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`Filed: August 8, 2018
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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
`______________________
`
`ELI LILLY AND COMPANY
`Petitioner
`v.
`TEVA PHARMACEUTICALS INTERNATIONAL GMBH
`Patent Owner
`______________________
`
`Case No. IPR2018-01426
`Patent No. 9,890,211
`______________________
`
`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 ................. 3
`A. Grounds for Standing ............................................................................ 3
`B.
`Identification of Challenge .................................................................... 3
`III. The ’211 Patent and Its Provisional Application ............................................. 4
`A.
`The Challenged Claims ......................................................................... 5
`B.
`Patent Owner Admissions in the Specification ..................................... 7
`1.
`Anti-CGRP Antagonist Antibodies and Methods of
`Making Them, Including Humanization Techniques,
`Were Known ............................................................................... 7
`2. Methods to Obtain and Measure Particular Binding
`Affinities by SPR Were Known .................................................. 9
`Limitations of Dependent Claims Were Also Known ................ 9
`a)
`Anti-CGRP Antagonist Antibodies That Bound to
`the C-Terminus of CGRP Were Known ......................... 10
`IgG Sub-Types and Constant Regions Were
`Known ............................................................................. 10
`Prosecution of the ’211 Patent ............................................................ 10
`C.
`IV. Background and the Asserted Prior Art ......................................................... 11
`A.
`CGRP Structure, Isoforms, and Function ........................................... 11
`B.
`Anti-CGRP Antagonist Antibodies Were Well Known in the
`Art and Had Been Disclosed for Therapeutic Use in Humans ........... 12
`IgG Antibodies .................................................................................... 13
`C.
`D. Humanization of Antibodies ............................................................... 16
`E.
`Binding Affinity .................................................................................. 17
`
`3.
`
`b)
`
`i
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`

`

`F.
`
`2.
`
`3.
`
`4.
`
`The Asserted Prior Art ........................................................................ 17
`1.
`Tan 1995 ................................................................................... 17
`2. Wimalawansa ............................................................................ 19
`3.
`Queen ........................................................................................ 20
`Person of Ordinary Skill in the Art ................................................................ 22
`V.
`VI. Claim Construction ........................................................................................ 22
`VII. Claim 1 Is Obvious over Tan 1995, Wimalawansa, and Queen ................... 24
`A. A POSA Would Have Been Motivated to Generate the
`Humanized Anti-CGRP Antagonist Antibody of Claim 1 ................. 25
`1.
`The Prior Art Recommended the Use of Anti-CGRP
`Antagonist Antibodies, Including Humanized Antibodies,
`for Therapeutic Use in Humans ................................................ 25
`The Confirmed In Vivo Effectiveness of Prior Art Anti-
`CGRP Antagonist Antibodies Provided Additional
`Motivation to Prepare a Humanized Antibody ......................... 28
`A POSA Would Have Targeted a Binding Affinity of 10
`nM or Less ................................................................................ 30
`The Prior Art Provided Additional Motivation to Prepare
`a Humanized Antibody ............................................................. 32
`A POSA Would Have Had a Reasonable Expectation of
`Successfully Making a Humanized Anti-CGRP Antagonist
`Antibody of Claim 1 ............................................................................ 34
`1.
`A POSA Would Have Had a Reasonable Expectation of
`Successfully Producing an Antibody Against Human
`CGRP ........................................................................................ 34
`A POSA Would Have Had a Reasonable Expectation of
`Success of Producing an Anti-CGRP Antagonist
`Antibody with a Binding Affinity of 10 nM or Less ................ 36
`
`B.
`
`
`
`ii
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`2.
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`

