Case 1:18-cv-12029-ADB Document 291 Filed 03/28/22 Page 1 of 108
`Case 1:18-cv-12029-ADB Document 291 Filed 03/28/22 Page 1 of 108
`
`IN THE UNITED STATES DISTRICT COURT
`
`FOR THE DISTRICT OF MASSACHUSETTS
`
`NueeBS
`
`TEVA PHARMACEUTICALS
`INTERNATIONAL GMBHand
`TEVA PHARMACEUTICALSUSA,INC.,
`
`Plaintiffs,
`
`V.
`
`ELI LILLY AND COMPANY,
`
`Defendant.
`
`Case No. 1:18-cv-12029-ADB
`
`Leave to File Granted on
`Feb. 22, 2022 (ECF No. 272)
`
`Leave to File Under Seal Granted on
`Mar. 28, 2022 (ECF No 285)
`
`L.R. 56.1 STATEMENT OF MATERIAL FACTSIN SUPPORT OF DEFENDANT
`ELI LILLY AND COMPANY’S MOTION FOR
`
`SUMMARY JUDGMENT OF INVALIDITY FOR LACK OF ENABLEMENT
`
`

`

`Case 1:18-cv-12029-ADB Document 291 Filed 03/28/22 Page 2 of 108
`Case 1:18-cv-12029-ADB Document 291 Filed 03/28/22 Page 2 of 108
`
`TABLE OF ABBREVIATIONS
`
` Blood-brain barrier
`
`i
`
`i
`
`
`Patent-in-suit. U.S. Patent No. 8,586,045 to Joerg Zeller et al., issued
`November19, 2013, entitled “Methods of Using Anti-CGRP Antagonist
`Antibodies” currently assigned to Teva Pharmaceuticals International
`GmbH
`USS. Patent No. 9,890,210 to Joerg Zeller et al., issued February 13, 2018,
`entitled “Antagonist Antibodies Directed Against Calcitonin Gene-
`Related Peptide” currently assigned to Teva Pharmaceuticals International
`GmbH
`USS. Patent No. 9,890,211 to Joerg Zeller et al., issued February 13, 2018,
`entitled “Antagonist Antibodies Directed Against Calcitonin Gene-
`Related Peptide” currently assigned to Teva Pharmaceuticals International
`GmbH
`U.S. Patent No. 9,340,614 to Joerg Zeller et al., issued May 17, 2016,
`entitled “Antagonist Antibodies Directed Against Calcitonin Gene-
`Related Peptide and Methods Using Same”currently assigned to Teva
`Pharmaceuticals International GmbH
`US. Patent No. 8,597,649 to Joerg Zeller et al., issued December 3, 2013,
`entitled “Antagonist Antibodies Directed Against Calcitonin Gene-
`Related Peptide and Methods Using Same”currently assigned to Teva
`Pharmaceuticals International GmbH
`US. Patent No. 9,346,881 to Joerg Zeller et al., issued May 24, 2016,
`entitled “Antagonist Antibodies Directed Against Calcitonin Gene-
`Related Peptide and Methods Using Same”currently assigned to Teva
`Pharmaceuticals International GmbH
`Patent-in-suit. U.S. Patent No. 9,884,907 to Joerg Zeller et al., issued
`February 6, 2018, entitled “Methods for Treating Headache Using
`Antagonist Antibodies Directed Against Calcitonin Gene-Related
`Peptide” currently assigned to Teva Pharmaceuticals International GmbH
`Patent-in-suit. U.S. Patent No. 9,884,908 to Joerg Zeller etal., issued
`February 6, 2018, entitled “Methods for Treating Headache Using
`Antagonist Antibodies Directed Against Calcitonin Gene-Related
`Peptide” currently assigned to Teva Pharmaceuticals International GmbH
`USS. Patent No. 9,266,951 to Joerg Zeller et al., issued February 23, 2016,
`entitled “Antagonist Antibodies Directed Against Calcitonin Gene-
`Related Peptide and Methods Using Same”currently assigned to Teva
`Pharmaceuticals International GmbH
`Transcript of deposition of Yasmina Noubia Abdiche, namedinventor of
`the patents-in-suit, dated August 17, 2021
`
`Short Cite
`’045 patent
`
`°210 patent
`
`°211 patent
`
`614 patent
`
`°649 patent
`
`°881 patent
`
`°907 patent
`
`°908 patent
`
`°951 patent
`
`AbdicheTr.
`
`L B
`
`BB
`
`

