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. IPR2018-01423
`Patent No. 9,266,951
`______________________
`
`PETITION FOR INTER PARTES REVIEW
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`

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`I.
`II.
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`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 ’951 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 ............................................................................... 6
`2. Methods of Measuring Inhibition of CGRP-Induced
`cAMP Activation Were Known .................................................. 8
`Limitations of Dependent Claims Were Also Known ................ 8
`a)
`Anti-CGRP Antagonist Antibodies That Bound to
`the C-Terminus of CGRP Were Known ........................... 9
`IgG Sub-types, Constant Regions, and Fc Regions
`Were Known ..................................................................... 9
`Antibody Formulations and Methods of
`Administering Them Were Known ................................10
`Prosecution of the ’951 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 ...........13
`IgG Antibodies ....................................................................................14
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`C.
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`
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`i
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`3.
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`b)
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`c)
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`D. Humanization of Antibodies ...............................................................17
`E.
`The Asserted Prior Art ........................................................................18
`1.
`Tan 1995 ...................................................................................18
`2. Wimalawansa ............................................................................20
`3.
`Queen ........................................................................................20
`4.
`Doods ........................................................................................22
`Person of Ordinary Skill in the Art ................................................................24
`V.
`VI. Claim Construction ........................................................................................24
`VII. Claim 1 Is Obvious over Tan 1995, Wimalawansa, Queen, and Doods .......26
`A. A POSA Would Have Been Motivated to Generate the
`Humanized Anti-CGRP Antagonist Antibody of Claim 1..................27
`1.
`The Prior Art Recommended the Use of Anti-CGRP
`Antagonist Antibodies, Including Humanized Antibodies,
`for Therapeutic Use in Humans ................................................27
`The Confirmed In Vivo Effectiveness of Prior Art Anti-
`CGRP Antagonist Antibodies Provided Additional
`Motivation to Prepare a Humanized Antibody .........................30
`The Prior Art Provided Additional Motivation to Prepare
`a Humanized Antibody .............................................................32
`A POSA Would Have Been Motivated to Make an
`Antibody that Inhibits cAMP Activation in Cells ....................34
`A POSA Would Have Had a Reasonable Expectation of
`Successfully Making a Humanized Anti-CGRP Antagonist
`Antibody of Claim 1 ............................................................................36
`1.
`A POSA Would Have Had a Reasonable Expectation of
`Successfully Producing an Antibody Against Human
`αCGRP ......................................................................................36
`
`B.
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`3.
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`4.
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`ii
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`2.
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`A POSA Would Have Had a Reasonable Expectation of
`Successfully Producing an Anti-CGRP Antagonist
`Antibody that Inhibits cAMP Activation ..................................38
`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 ..............................................................................42
`The Claimed Antibodies Would Have Been Obvious ........................47
`D.
`VIII. The Challenged Dependent Claims Would Have Been Obvious ..................49
`A.
`Claims 3 and 5 .....................................................................................50
`B.
`Claims 2, 4, and 6 ................................................................................52
`C.
`Claim 14 ..............................................................................................53
`D.
`Claim 15 ..............................................................................................55
`E.
`Claim 16 ..............................................................................................56
`F.
`Claim 17 ..............................................................................................58
`G.
`Claim 18 ..............................................................................................58
`H.
`Claim 19 ..............................................................................................59
`IX. Secondary Considerations Do Not Support Nonobviousness .......................60
`A.
`Teva Cannot Establish Nexus to the Full Scope of the
`Challenged Claims ..............................................................................60
`Lilly’s and Other’s Own Near-Simultaneous Development
`Precludes a Holding of Nonobviousness .............................................61
`The Evidence Submitted in this Petition Was Not Previously
`Considered by the Office ...............................................................................63
`XI. Mandatory Notices Under 37 C.F.R. § 42.8 ..................................................63
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`X.
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`C.
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`B.
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`2.
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`3.
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`iii
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`A.
`Real Parties-in-Interest ........................................................................63
`Related Matters ....................................................................................64
`B.
`Lead and Backup Counsel ....................................................................64
`C.
`Service Information .............................................................................66
`D.