`

`3.
`
`C.
`
`A POSA Would Have Had a Reasonable Expectation of
`Successfully Producing a Humanized Anti-CGRP
`Antagonist Antibody of Claim 1 ............................................... 39
`The Prior Art Did Not Teach Away from Humanizing Anti-
`CGRP Antagonist Antibodies, as Teva Incorrectly Argued
`During Prosecution .............................................................................. 43
`The Claimed Antibodies Would Have Been Obvious ........................ 48
`D.
`VIII. The Challenged Dependent Claims Would Have Been Obvious .................. 50
`A.
`Claim 2 ................................................................................................ 51
`B.
`Claims 3, 7, and 12 .............................................................................. 53
`C.
`Claims 4, 8, 9, and 13 .......................................................................... 56
`D.
`Claims 5, 10, and 14 ............................................................................ 58
`E.
`Claims 6, 11, and 15 ............................................................................ 58
`IX. Secondary Considerations Do Not Support Nonobviousness ....................... 61
`A.
`Teva Cannot Establish Nexus to the Full Scope of the
`Challenged Claims .............................................................................. 61
`Lilly’s and Other’s Own Near-Simultaneous Development
`Precludes a Holding of Nonobviousness ............................................. 62
`The Evidence Submitted in this Petition Was Not Previously
`Considered by the Office ............................................................................... 64
`XI. Mandatory Notices Under 37 C.F.R. § 42.8 .................................................. 64
`A.
`Real Parties-in-Interest ........................................................................ 64
`B.
`Related Matters .................................................................................... 65
`C.
`Lead and Backup Counsel .................................................................... 65
`D.
`Service Information ............................................................................. 67
`XII. Payment of Fees ............................................................................................. 67
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`X.
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`
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`iii
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`B.
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`XIII. Conclusion ..................................................................................................... 67
`CERTIFICATION OF COMPLIANCE .................................................................... 1
`CERTIFICATE OF SERVICE .................................................................................. 2
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`
`iv
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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) ........................................................... 34, 42
`AbbVie Deutschland GmbH v. Janssen Biotech, Inc.,
`759 F.3d 1285 (Fed. Cir. 2014) .......................................................................... 61
`Akorn, Inc. v. Senju Pharm. Co.,
`IPR2015-01205, Paper 39 (PTAB Nov. 22, 2016) ............................................. 43
`Allergan, Inc. v. Apotex Inc.,
`754 F.3d 952 (Fed. Cir. 2014) ............................................................................ 61
`Ecolochem, Inc. v. S. Cal. Edison Co.,
`227 F.3d 1361 (Fed. Cir. 2000) .......................................................................... 62
`Geo. M. Martin Co. v. Alliance Mach. Sys. Int’l LLC,
`618 F.3d 1294 (Fed. Cir. 2010) .................................................................... 62, 63
`In re Am. Acad. of Sci. Tech Ctr.,
`367 F.3d 1359 (Fed. Cir. 2004) .......................................................................... 23
`In re Menig,
`486 F.2d 1066 (C.C.P.A. 1973) .......................................................................... 39
`In re Mouttet,
`686 F.3d 1322 (Fed. Cir. 2012) .................................................................... 45, 46
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ...................................................................................... 34, 48
`Paice LLC v. Ford Motor Co.,
`881 F.3d 894 (Fed. Cir. 2018) ............................................................................ 42
`PharmaStem Therapeutics, Inc. v. ViaCell, Inc.,
`491 F.3d 1342 (Fed. Cir. 2007) ...................................................................... 7, 36
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) (en banc) .......................................................... 23
`
`v
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`

`

`
`
`Senju Pharm. Co. v. Lupin Ltd.,
`780 F.3d 1337 (Fed. Cir. 2015) .......................................................................... 43
`Statutes
`35 U.S.C. § 102(b) ..................................................................................................... 4
`35 U.S.C. § 103(a) ..................................................................................................... 3
`35 U.S.C. § 311 .......................................................................................................... 3
`35 U.S.C. § 325(d) ................................................................................................... 64
`Regulations
`37 C.F.R. § 42.8 ....................................................................................................... 64
`37 C.F.R. § 42.15(a) ................................................................................................. 67
`37 C.F.R. § 42.100(b) ................................................................................................ 2
`37 C.F.R. § 42.103(a) ............................................................................................... 67
`37 C.F.R. § 42.104 ..................................................................................................... 3
`Other Authorities
`Notice of Proposed Rulemaking (May 3, 2018) ...................................................... 23
`
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`
`vi
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`

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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
`RIA
`Radioimmunoassay
`SPR
`Surface plasmon resonance
`Teva or Patent Owner Teva Pharmaceuticals International GmbH
`USPTO or Office
`U.S. Patent and Trademark Office
`’211 patent
`U.S. Patent No. 9,890,211
`’438 patent
`U.S. Patent No. 6,344,438
`
`vii
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`