`

`Case 1:18-cv-12029-ADB Document 291 Filed 03/28/22 Page 3 of 108
`Case 1:18-cv-12029-ADB Document 291 Filed 03/28/22 Page 3 of 108
`
`
`
`
`
`Expert Report of Mark P. Berkman, on behalf of Teva, served September
`16, 2021
`Transcript of deposition of fact witness Marcelo Eduardo Bigal, defended
`by Teva counsel, dated June 10, 2021
`Opening Expert Report of Pamela Blake, M.D., FAHS, Regarding
`Infringement, on behalf of Teva, served September 16, 2021
`Reply Expert Report of Pamela Blake, M.D., FAHS, Regarding
`Infringement, on behalf of Teva, served December 7, 2021
`Transcript of deposition of expert Pamela Blake, M.D., FAHS,on behalf
`of Teva, dated Jan
`10, 2022
`Responsive Expert Report of Andrew Blumenfeld, M.D. Regarding
`Validity, on behalf of Teva, served November1, 2021
`Transcript of deposition of expert Andrew Blumenfeld, M.D., on behalf of
`Teva, dated January
`26, 2022
`
`
`
`Opening Expert Report of Dr. Andrew Charles Regarding Invalidity of
`US. Patent Nos. 8,586,045, 9,884,907, and 9,884,908, on behalf ofLilly,
`served September 16, 2021
`Rebuttal Expert Report of Dr. Andrew Charles Regarding
`Noninfringement, on behalf of Lilly, served November 1, 2021
`Reply Expert Report of Dr. Andrew Charles Regarding Invalidity of U.S.
`Patent Nos. 8,586,045, 9,884,907, and 9,884,908, on behalf of Lilly,
`served December 7, 2021
`
`
`
`
`
`
`Berkman Op.
`
`Bigal Tr.
`
`Blake Op.
`
`Blake Reply
`
`Blake Tr.
`
`Blumenfeld Resp.
`
`Blumenfeld Tr.
`
`CGRP
`Charles Op.
`
`Charles Reb.
`
`Charles Reply
`
`ECF No.
`
`EX,
`FDA
`Ferrari Decl.
`
`Foord Decl.
`
`Foord Tr.
`
`FWD
`
`Hale Resp.
`
`Hale Supp.
`
`Hale Tr.
`
`Documents from the public docketfiled through the CM/ECFsystem.
`Unless otherwise noted, citations are to the public docket of Case No.
`1:18-cv-12029-ADB, D. Mass.
`
`Food and Drug Administration
`Declaration of expert Dr. Michel D.Ferrari, M.D., Ph.D. on behalf of
`Teva,filed July 3, 2019 in IPR2018-01710, Eli Lilly & Co. v. Teva
`Pharms. Int’l GnbH
`Declaration of expert Steven M. Foord, Ph.D., on behalf of Teva, filed
`July 3, 2019 in IPR2018-01710, Eli Lilly & Co. v. Teva Pharms. Int’l
`GmbH
`Transcript of deposition of expert Steven M. Foord, Ph.D., on behalf of
`Teva, dated September 27, 2019
`Final Written Decision in an Jnter Partes Review proceeding before the
`United States Patent and Trademark Office Patent Trial and Appeal Board
`Responsive Expert Report of Geoffrey Hale, Ph.D., Regarding Validity,
`on behalf of Teva, served November 1, 2021
`Supplemental Responsive Expert Report of Geoffrey Hale, Ph.D.,
`Regarding Validity, on behalf of Teva, served Janu
`7, 2022
`Transcript of deposition of expert Geoffrey Hale, Ph.D., on behalf of
`Teva, dated January
`25, 2022
`
`il
`
`

