
`
`monoclonal antibodies that bound to CGRP and prevented it from binding to its
`
`receptors. (Ex. 1010 ¶¶48-59.) This is known as “immunoblockade.” (Ex. 1022,
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`566; Ex. 1010 ¶48.) By 2005, immunoblockade with monoclonal anti-CGRP
`
`antibodies was shown to inhibit the effects of CGRP in vivo and was recognized to
`
`have “inherent advantages of defined specificity, known affinity, reproducibility, and
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`unlimited availability.” (Ex. 1010 ¶59; Ex. 1022, 572.)
`
`B. 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
`
`and methods of making them. (Ex. 1021; Ex. 1022; Ex. 1032; Ex. 1033; Ex. 1055.)
`
`These well-established prior art methods generally involve immunizing mice with
`
`CGRP, 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,
`
`e.g., Ex. 1021, 704; Ex. 1033, 95-96; see Ex. 1011 ¶¶28-30.) Anti-CGRP antagonist
`
`antibodies had been prepared against both human and rat CGRP (Ex. 1021, 704;
`
`Ex. 1033, 95-96, 102. Ex. 1055, 88.) Because of their sequence homology,
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`antibodies raised against rat CGRP were known to bind both human and rat CGRP.
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`(Ex. 1011 ¶100; Ex. 1033, 94, 102; Ex. 1021, 704, 706.)
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`The prior art specifically identified anti-CGRP antagonist antibodies,
`
`including humanized antibodies, to treat a variety of human diseases and conditions,
`
`such as migraine, neurogenic inflammatory pain, eye pain, and psoriasis. (See infra
`
`§ VII.A.1.)
`
`IgG Antibodies
`C.
`The anti-CGRP antagonist antibodies of the prior art included IgG antibodies.
`
`(Ex. 1022, 566; Ex. 1033, 93; Ex. 1055, 89.) As of 2005, IgG was the preferred
`
`immunoglobulin class for all therapeutic antibodies, regardless of target antigen.
`
`(Ex. 1010 ¶28; Ex. 1062, 43; Ex. 1011 ¶22.)
`
`The structure of an IgG antibody is shown in the simplified depiction below
`
`(Figure 1). It possesses two heavy chains and two light chains. (Ex. 1010 ¶29;
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`Ex. 1011 ¶16; Ex. 1058, 95, 100.)
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`U.S. Patent No. 9,890,210
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`Figure 1: Exemplary IgG Antibody Structure
`
`
`
`(Ex. 1058, 95.)
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`Each “arm” of an IgG antibody is known as a Fab (“fragment antigen
`
`binding”). (Ex. 1010 ¶30; Ex. 1011 ¶17; Ex. 1058, 96-97.) A Fab’ fragment is a
`
`portion of an antibody that corresponds to one of its arms and includes the complete
`
`light chain and part of the heavy chain. (Ex. 1063, 60-61.) In each arm, the N-
`
`terminal regions of the heavy and light chains (shown in yellow in Figure 1) form
`
`the antigen binding site, also referred to as the variable region of an
`
`antibody. (Ex. 1010 ¶30.) The variable region includes two heavy chain variable
`
`domains and two light chain variable domains. (Ex. 1010 ¶30; Ex. 1011 ¶18;
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`Ex. 1058, 96.)
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`U.S. Patent No. 9,890,210
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`The heavy and light chain variable domains each contain three CDRs, which
`
`are primarily responsible for antigen binding. (Ex. 1010 ¶31; Ex. 1011 ¶19;
`
`Ex. 1058, 100-01.) In Figure 1 above, the CDRs are shown as black lines traversing
`
`the yellow variable regions. CDRs possess variable amino acid sequences that
`
`specifically bind to antigens. (Ex. 1010 ¶31; Ex. 1011 ¶19; Ex. 1058, 100-01.) The
`
`three CDRs are generally designated CDR1, CDR2, and CDR3, respectively.
`
`(Ex. 1010 ¶31; Ex. 1011 ¶19.)