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`
`
`I.
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`
`
`Petition for Inter Partes Review
`U.S. Patent No. 9,890,211
`
`Introduction
`Teva’s ’211 patent broadly claims humanized monoclonal anti-CGRP
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`antagonist IgG antibodies that bind to human CGRP with a particular binding affinity
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`as measured by a well-known prior art technique. 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”)), a binding
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`specificity for human CGRP possessed by many prior art antibodies, and an
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`unexceptional binding affinity as measured by the well-known technique of SPR.
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`Teva’s claims are obvious over the prior art. By Teva’s earliest possible filing
`
`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
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`anti-CGRP antibodies in vitro and in vivo, including antibodies that specifically
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`bound to human CGRP with binding affinities within the range Teva has attempted
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`to claim. Thus, the prior art provided express motivation to prepare a humanized
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`anti-CGRP antagonist antibody that binds human CGRP.
`
`Moreover, as Teva’s ’211 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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`1
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`humanized antibodies advantageously avoided immunogenic reactions caused by
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`
`
`Petition for Inter Partes Review
`U.S. Patent No. 9,890,211
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`administering murine or chimeric antibodies to humans. By 2005, half of the FDA-
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`approved antibodies were humanized antibodies, and most antibodies in phase 2 and
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`3 clinical trials were humanized.
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`The recited binding affinity of the claimed antibodies had also already been
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`disclosed in the prior art as a desirable property for both anti-CGRP antagonist
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`antibodies specifically, and for therapeutic antibodies as a class generally. By
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`November 2005, nearly all FDA-approved antibodies were reported to have such
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`binding affinities. A POSA would therefore have been motivated to make a
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`humanized IgG anti-CGRP antagonist antibody as claimed, and would have
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`reasonably expected to succeed in doing so.
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`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. 1012 ¶¶1-17; Ex. 1013 ¶¶1-16.) 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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`2
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`

`

`
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`Lilly to pursue only claims to the prevention and treatment of headaches.
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`
`
`Petition for Inter Partes Review
`U.S. Patent No. 9,890,211
`
`Accordingly, Lilly requests inter partes review of claims 1-15 of the ’211 patent.
`
`II. Requirements for Inter Partes Review Under 37 C.F.R. § 42.104
`A. Grounds for Standing
`Petitioner certifies that the ’211 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. 1196, 4-6 (listing priority chain and
`
`declining to designate as a transition application); Ex. 1001, 1:5-26, 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 1-15 of the
`
`’211 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
`
`of the following combination of references:
`
`
`1 Citations refer to the original page numbering of each exhibit except for references
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`that do not have any pagination in their original form. Citations to such references
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`refer to the stamped-on page numbers.
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`3
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`