`

`Case 1:18-cv-12029-ADB Document 291 Filed 03/28/22 Page 4 of 108
`Case 1:18-cv-12029-ADB Document 291 Filed 03/28/22 Page 4 of 108
`
`
`
`
`
`Transcript of deposition of fact witness Douglas Harnish, Ph.D., defended
`by Teva counsel, dated July 29, 2021
`Rebuttal Expert Report of RaymondHill, Ph.D., Regarding Validity of
`U.S. Patent Nos. 8,586,045, 9,884,907, and 9,884,908, on behalf of Teva,
`served November 1, 2021
`Transcript of deposition of expert Dr. Raymond Hill, on behalf of Teva,
`dated January
`20, 2022
`
`Inter partes review proceedingsat the United States Patent and
`Trademark Office
`Declaration of expert Dr. Alain P. Vasserot, Ph.D., on behalf of Lilly,
`dated September 9, 2018 in IPR2018-01710, Eli Lilly & Co. v. Teva
`Pharms. Int’l GnbH
`Declaration of expert Dr. Alain P. Vasserot, Ph.D., on behalf of Lilly,
`dated September 27, 2018 in IPR2018-01711, Eli Lilly & Co. v. Teva
`Pharms. Int’! GnbH
`Declaration of expert Dr. Alain P. Vasserot, Ph.D., on behalf of Lilly,
`dated September 27, 2018 in IPR2018-01712, Eli Lilly & Co. v. Teva
`Pharms. Int’! GnbH
`
`Opening Expert Report of James M. McDonnell, Ph.D., Regarding
`Invalidity of U.S. Patent Nos. 8,586,045, 9,884,907, and 9,884,908, on
`behalf of Lilly, served September 16, 2021
`Rebuttal Expert Report of James M. McDonnell, Ph.D., Regarding
`Noninfringementof U.S. Patent Nos. 8,586,045, 9,884,907, and
`9,884,908, on behalf of Lilly, served November 1, 2021
`Reply Expert Report of James M. McDonnell, Ph.D., Regarding Invalidity
`of U.S. Patent Nos. 8,586,045, 9,884,907, and 9,884,908, on behalf of
`Lilly, served December 7, 2021
`Supplemental Reply Expert Report of James M. McDonnell, Ph.D.,
`Regarding Invalidity of U.S. Patent Nos. 8,586,045, 9,884,907, and
`
`
`
`
`9,884,908, on behalf of Lilly, served January 21, 2022 Mould Op.
`
`Harnish Tr.
`
`Hill Reb.
`
`Hill Tr.
`
`ICHD-II
`IPR
`
`IPR2018-1710
`Vasserot Decl.
`
`IPR2018-1711
`Vasserot Decl.
`
`IPR2018-1712
`Vasserot Decl.
`
`LR.
`McDonnell Op.
`
`McDonnell Reb.
`
`McDonnell Reply
`
`McDonnell Supp.
`
`Mould Reply
`
`Pons Decl.
`
`Pons Tr.
`
`POSA
`
`Opening Expert Report of Diane R. Mould, Ph.D., FCP, FAAPS, on
`behalf of Lilly, served September 16, 2021
`Reply Expert Report of Diane R. Mould, Ph.D., on behalf of Lilly, served
`December7, 2021
`Declaration of Jaume Pons, Ph.D., named inventor of the patents-in-suit,
`on behalf of Teva, filed July 3, 2019 in IPR2018-01710, Eli Lilly & Co.v.
`Teva Pharms. Int’! GnbH
`Transcript of deposition of Jaume Pons, Ph.D., named inventor of the
`patents-in-suit, dated August 20, 2021
`
`United States Patent and Trademark Office Patent Trial and Appeal Board
`
`ill
`
`