`
`In both the heavy and light chains, the three CDRs are interspersed between
`
`four regions called FRs that support the CDRs. (Ex. 1010 ¶32; Ex. 1011 ¶19;
`
`Ex. 1058, 100-01.) In Figure 1, the four FRs are represented by the four yellow areas
`
`interspersed around the three CDRs. (Ex. 1010 ¶32; Ex. 1011 ¶19; Ex. 1058, 100-
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`01.)
`
`The remainder of an IgG antibody (shown in white in Figure 1) is referred to
`
`as the constant region. (Ex. 1010 ¶33; Ex. 1011 ¶20; Ex. 1058, 96-97.) Each light
`
`chain has one constant domain (“CL”), and each heavy chain has three constant
`
`domains (“CH1,” “CH2,” and “CH3”). (Ex. 1010 ¶33; Ex. 1011 ¶20; Ex. 1058, 96-
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`97.) Portions of the CH2 and CH3 domains on the two heavy chains of an IgG
`
`antibody form an Fc region. (Ex. 1010 ¶33; Ex. 1011 ¶20.) The constant region
`
`may interact with the immune system, invoking cellular responses, including cell
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`destruction. Such responses are known as “effector functions.” (Ex. 1010 ¶33;
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`Ex. 1011 ¶¶20, 24-25; Ex. 1058, 96-97.)
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`D. Humanization of Antibodies
`Well before Teva filed its provisional application, researchers recognized that
`
`administering non-human antibodies to human patients resulted in immunogenicity
`
`that could eliminate the therapeutic effects of an antibody drug, or worse, cause
`
`harmful effects in patients. (Ex. 1011 ¶¶31-34; Ex. 1023, 1:44-57.) As a result,
`
`researchers developed therapeutic antibodies that were more “human.” (Ex. 1011
`
`¶¶35-37; see also id. ¶¶38-47.)
`
`One prominent method was to humanize antibodies by grafting CDRs from a
`
`non-human antibody into a human antibody scaffold. (Id. ¶40.) This technique was
`
`first introduced nearly twenty years before Teva’s earliest filing date, and was
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`thereafter refined by the work of Queen and others. (Id. ¶41; Ex. 1101, 522;
`
`Ex. 1075, 10029; Ex. 1023, 2:61-3:32.) By 2005, antibody humanization was
`
`considered a “clinically well-validated technology.” (Ex. 1073, 120; Ex. 1056,
`
`1077; Ex. 1011 ¶42.) Moreover, FDA had approved many humanized antibodies,
`
`and most monoclonal antibodies in phase 2 and phase 3 trials were humanized.
`
`(Ex. 1056, 1077; Ex. 1073, 120.) IgG antibodies were the preferred scaffold for
`
`humanized antibodies. (Ex. 1011 ¶¶22, 93; Ex. 1010 ¶107.)
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`E.
`
`The Asserted Prior Art
`Tan 1995
`1.
`Tan and coworkers published two papers, one in 1994 and one in 1995, that
`
`describe the preparation of murine anti-CGRP antagonist antibodies, their binding
`
`characteristics, and their in vitro and in vivo ability to block CGRP biological
`
`activity. (Ex. 1021; Ex. 1022; Ex. 1010 ¶68.)
`
`Specifically, Tan 1995 identified the murine monoclonal anti-CGRP
`
`antagonist antibody MAb C4.19, which was prepared using standard techniques.
`
`(Ex. 1022, 566; Ex. 1021, 704; Ex. 1010 ¶69.) MAb C4.19 specifically binds both
`
`α and β forms of both human and rat CGRP. (Ex. 1021, 706, 709; Ex. 1010 ¶69.) It
`
`does not bind amylin. (Ex. 1022, 572.) It also does not bind isoprenaline, β-
`
`endorphin, or somatostatin. (Ex. 1021, 707, 709.)
`
`In addition, Tan 1995 describes in vivo studies using MAb C4.19 and its Fab’
`
`fragment. (Ex. 1010 ¶70.) Tan 1995 first analyzed whether these antibodies could
`
`inhibit the hypotensive effect of exogenously administered αCGRP. (Ex