`

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`
`
`Petition for Inter Partes Review
`U.S. Patent No. 9,890,211
`
`Reference 1: K.K.C. Tan et al., Clin. Sci. 89:565-573 (1995) (“Tan 1995”)
`
`(Ex. 1022), published on December 1, 1995. Tan 1995 is prior art to the ’211 patent
`
`under 35 U.S.C. § 102(b).
`
`Reference 2: S.J. Wimalawansa, Endocrine Reviews 17(5):533-585 (1996)
`
`(“Wimalawansa”) (Ex. 1096), published in 1996. Wimalawansa is prior art to the
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`’211 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 ’211 patent under 35 U.S.C. § 102(b).
`
`III. The ’211 Patent and Its Provisional Application
`The ’211 patent is entitled “Antagonist Antibodies Directed Against
`
`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., 1:30-33; Ex. 1012 ¶81.)
`
`The ’211 patent discloses a sole humanized antagonist antibody (G1) and its
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`purported derivatives. (E.g., Ex. 1001, Abstract, Example 4.) The ’211 patent does
`
`not include any clinical or other human data.
`
`The ’211 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. 1012 ¶82.) Lilly has
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`4
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`
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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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`
`
`Petition for Inter Partes Review
`U.S. Patent No. 9,890,211
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`9,346,881; and 9,890,210. These patents are similarly directed to anti-CGRP
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`antagonist antibodies.
`
`The provisional application, like the ’211 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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`specific purpose of evaluating anti-CGRP antagonist antibodies. (Compare
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`Ex. 1019, ¶[0244] (citing Ex. 1052), with Ex. 1022, 572 (citing Ex. 1052 as
`
`reference 9); Ex. 1012 ¶¶91-92.) 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 ’211 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
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`5
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`Petition for Inter Partes Review
`U.S. Patent No. 9,890,211
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`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, and wherein the
`antibody binds to the CGRP with a binding affinity (KD)
`of about 10 nM or less as measured by surface plasmon
`resonance at 37° C.
`(Ex. 1001, claim 1; Ex. 1012 ¶¶83-84; Ex. 1013 ¶¶71.) The recited sequence IDs
`
`correspond to human αCGRP and βCGRP, respectively. (Ex. 1012 ¶85; Ex. 1013
`
`¶72; Ex. 1001, cols. 53-54 (Table 4 designates human αCGRP and βCGRP as SEQ
`
`ID NOS:15 and 43).) The recited “heavy chain” and “light chain” limitations are
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`generic to IgG antibodies and do not provide meaningful structure that correlates
`
`with the recited function of specific binding or the claimed binding affinity. (Ex.
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`1013 ¶73.)
`
`Dependent claim 2 recites a binding affinity of about 1 nM or less, about 500
`
`pM or less, or about 100 pM or less as measured by SPR at 37 °C. (Ex. 1001, claim
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`2; Ex. 1012 ¶86; Ex. 1013 ¶76.)
`
`Dependent claims 3, 7, and 12 further recite IgG1, IgG2, or IgG4 heavy chain
`
`constant regions. (Ex. 1001, claims 3, 7, 12; Ex. 1012 ¶87; Ex. 1013 ¶77.) The
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`challenged claims that further depend from claims 3, 7, and 12 additionally require:
`
`6
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`Petition for Inter Partes Review
`U.S. Patent No. 9,890,211
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`• CDRs imparting to the antibody specific binding to a fragment
`
`comprising CGRP8-37 of human αCGRP (claims 4, 8, and 13);
`
`• CDRs imparting to the antibody specific binding to a fragment
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`comprising CGRP33-37 of human αCGRP (claim 9);
`
`• CDRs of the humanized monoclonal antibody derived from mouse, rat,
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`or rabbit CDRs (claims 5, 10, and 14); 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 6, 11, and 15).
`
`(Ex. 1001, claims 4-6, 8-11, 13-15; Ex. 1012 ¶¶88-89; Ex. 1013 ¶¶78.)
`
`Patent Owner Admissions in the Specification
`B.
`The ’211 patent itself expressly discloses that multiple claim limitations were
`
`known in the art. “Admissions in the specification regarding the prior art are binding
`
`on the patentee for the purposes of a later inquiry into obviousness.” PharmaStem
`
`Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1362 (Fed. Cir. 2007).
`
`1.
`
`Anti-CGRP Antagonist Antibodies and Methods of Making
`Them, Including Humanization Techniques, Were Known
`The ’211 patent states that “[a]nti-CGRP antagonist antibodies are known in
`
`the art.” (Ex. 1001, 26:26-30 (citing Ex. 1022).) It confirms that anti-CGRP
`
`antibodies were commercially available, such as antibody #4901 from Sigma
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`7
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`