`

`Case 1:18-cv-12029-ADB Document 291 Filed 03/28/22 Page 5 of 108
`Case 1:18-cv-12029-ADB Document 291 Filed 03/28/22 Page 5 of 108
`
`
`
`Transcript of deposition of Kristian T. Poulsen, named inventorof the
`patents-in-suit, dated August 5, 2021
`
`Office
`
`
`
`by Teva counsel, dated August 10, 2021
`Transcript of deposition of expert Alan M. Rapoport, M.D., on behalf of
`Teva, dated August 22, 2019
`Expert Declaration of Jeffrey V. Ravetch, M.D., Ph.D. (ECF No. 70), on
`behalf of Teva, filed September 11, 2020
`Transcript of deposition of expert Jeffrey V. Ravetch, M.D., Ph.D., on
`behalf of Teva, dated September 30, 2020
`Declaration of Dr. Jeffrey V. Ravetch in Support of Petition for Post
`Grant Review of U.S. Patent Number 10,611,836 filed January 7, 2021 in
`PGR2021-00036, Merck Sharp & Dohme Corp. v. Genentech, Inc.
`Opening Expert Report of Jeffrey V. Ravetch, M.D., Ph.D., Regarding
`Infringement, on behalf of Teva, served September 16, 2021
`Reply Expert Report of Jeffrey V. Ravetch, M.D., Ph.D., Regarding
`Infringement, on behalf of Teva, served December7, 2021
`Request for Admission
`
`
`Pharms. Int’?| GmbH Tomlinson Tr.
`
`Poulsen Tr.
`
`™
`
`Rapoport Tr.
`
`Ravetch CC Decl.
`
`Ravetch CC Tr.
`
`Ravetch
`Declaration
`
`Ravetch Op.
`
`Ravetch Reply
`
`RFA
`
`
`
`Stratton Tr.
`
`Tomlinson Decl.
`
`USPTO
`Walter Tr.
`
`Zeller Tr.
`
`
`
`Transcript of deposition of fact witness Jennifer Renee Stratton, Ph.D.,
`defended by Teva counsel, dated June 29, 2021
`Declaration of expert Dr. Ian M. Tomlinson, M.A., Ph.D., on behalf of
`Teva,filed July 3, 2019 in IPR2018-01710, Eli Lilly & Co. v. Teva
`
`Transcript of deposition of expert Ian M. Tomlinson, M.A., Ph.D., on
`behalf of Teva, dated August 7, 2019
`United States Patent and Trademark Office
`Transcript of deposition of fact witness Sarah Walter, Ph.D., defended by
`Teva counsel, dated June 4, 2021
`Transcript of deposition of Jéerg Zeller, named inventor of the patents-in-
`suit, dated August 11, 2021
`
`iv
`
`

`

`Pursuant to Local Rule 56.1, Defendant Eli Lilly and Company (“Lilly”) submits this
`
`Statement of Material Facts in Support of its Motion for Summary Judgment of Invalidity for Lack
`
`of Enablement, showing there is no genuine issue to be tried.
`
`I.
`
`Procedural Posture
`
`1
`
`
`
`
`
`
`

`

`2
`
`
`
`
`
`
`

`

`[IPR2018-01422 POR] at 1.) In the Antibody Method of Treatment IPRs, Teva also relied on a
`
`fact declaration from named inventor Jaume Pons. (Ex. 65 [IPR2018-01710 POR] at 1.)
`
`3
`
`
`
`
`
`
`

`

`Teva argues, the Board’s decision was based on the uncertainty about whether migraine treatment
`
`must cross the blood-brain barrier, and Lilly’s identification of one reference among many is not
`
`sufficient to overturn the Board’s analysis. We again agree with Teva.” Id. at 1348. The Federal
`
`Circuit further stated: “The Board weighed the evidence supporting each side of the factual dispute
`
`and found that sufficient uncertainty and unpredictability remained—i.e., that Lilly’s evidence
`
`failed to demonstrate enough certainty that migraine treatment does not have to cross the blood-
`
`brain barrier to give a skilled artisan a reasonable expectation of success.” Id. at 1349.
`
`4
`
`
`
`
`
`
`