`XII. Payment of Fees .............................................................................................66
`XIII. Conclusion .....................................................................................................66
`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) ........................................................... 35, 41
`AbbVie Deutschland GmbH v. Janssen Biotech, Inc.,
`759 F.3d 1285 (Fed. Cir. 2014) .......................................................................... 60
`Akorn, Inc. v. Senju Pharm. Co.,
`IPR2015-01205, Paper 39 (PTAB Nov. 22, 2016) ....................................... 42, 48
`Allergan, Inc. v. Apotex Inc.,
`754 F.3d 952 (Fed. Cir. 2014) ............................................................................ 60
`Ecolochem, Inc. v. S. Cal. Edison Co.,
`227 F.3d 1361 (Fed. Cir. 2000) .......................................................................... 61
`Geo. M. Martin Co. v. Alliance Mach. Sys. Int’l LLC,
`618 F.3d 1294 (Fed. Cir. 2010) .................................................................... 61, 62
`In re Mouttet,
`686 F.3d 1322 (Fed. Cir. 2012) .................................................................... 44, 47
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ...................................................................................... 35, 47
`Paice LLC v. Ford Motor Co.,
`881 F.3d 894 (Fed. Cir. 2018) ............................................................................ 41
`PharmaStem Therapeutics, Inc. v. ViaCell, Inc.,
`491 F.3d 1342 (Fed. Cir. 2007) ...................................................................... 6, 37
`Senju Pharm. Co. v. Lupin Ltd.,
`780 F.3d 1337 (Fed. Cir. 2015) .................................................................... 42, 48
`Statutes
`35 U.S.C. § 102(b) ........................................................................................... 3, 4, 22
`35 U.S.C. § 103(a) ..................................................................................................... 3
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`v
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`
`35 U.S.C. § 311 .......................................................................................................... 3
`35 U.S.C. § 325(d) ................................................................................................... 63
`Regulations
`37 C.F.R. § 42.8 ....................................................................................................... 63
`37 C.F.R. § 42.15(a) ................................................................................................. 66
`37 C.F.R. § 42.100(b) .............................................................................................. 24
`37 C.F.R. § 42.103(a) ............................................................................................... 66
`37 C.F.R. § 42.104 ..................................................................................................... 3
`Other Authorities
`Notice of Proposed Rulemaking (May 3, 2018) ...................................................... 25
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`vi
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`
`GLOSSARY
`
`Antibody-dependent cellular cytotoxicity
`ADCC
`America Invents Act
`AIA
`Broadest reasonable interpretation
`BRI
`3’,5’-cyclic adenosine monophosphate
`cAMP
`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
`’951 patent
`U.S. Patent No. 9,266,951
`’438 patent
`U.S. Patent No. 6,344,438
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`vii
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`
`I.
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`
`
`Petition for Inter Partes Review
`U.S. Patent No. 9,266,951
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`Introduction
`Teva’s U.S. Patent No. 9,266,951 (“the ’951 patent”) broadly claims any
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`humanized or human monoclonal anti-CGRP antagonist antibody that binds to
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`human αCGRP and inhibits cAMP activation in cells.
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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 bound to human
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`αCGRP and inhibited the CGRP pathway. The recited property of inhibiting cAMP
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`activation in cells had also already been disclosed in the prior art as a known property
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`for CGRP antagonists generally, and for anti-CGRP antagonist antibodies
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`specifically. Indeed, as the ’951 patent admits, measuring inhibition of cAMP
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`activation is a conventional means of evaluating whether an anti-CGRP antagonist
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`antibody is, in fact, an anti-CGRP antagonist. Thus, the prior art provided express
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`motivation to prepare a humanized anti-CGRP antagonist antibody that binds human
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`αCGRP, and to measure inhibition of cAMP activation in cells.
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`1
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`Petition for Inter Partes Review
`U.S. Patent No. 9,266,951
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`Moreover, as Teva’s ’951 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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`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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`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. 1004 ¶¶1-17; Ex. 1005 ¶¶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 1-6 and 14-19 of the ’951
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`patent.
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`2
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`

`Petition for Inter Partes Review
`U.S. Patent No. 9,266,951
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`
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`
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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 ’951 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. (Exs. 1146-1147 (listing priority chain
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`and declining to designate as a transition application); Ex. 1001, 1:8-24, title page,
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`item (60).)1
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`Identification of Challenge
`B.
`Lilly respectfully requests review under 35 U.S.C. § 311 of claims 1-6 and 14-
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`19 of the ’951 patent. In the sole ground presented in this Petition, Lilly requests
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`that the Board find these claims unpatentable as obvious under 35 U.S.C. § 103(a)
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`in view 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 ’951 patent
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`under 35 U.S.C. § 102(b).