`

`
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`Aldrich. (Id.; Ex. 1051, 350.) The ’211 patent also expressly discloses that the
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`
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`Petition for Inter Partes Review
`U.S. Patent No. 9,890,211
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`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, 28:8-14, 32:1-5 (“Anti-CGRP antagonist antibodies and polypeptides
`
`derived from antibodies can be identified or characterized using methods known in
`
`the art . . . .”), 28:13-14 (“General techniques for production of human and mouse
`
`antibodies are known in the art and are described herein.”).)
`
`
`
`The ’211 patent states that preparing humanized and human antibodies from
`
`non-human antibodies, such as murine antibodies, was “known” and “conventional.”
`
`(Id., 28:8-14, 32:1-5, 32:48-49, 36:20-22, 38:4-9; see also id., cols. 28-30; Ex. 1013
`
`¶79.) According to the ’211 patent, the prior art taught methods to humanize a
`
`monoclonal antibody:
`
`(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
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`8
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`Petition for Inter Partes Review
`U.S. Patent No. 9,890,211
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`methodologies/techniques[;] and (4) the transfection and
`expression of the humanized antibody.
`
`(Ex. 1001, 29:25-34 (citing Queen (Ex. 1023) and other prior art patents); Ex. 1013
`
`¶80.)
`
`
`
`The ’211 patent also states that humanized anti-CGRP antagonist antibodies
`
`“are designed to minimize unwanted immunological response toward rodent anti-
`
`human antibody molecules.” (Ex. 1001, 29:52-57.)
`
`2. Methods to Obtain and Measure Particular Binding Affinities
`by SPR Were Known
`The ’211 patent states that “[m]odification of polypeptides is routine practice
`
`in the art and need not be described in detail herein,” including methods to obtain a
`
`desired binding affinity. (Ex. 1001, 38:14-19 (“[amino acid sequence] may be
`
`mutated to obtain an antibody with the desired binding affinity to CGRP”); Ex. 1013
`
`¶81.) The ’211 patent also states that “[m]ethods for determining binding affinity
`
`are well-known in the art,” and specifically lists SPR as a suitable, known method.
`
`(Ex. 1001, 42:10-23; see also id., 27:36-28:7 (stating that SPR may be used to obtain
`
`binding affinity); Ex. 1013 ¶81.)
`
`Limitations of Dependent Claims Were Also Known
`3.
`The ’211 patent also acknowledges that many of the limitations recited in its
`
`dependent claims were known, conventional, or routine.
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`9
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`Petition for Inter Partes Review
`U.S. Patent No. 9,890,211
`
`a)
`
`Anti-CGRP Antagonist Antibodies That Bound to the
`C-Terminus of CGRP Were Known
`The ’211 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, 26:26-30 (identifying #4901 as
`
`commercially available from Sigma), 51:52-61 (“The data indicate that these anti-
`
`CGRP antibodies generally bind to the C-terminal end of CGRP.”), Fig. 1; see
`
`Ex. 1033, 104, 102 (“The monoclonal antibody recognizes an epitome [sic] in the
`
`10 amino acid C-terminal region of the rat α-CGRP.”).)
`
`IgG Sub-Types and Constant Regions Were Known
`b)
`The ’211 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, 5:22-42, 12:60-61
`
`(“The subunit structures and three-dimensional configurations of different classes of
`
`immunoglobulins are well known.”); Ex. 1013 ¶82; see also id. ¶83.)
`
`Prosecution of the ’211 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
`
`10
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`
`
`Petition for Inter Partes Review
`U.S. Patent No. 9,890,211
`
`
`
`
`• U.S. Patent No. 9,346,881
`
`• U.S. Patent No. 9,340,614
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`• U.S. Appl. No. 15/588,432 (issued as U.S. Patent No. 9,890,210).
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`(Ex. 1197, 3-4.) Teva did not substantively dispute these obviousness rejections but
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`instead filed terminal disclaimers. (Ex. 1198, 6; Ex. 1199.)
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`IV. Background and the Asserted Prior Art
`A. CGRP Structure, Isoforms, and Function
`By 2005, CGRP had been identified and extensively studied. (Ex. 1012 ¶¶18-
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`25.) Human CGRP is expressed in two closely related isoforms, αCGRP and
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`βCGRP, both 37 amino acids in length. (Id. ¶18; Ex. 1032, 275; Ex. 1096, 534.)
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`Human αCGRP and βCGRP differ by only three amino acids. (Ex. 1012 ¶18;
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`Ex. 1032, 275; Ex. 1096, 534.) Rat CGRP is also expressed in α and β isoforms, and
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`they differ by only one amino acid. (Ex. 1012 ¶18; Ex. 1032, 275; Ex. 1096, 534.)
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`CGRP shows significant homology across species: human αCGRP and βCGRP
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`differ from their rat counterparts by only four and three variations, respectively.
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`(Ex. 1012 ¶18; Ex. 1033, 93-94; Ex. 1096, 534.) Whereas human βCGRP is
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`predominantly expressed in the enteric nervous system and pituitary gland, αCGRP
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`was known to be expressed in sensory neurons, suggesting that αCGRP had an
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`important role in diseases such as migraine. (Ex. 1012 ¶23; Ex. 1031, 317 (citing
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`Ex. 1096).)
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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, neurogenic pain, and
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`psoriasis. (Ex. 1012 ¶¶35-47; Ex. 1026, 7:5-12, 7:19-24, 10:25-30, claims 2, 7;
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`Ex. 1025, 1105; Ex. 1040, 182-83; Ex. 1096, 533, 567-70.) Moreover, in 2004,