`

`Case 1:18-cv-12029-ADB Document 291 Filed 03/28/22 Page 10 of 108
`Case 1:18-cv-12029-ADB Document 291 Filed 03/28/22 Page 10 of 108
`
`16.|Teva appealed the decisions in the Antibody IPRs to the United States Court of
`
`Appeals for the Federal Circuit. (Teva Pharm Int’] GmbHv. Eli Lilly, Case Nos. 2020-1747, 2020-
`
`1748, 2020-1749, 2020-1750, 2020-1751, 2020-1752 (Fed. Cir. 2020).) The Federal Circuit panel
`
`ultimately affirmed the PTAB’srulings in the Antibody IPRs on August 16, 2021. See Teva Pharm
`
`Int'l GmbHv. Eli Lilly, 8 F4th 1349 (Fed. Cir. 2021); Teva Pharm Int’l GmbHv. Eli Lilly, 856 F.
`
`App’x. 312 (Fed. Cir. 2021).
`
`17.
`
`The antibody genusof claims 17 and 20 of the ’045 patent uses functional language
`
`like that in the antibody genus of claim 1 of the ’649 patent considered by the PTAB andthe
`
`Federal Circuit.
`
`(Ex. 91 [IPR2018-01424 FWD] (881 patent, ’211 patent, ’649 patent) at 10);
`
`Teva, 856 F. App’x. at 313.
`
`Claim 1 of the ’649 patent
`Claims 17 and 20 of the ’045 patent
`17. A method for reducing incidence of or|1. An isolated human or humanized anti-
`treating headache in a human, comprising|CGRP antagonist antibody with a binding
`administering to the human an effective|affinity (Kp) to human o-CGRP of 50 nM or
`amount of an anti-CGRP antagonist antibody,|less as measured by surface plasmon resonance
`wherein said anti-CGRP antagonist antibodyis|at 37° C.
`a human monoclonal antibody or a humanized
`monoclonal antibody.
`
`resonance at 37° C.
`
`20. The method according to claim 17, wherein
`the anti-CGRP antagonist antibody has a
`binding affinity (Kp) to human o-CGRP of 50
`nM or less as measured by surface plasmon
`
`18.|The antibody genus of claim 1 of the 907 patent uses functional languagelike that
`
`in the antibody genus of claim 1 ofthe ’210 patent considered by the PTAB andthe Federal Circuit.
`
`(Ex. 67 [IPR2018-01422 FWD] (614 patent, ’951 patent, ’210 patent) at 9-10); Teva, 8 F.4th at
`
`1353-54.
`
`

`

`Case 1:18-cv-12029-ADB Document 291 Filed 03/28/22 Page 11 of 108
`Case 1:18-cv-12029-ADB Document 291 Filed 03/28/22 Page 11 of 108
`
`Claim 1 of the ’210 patent
`
`1. 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
`twolight 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
`
`Claim 1 of the ?907 patent
`1. A method for treating headache in an
`individual, comprising:
`administering to the individual an effective
`amount of 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
`twolight 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
`
`NO:15 or SEQ
`amino acid residues 1 to 37 of SEQ
`
`19.
`
`The antibody genusof claim 1 of the ’908 patent uses functional languagelike that
`
`in the antibody genus of claim 1 ofthe ’211 patent considered by the PTAB and the Federal Circuit.
`
`(Ex. 91 [IPR2018-01424 FWD] (881 patent, ’211 patent, 649 patent) at 9); Teva, 856 F. App’x.
`
`at 313.
`
`Claim 1 of the ’908 patent
`1. A method for treating headache in an}
`individual, comprising:
`administering to the individual an effective
`amount of 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 Fe
`region; and
`twolight chains, each light chain comprising
`three CDRs andfour framework regions;
`wherein the CDRs impart to the antibody
`specific binding to a CGRP consisting of
`amino acid residues 1 to 37 of SEQ
`
`Claim 1 of the ’211 patent
`1. 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 Fe
`region; and
`twolight 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
`
`

`

`Case 1:18-cv-12029-ADB Document 291 Filed 03/28/22 Page 12 of 108
`Case 1:18-cv-12029-ADB Document 291 Filed 03/28/22 Page 12 of 108
`
`37°C.
`
`Claim 1 of the ’908 patent
`NO:15 or SEQ ID NO:43, and wherein the
`antibody binds to the CGRP with a binding
`affinity (Kp) of about 10 nM orless as
`measured by surface plasmon resonance at
`37°C.
`
`Claim 1 of the ’211 patent
`NO:15 or SEQ ID NO:43, and wherein the
`antibody binds to the CGRP with a binding
`affinity (Kp) of about 10 nM orless as
`measured by surface plasmon resonance at
`
`20.
`
`The Federal Circuit’s opinion on the Antibody IPRs states: “the antibodies in the
`
`claims at issue in this case are described, not in terms oftheir structure, but rather in terms of their
`
`function—in particular, their ability to bind to the CGRP ligand.” Teva, 8 F.4th at 1362.
`
`It also
`
`stated that the “claims in this case have a broad scope dueto their lack of structural limitations.”
`
`Id. it further held that nexus between the patent claims and the Ajovy product could not be
`
`presumed: “A claim to ‘anything that works’ hardly has a nexusto any particular product.” Jd.
`
`Il.
`
`CGRP and Headache Disorders
`
`21.
`
`“Migraine is a common chronic, recurrent neurological disorder that affects greater
`
`than 10% of adults globally and approximately 39 million individuals in the United States.” (Ex.
`
`5 [Blake Op.] at § 52.)
`
`22.
`
`Lilly expert Dr. Charles has opined that “headache disorders are categorized as
`
`primary headaches and secondary headaches,” and “[s]econdary headaches are those with an
`
`identifiable cause, such as trauma, infection, or other events.” (Ex. 48 [Charles Op.] at § 38.)
`
`23.|Teva expert Dr. Blumenfeld has opined that“[s]econdary headaches are headaches
`
`caused by some other condition or disorder,” and “[e]xamples of secondary headaches include
`
`headachesassociated with trauma, headachesassociated with substances, such as medications, and
`
`headachesassociated with cranial diseases.” (Ex. 51 [Blumenfeld Resp.] at § 18.)
`
`24.—Dr. Charles has opinedthat “[a]s of 2005-2006, there were over 200 recognized
`
`headache disorders. Prior to that time, the most recent authoritative list was developed and
`
`publishedas the International Classification of Headache Disorders, 2" edition, in 2004. ... The
`
`7
`
`