`
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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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`3
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`Petition for Inter Partes Review
`U.S. Patent No. 9,266,951
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`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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`’951 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 ’951 patent under 35 U.S.C. § 102(b).
`
`Reference 4: Doods, H. et al., Br. J. Pharmacol. (2000) 129:420-423
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`(“Doods”) (Ex. 1024), published in 2000. Doods is prior art to the ’951 patent under
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`35 U.S.C. § 102(b).
`
`III. The ’951 Patent and Its Provisional Application
`The ’951 patent is entitled “Antagonist Antibodies Directed Against
`
`Calcitonin Gene-Related Peptide and Methods Using Same.” (Ex. 1001, title page,
`
`item (54).) It states that the alleged invention “relates to the use of anti-CGRP
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`antagonist antibodies for the prevention, amelioration, or treatment of vasomotor
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`symptoms, such as CGRP related headaches (e.g., migraine) and hot flushes.” (Id.,
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`1:36-39; Ex. 1004 ¶92.) The ’951 patent discloses a sole humanized antagonist
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`antibody (G1) and its purported derivatives. (E.g., Ex. 1001, Abstract, Example 4.)
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`The ’951 patent does not include any clinical or other human data.
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`The ’951 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
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`provisional
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`application”),
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`filed
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`on
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`November
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`14,
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`2005.
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`4
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`(Ex. 1004 ¶93.) Lilly has also filed IPR petitions for related U.S. Patent Nos.
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`
`
`Petition for Inter Partes Review
`U.S. Patent No. 9,266,951
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`8,597,649; 9,340,614; 9,346,881; 9,890,210; and 9,890,211. These patents are
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`similarly directed to anti-CGRP antagonist antibodies.
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`The provisional application, like the ’951 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 of anti-CGRP antagonist antibodies. (Compare
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`Ex. 1019, Ex. 3 (citing Ex. 1052), with Ex. 1022, 572 (citing Ex. 1052 as reference
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`9); Ex. 1004 ¶¶99-100.) When filing its PCT application a year later, Teva only
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`added additional animal study results, and not any clinical data, to the disclosure of
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`its provisional application. (Ex. 1020, 66-68 (adding Examples 6-8).)
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`A. The Challenged Claims
`Claim 1 of the ’951 patent, the only independent claim, recites:
`
`A human or humanized monoclonal anti-CGRP antagonist
`antibody that (1) binds human α-CGRP and (2) inhibits
`cyclic adenosine monophosphate (cAMP) activation in
`cells.
`(Ex. 1001, claim 1; Ex. 1004 ¶¶94-95; Ex. 1005 ¶59.)
`
`The challenged dependent claims 2-6 and 14-19 additionally require:
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`Petition for Inter Partes Review
`U.S. Patent No. 9,266,951
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`• binding to a particular fragment or epitope of human αCGRP (claims 2-
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`6);
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`• a heavy chain constant region derived from IgG2 (claim 14);
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`• an Fc region, including one with an impaired effector function (claims
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`15 and 16);
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`• a humanized antibody (claim 17);
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`• inhibition of cAMP activation in SK-N-MC cells (claim 18); and
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`• a pharmaceutical composition with a pharmaceutically acceptable
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`excipient (claim 19).
`
`(Ex. 1001, claims 2-6, 14-19; Ex. 1005 ¶60; Ex. 1004 ¶¶96-97.)
`
`Patent Owner Admissions in the Specification
`B.
`The ’951 patent itself expressly discloses that multiple claim limitations were
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`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
`
`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 ’951 patent states that “[a]nti-CGRP antagonist antibodies are known in
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`the art.” (Ex. 1001, 26:7-11 (citing Ex. 1022).) It confirms that anti-CGRP
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`antibodies were commercially available, such as antibody #4901 from Sigma
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`6
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`

`
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`Aldrich. (Id.; Ex. 1051, 350.) The ’951 patent also expressly discloses the claimed
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`Petition for Inter Partes Review
`U.S. Patent No. 9,266,951
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`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, 27:56-60, 31:42-46 (“Anti-CGRP antagonist antibodies and polypeptides
`
`derived from antibodies can be identified or characterized using methods known in
`
`the art . . . .), 27:60-62 (“General techniques for production of human and mouse
`
`antibodies are known in the art and are described herein.”).)