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`Olesen reported successful human clinical trials demonstrating proof of concept that
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`blocking the CGRP pathway leads to migraine relief. (Ex. 1012 ¶¶40-43; Ex. 1025,
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`1104, 1108-09.)
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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. 1012 ¶¶48-59.) This is known as “immunoblockade.” (Id.;
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`Ex. 1022, 566; Ex. 1012 ¶48.) By 2005, immunoblockade with monoclonal anti-
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`CGRP antibodies was shown to inhibit the effects of CGRP in vivo and was
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`recognized to have “inherent advantages of defined specificity, known affinity,
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`reproducibility, and unlimited availability.” (Ex. 1012 ¶59; Ex. 1022, 572.)
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`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
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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 involve immunizing mice with
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`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,
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`e.g., Ex. 1021, 704; Ex. 1033, 95-96; see Ex. 1013 ¶¶29-31.) Anti-CGRP antagonist
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`antibodies had been prepared against both human and rat CGRP (Ex. 1021, 704;
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`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. 1013 ¶117; Ex. 1033, 94, 102; Ex. 1021, 704, 706.)
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`The prior art specifically identified anti-CGRP antagonist antibodies,
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`including humanized antibodies, to treat a variety of human diseases and conditions,
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`such as migraine, neurogenic inflammatory pain, eye pain, and psoriasis. (See infra
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`§ VII.A.1.)
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`IgG Antibodies
`C.
`The anti-CGRP antagonist antibodies of the prior art included IgG antibodies.
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`(Ex. 1022, 566; Ex. 1033, 93; Ex. 1055, 89.) As of 2005, IgG was the preferred
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`immunoglobulin class for all therapeutic antibodies, regardless of target antigen.
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`(Ex. 1012 ¶28; Ex. 1013 ¶23; Ex. 1062, 43.)
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`The structure of an IgG antibody is shown in the simplified depiction below
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`(Figure 1). It possesses two heavy chains and two light chains. (Ex. 1012 ¶29;
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`Ex. 1013 ¶17; Ex. 1058, 95, 100.)
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`Figure 1: Exemplary IgG Antibody Structure
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`(Ex. 1058, 95.)
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`Each “arm” of an IgG antibody is known as a Fab (“fragment antigen
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`binding”). (Ex. 1012 ¶30; Ex. 1013 ¶18; Ex. 1058, 96-97.) A Fab’ fragment is a
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`portion of an antibody that corresponds to one of its arms and includes the complete
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`light chain and part of the heavy chain. (Ex. 1063, 60-61.) In each arm, the N-
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`terminal regions of the heavy and light chains (shown in yellow in Figure 1) form
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`the antigen binding site, also referred to as the variable region of an
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`antibody. (Ex. 1012 ¶30.) The variable region includes two heavy chain variable
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`domains and two light chain variable domains. (Ex. 1012 ¶30; Ex. 1013 ¶19;
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`Ex. 1058, 96.)
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`The heavy and light chain variable domains each contain three CDRs, which
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`are primarily responsible for antigen binding. (Ex. 1012 ¶31; Ex. 1013 ¶20;
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`Ex. 1058, 100-01.) In Figure 1 above, the CDRs are shown as black lines traversing
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`the yellow variable regions. CDRs possess variable amino acid sequences that
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`specifically bind to antigens. (Ex. 1012 ¶31; Ex. 1013 ¶20; Ex. 1058, 100-01.) The
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`three CDRs are generally designated CDR1, CDR2, and CDR3, respectively.
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`(Ex. 1012 ¶31; Ex. 1013 ¶20.)
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`In both the heavy and light chains, the three CDRs are interspersed between
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`four regions called FRs that support the CDRs. (Ex. 1012 ¶32; Ex. 1013 ¶20;
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`Ex. 1058, 100-01.) In Figure 1, the four FRs are represented by the four yellow areas
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`interspersed around the three CDRs. (Ex. 1012 ¶32; Ex. 1013 ¶20; Ex. 1058, 100-
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`01.)
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`The remainder of an IgG antibody (shown in white in Figure 1) is referred to
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`as the constant region. (Ex. 1012 ¶33; Ex. 1013 ¶21; Ex. 1058, 96-97.) Each light
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`chain has one constant domain (“CL”), and each heavy chain has three constant
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`domains (“CH1,” “CH2,” and “CH3”). (Ex. 1012 ¶33; Ex. 1013 ¶21; Ex. 1058, 9