`

`ICHD guidelines were developed by an extensive collection of members and advisors in the
`
`headache field who served on various committees, subcommittees, and working groups to
`
`formulate diagnostic criteria for each recognized headache disorder.” (Ex. 48 [Charles Op.] at
`
`¶¶ 34-35.)
`
`8
`
`
`
`
`
`
`

`

`in receptor binding (amino acids 28-37). (Ex. 48 [Charles Op.] at ¶¶ 19, 20; Ex. 33 [Hill Reb.] at
`
`¶ 45; Ex. 31 [Hale Resp.] at ¶¶ 110, 112.)
`
`9
`
`
`
`
`
`
`

`

`severe headache caused by pituitary tumors and CGRP” citing Levy. Do you
`believe that statement to be true when you made it?
`A I did.
`
`(Ex. 24 [Hill Tr.] at 274:22-275:7; 276:6-14.)
`
`10
`
`
`
`
`
`
`

`

`11
`
`
`
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`

`

`43.
`
`The portion of an antigen bound by an antibody is called an epitope. (Ex. 37
`
`[Janeway] at 93; Ex. 31 [Hale Resp.] at ¶ 32; Ex. 15 [McDonnell Op.] at ¶¶ 36, 53.)
`
`44.
`
`The portion of the antibody that binds to the antigen is called a paratope. (Ex. 31
`
`[Hale Resp.] at ¶ 220.)
`
`12
`
`
`
`
`
`
`

`

`13
`
`
`
`
`
`
`

`

`of antibodies including binding characteristics, including affinity (e.g., how
`strongly antibodies bind to their target molecules), potency (e.g., how strongly
`antibodies inhibit or activate biological functions of their target molecules), effector
`functions (e.g., how strongly antibodies trigger certain types of cytotoxicity),
`pharmacokinetics (e.g., how long antibodies remain in the body of living
`organisms), and pharmacodynamics (e.g., how long and effectively antibodies
`produce their intended biological responses).
`
`(Ex. 15 [McDonnell Op.] at ¶ 43.)
`
`14
`
`
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`
`
`

`

`15
`
`
`
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`

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`16
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`Case 1:18-cv-12029-ADB Document 291 Filed 03/28/22 Page 22 of 108
`Case 1:18-cv-12029-ADB Document 291 Filed 03/28/22 Page 22 of 108
`
`understood at
`
`the time,” and “[a] POSA would have understood from the differences in
`
`pharmacokinetic and pharmacodynamic properties of full-length antibodies and antibody
`
`fragments that using fragments in the claimed methods of treatment may require larger and/or
`
`more frequent doses to compensate for the rapid clearance.” (Ex. 33 [Hill Reb.] at § 359.)
`
`74.
`
`Antibodies can be madein a laboratory, i.e., engineered, and engineered antibodies
`
`exhibit variable functions, such as inhibiting (“antagonizing”) or enhancing (“agonizing”) the
`
`functions of a target antigen. (Ex. 31 [Hale Resp.] at § 55.)
`
`75.
`
`==So
`
`— ~—
`
`