`
`The ’951 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., 27:56-62, 29:3-27, 31:42-46, 32:22-23, 35:60-61, 37:42-47; see also id., cols.
`
`28-30; Ex. 1005 ¶61.) According to the ’951 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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`Petition for Inter Partes Review
`U.S. Patent No. 9,266,951
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`methodologies/techniques[;] and (4) the transfection and
`expression of the humanized antibody.
`
`(Ex. 1001, 29:3-12 (citing Queen (Ex. 1023) and other prior art patents); Ex. 1005
`
`¶62.)
`
`
`
`The ’951 patent also states that humanized anti-CGRP antagonist antibodies
`
`“are designed to minimize unwanted immunological response toward rodent anti-
`
`human antibody molecules.” (Ex. 1001, 29:30-34.)
`
`2. Methods of Measuring Inhibition of CGRP-Induced cAMP
`Activation Were Known
`The ’951 patent also acknowledges that “known” bioassays can be used either
`
`to test anti-CGRP antagonist antibodies for biological activity or to screen for anti-
`
`CGRP antagonist activities. The patent lists cAMP stimulation in cells as an example
`
`of a known bioassay, including specifically the use of SK-N-MC cells. (Ex. 1001,
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`32:5-12, 51:15-42 (Table 2); Ex. 1005 ¶63.)
`
`The ’951 patent tested and confirmed that the “commercially available”
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`antibody #4901, described in a 1993 publication by Wong et al., blocked cAMP
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`activation, and thus concluded that it blocked human αCGRP from binding to its
`
`receptor. (Ex. 1001, 26:9-10, 51:15-42 (Table 2); Ex. 1033.)
`
`Limitations of Dependent Claims Were Also Known
`3.
`The ’951 patent also acknowledges that many of the limitations recited in its
`
`dependent claims were known, conventional, or routine.
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`8
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`Petition for Inter Partes Review
`U.S. Patent No. 9,266,951
`
`a)
`
`Anti-CGRP Antagonist Antibodies That Bound to the
`C-Terminus of CGRP Were Known
`The ’951 patent confirms that prior art anti-CGRP antagonist antibody #4901
`
`binds to the C-terminal fragment of αCGRP (e.g., amino acids 25-37 and 33-37), just
`
`as the literature had earlier reported. (Ex. 1001, 26:7-11 (identifying #4901 as
`
`commercially available from Sigma), 50:57-64 (“The data indicate that these anti-
`
`CGRP antibodies generally bind to the C-terminal end of CGRP.”), Fig. 1; see Ex.
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`1033, 104, 102 (“The monoclonal antibody recognizes an epitome [sic] in the 10
`
`amino acid C-terminal region of the rat α-CGRP.”).)
`
`b)
`
`IgG Sub-types, Constant Regions, and Fc Regions
`Were Known
`The ’951 patent states that anti-CGRP antagonist antibodies may include a
`
`heavy chain constant region derived from human IgG2 constant regions, and that
`
`such regions were known in the art. (Ex. 1001, 5:11-24, 12:45-53 (“The subunit
`
`structures and
`
`three-dimensional configurations of different classes of
`
`immunoglobulins are well known.”).)
`
`The ’951 patent acknowledges that antibodies with Fc regions, including
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`modified Fc regions, were known. (Id., 40:30-40; see also id., 44:11-15; Ex. 1005
`
`¶64; see also id. ¶70.)
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`Petition for Inter Partes Review
`U.S. Patent No. 9,266,951
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`c)
`
`Antibody Formulations and Methods of
`Administering Them Were Known
`The ’951 patent indicates that pharmaceutical formulations, including
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`pharmaceutically acceptable excipients, of antibodies are well known. (Ex. 1001,
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`19:39-54, 21:10-17, 21:48-56.)
`
`The ’951 patent states that the anti-CGRP antagonist antibody is administered
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`in accord with known methods, such as by intravenous and subcutaneous
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`administration. (Id., 21:18-37, 21:64-66.) The patent also acknowledges that
`
`intravenous administration is a type of systemic administration. (Id., 21:29-30, 6:4-
`
`5.)
`
`Prosecution of the ’951 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. Appl. No. 14/841,440 (issued as U.S. Patent No. 9,346,881)
`
`• U.S. Appl. No. 14/841,479 (issued as U.S. Patent No. 9,340,614)
`
`(Ex. 1148, 3.) Teva did not substantively dispute these obviousness rejections but
`
`instead filed terminal disclaimers. (Ex. 1149, 5; Ex. 1150.)
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`Petition for Inter Partes Review
`U.S. Patent No. 9,266,951
`
`
`
`
`
`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. 1004 ¶¶18-23.) Human CGRP is expressed in two closely related isoforms,
`
`αCGRP and βCGRP, both 37 amino acids in length. (Ex. 1032, 275; Ex. 1096, 534.)
`
`Human αCGRP and βCGRP differ by only three amino acids. (Ex. 1004 ¶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. 1004 ¶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. 1004 ¶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. 1004 ¶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. 1004 ¶¶40-52; Ex. 1026, 7:5-12, 7:19-24, 10:25-30, claims 2, 7; Ex.
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`1025, 1105; Ex. 1040, 182-83; Ex. 1096, 533, 567-70.) Moreover, in 2004, Olesen
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`reported successful human clinical trials demonstrating proof of concept that
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`blocking the CGRP pathway leads to migraine relief. (Ex. 1004 ¶¶45-46; Ex. 1025,
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`1104, 1108-09.)
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`Upon binding to its receptor on cells, CGRP was well known to stimulate
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`production of cAMP, a chemical involved in muscle relaxation and dilation of blood
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`vessels (i.e., vasodilation). (Ex. 1040, 183-84 (activation of CGRP receptors “is
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`coupled to production of cAMP”); Ex. 1004 ¶¶24-30.) Various research groups had
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`analyzed CGRP’s effects on cAMP production in SK-N-MC (human neuroblastoma)
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`cells, which express human CGRP receptors. (Ex. 1061, 195; Ex. 1024, 420-21.)
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`They reported that incubating SK-N-MC cells with CGRP induces significant cAMP
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`production. (Ex. 1061, 197 (Table II reporting that CGRP induces ten times greater
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`cAMP production than other peptides); Ex. 1024, 421 (Fig 2), 422.) By pre-
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`incubating cells with compounds that prevent CGRP from binding to its receptors,
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`researchers reported blocking the CGRP pathway and thereby inhibiting cAMP
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`production. (Ex. 1024, 421 (Fig. 2), 422 (blocking CGRP pathway with
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`BIBN4096BS, a CGRP receptor antagonist); Ex. 1098, H319-20 (blocking CGRP
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`pathway with anti-CGRP antagonist antibodies); Ex. 1004 ¶26.) Thus, by 2005, it
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`was well established that CGRP induces cAMP activation in cells expressing the
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`CGRP receptor, and that blocking the CGRP pathway (including with anti-CGRP
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`antagonist antibodies) inhibits this activation. This had become a common way to
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`measure antagonist activity. (Ex. 1004 ¶¶27-29.)
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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. 1004 ¶¶53-64.) This is known as “immunoblockade.” (Ex. 1022,
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`566; Ex. 1004 ¶53.) 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 to
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`have “inherent advantages of defined specificity, known affinity, reproducibility, and
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`unlimited availability.” (Ex. 1004 ¶64; 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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`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. 1005 ¶¶28-30.) 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.) Because of their sequence homology, antibodies
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`raised against rat CGRP were known to bind both human and rat CGRP. (Ex. 1005
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`¶92; Ex. 1033, 94, 102; Ex. 1021, 704, 706.)
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`In addition, anti-CGRP antagonist antibodies that bound to the C-terminal
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`region of CGRP (that generally includes amino acids 28-37) were reported.
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`(Ex. 1033, 102; Ex. 1048, 258.) Anti-CGRP antagonist antibodies, including
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`antibodies that bound to the C-terminal region of CGRP, had been reported to
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`successfully block the biological effects of CGRP both in vitro and in vivo.
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`(Ex. 1022, 568-69; Ex. 1033, 101.) In particular, researchers had reported that anti-
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`CGRP antagonist antibodies “significantly inhibit[]” CGRP’s stimulation of cAMP
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`production. (Ex. 1098, H317, H319-20; see also Ex. 1024, 420-22.)
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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. 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. 1004 ¶33; Ex. 1062, 43; Ex. 1005 ¶22.)
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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. 1004 ¶34;
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`Ex. 1005 ¶16; 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. 1004 ¶35; Ex. 1005 ¶17; 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. 1004 ¶35.) The variable region includes two heavy chain variable
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`domains and two light chain variable domains. (Ex. 1004 ¶35; Ex. 1005 ¶18;
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`Ex. 1058, 96.)
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