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`18
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`Case 1:18-cv-12029-ADB Document 291 Filed 03/28/22 Page 24 of 108
`Case 1:18-cv-12029-ADB Document 291 Filed 03/28/22 Page 24 of 108
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`77.|Dr. McDonnell has opined:
`
`As Teva’s IPR expert Dr. Tomlinson estimated, mutating each residue in the heavy
`and light chain variable domains of a single antibody can result in 207° different
`combinations and greater than 207° different antibodies if one also considers
`
`variations in antibody formats and isotypes.
`(See supra § VII.A.1: Tomlinson Tr.
`at 91:25-92:17.
`
`
`
`
`Further, claim 17
`
`encompasses a widearray of antibody formats, different antibody constant regions,
`and additional amino acid sequence mutations throughout the heavy and light
`chains. (See supra § VILA.1; see also 045 patent at 12:14-35.) As such, making
`and using the full scope of the claimed methods of claim 17 would involve making
`an enormous numberof antibodies and then empirically testing them to determine
`whetheror not they met the functional properties required by claim 17.
`
`(Ex. 15 [McDonnell Op.] at § 262.)
`
`78.
`
`Dr. Hale has opinedthat“given that the Patents-in-Suit demonstrate the usefulness
`
`of anti-CGRP antagonist antibodies for treating migraine, a POSA just needsto be able to generate
`
`those anti-CGRP antagonist antibodies that can be used for the claimed methods, which is a much
`
`smaller universe than all antibodies that bind to CGRP.” (Ex. 31 [Hale Resp.] at § 402.)
`
`79.
`
`In his January 25, 2022 deposition, Dr. Hale testified as follows:
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`20
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`21
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`in biologic systems, it is difficult to predict before testing which antibody sequences will bind a
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`chosen antigen, where on the antigen the antibody will bind, and the biologic effect the antibody
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`will have.” (Id. at ¶ 59.)
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`22
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`Case 1:18-cv-12029-ADB Document 291 Filed 03/28/22 Page 28 of 108
`Case 1:18-cv-12029-ADB Document 291 Filed 03/28/22 Page 28 of 108
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`Q It is true, I gather, in your opinion, that the only denote way to know whether
`an antibodythat the animal has produced for you blocks CGRPis to empirically
`test it, correct?
`
`A Correct.
`
`(Ex. 24 [Hill Tr.] at 148:3-14.)
`
`95.
`
` Inhis August 11,2021 deposition, named inventor Joerg Zellertestified as follows:
`
`
`
`96.
`
` Inhis August 20, 2021 deposition, named inventor Jaume Ponstestified as follows
`
`I ve: F3. 8. Civ P. 30006) (Ex. 40 [Pons Te]
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`17:18-18:21):
`
`ae
`
`97.
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` Inhis August 20, 2021 deposition, named inventor JaumePonstestified as follows
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`Pe underFed. R. Civ. P. 30(b)(6) (Ex. 40 [Pons Tr.] at
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`17:18-18:21):
`
`23
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`Case 1:18-cv-12029-ADB Document 291 Filed 03/28/22 Page 29 of 108
`Case 1:18-cv-12029-ADB Document 291 Filed 03/28/22 Page 29 of 108
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`ee
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`98.
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`On September 11, 2020, Dr. Ravetch submitted a declaration in support of Teva’s
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`proposed claim constructions. (ECF No. 70 (Ravetch CC Decl.)) In the declaration, Dr. Ravetch
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`opined that “considerations such as the biophysical properties of an antibody(e.g., its stability,
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`half-life, or tissue penetration) may impact in vivo response regardless of whether the antibody
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`exhibits CGRP antagonism” and that a POSA “would not be surprised to encounter anti-CGRP
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`antagonist antibodies that displayed antagonism invitro but did not perform well in more complex,
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`in vivo assays.” (Id. at § 33.)
`
`99.
`
`Inhis September 30, 2020 deposition, Dr. Ravetch testified as follows:
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`Q Is it true that a person of ordinary skill in the art can humanize an antibody for
`the purposesof testing it in an in vitro or in vivo assay?
`it has certain
`A Yes. Humanization is a structural change in an antibody,
`properties, as we’ve been discussing, and youcantest those properties in vitro
`or in vivo.
`Andthose assays can provide information as to whether a humanized antibody
`would be potentially useful as a human therapeutic or not, correct?
`A It depends on the assay and on the antibody. Not every in vitro assay is
`predictive of in vivo therapeutic activity. There are lots of other constraints that
`are introduced when one uses an antibody therapeutic, for that matter any
`therapeutic, going from even in the most well-designed in vivo preclinical
`models to an in vivo proof of concept in a human subject.
`
`(Ex. 43 [Ravetch CC Tr.] at 174:24-175:20.)
`
`100.
`
`Inhis September 30, 2020 deposition, Dr. Ravetch testified as follows:
`
`Q One with skill in the art can humanize an antibody without knowing whether
`the humanizedantibody will be safe or effective in humans, correct?
`A Once again, humanization is a process by which you convert an antibody of one
`species into an antibody that is as much human as youcan, while retaining
`biological properties. Those properties include binding to the target, perhaps
`other downstream signaling events that are part of the function of the antibody,
`and it may also include activities that occur in in vivo models. Extrapolating
`from the in vivo models to a human therapeutic is a complex process for which
`a development team is included with the POSAto be able to make those kinds
`
`ee0
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`24
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`of changes. One of the things that I stated in my humanization paragraph that
`we looked at before in Ravetch […] Okay. Changes can be introduced into an
`antibody that are introduced specifically to enhance its stability or its half-life
`or its penetration or other pharmacokinetic and pharmacodynamic properties
`that are not necessarily the activities directed at the target itself directly. So
`there are other considerations that might go into the design of an antibody
`beyond the humanization which is designed in general to minimize
`immunogenicity.
`
`(Ex. 43 [Ravetch CC Tr.] at 175:24-177:17.)
`
`101.
`
`In his January 25, 2022 deposition, Dr. Hale testified as follows:
`
`Q Would you agree that given the variability among antibodies, different antibody
`sequences may bind to the same or similar epitopes while, at the same time,
`similar antibodies with similar sequences may form three-dimensional
`structures that bind different antigens?
`A I mean, in general, that statement, as you’ve made it, seems to be reasonable. I
`think that’s as far as I can go.
`
`(Ex. 13 [Hale Tr.] at 134:17-135:4.)
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`Case 1:18-cv-12029-ADB Document 291 Filed 03/28/22 Page 31 of 108
`Case 1:18-cv-12029-ADB Document 291 Filed 03/28/22 Page 31 of 108
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`amino acid sequence, known as a “monoclonal” antibody.
`
`(Ex. 31 [Hale Resp.] at §§ 59-60; Ex.
`
`15 [McDonnell Op.] at § 57.)
`
`105.
`
`Immunizing animals to produce antibodies would have taken many weeks or
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`months. (Ex.
`
`1
`
`[’045 patent] at 49:24-37 (045 patent describing an immunization protocol
`
`involving injections on days 21, 44, 78, and 110 after the first injection); Ex. 31 [Hale Resp.] at §
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`458 (“the immunization process takes many weeks or months”); Ex. 15 [McDonnell Op.] at § 287;
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`Ex. 45 [McDonnell Reply] at § 320; Ex. 40 [Pons Tr.] at 103:5-15.)
`
`106.
`
`Inhis August 20, 2021 deposition, named inventor Jaume Ponstestified as follows
`
`Fe
`
`Civ. P. 30(b)(6) (Ex. 40 [Pons Tr.] 17:18-18:21):
`
`
`A Yeah, thea -- thea— is not = quick [...] quick.
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`Q Is that consistent with your own experience?
`
`(Ex. 40 [Pons Tr.] at 103:5-15.)
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`107. Using hybridomasto produce monoclonal antibodies may take weeks or months.
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`(Ex. 31 [Hale Resp.] at § 459 (“Simularly, it may take weeks or months for hybridomacell cultures
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`to proliferate and generate a sufficient amount of monoclonal antibody....”).)
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`108. By 2005-2006, it was well-known that administering an antibody generated in non-
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`human animals to human subjects would cause immunogenic responses in those human subjects,
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`resulting in elimination of the antibody, loss of therapeutic efficacy, and possibly serious allergic
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`es |ee
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`reactions and side effects. (Ex. 31 [Hale Resp.] at ¶¶ 58, 62; Ex. 15 [McDonnell Op.] at ¶¶ 60-
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`61.)
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`28
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`29
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`as Hale Exhibit 9. Dr. Hale reviewed it and confirmed that “it is one of my papers” and “I’m one
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`of the authors.” (Ex. 13 [Hale Tr.] at 83:19-24.) It is listed in Dr. Hale’s CV as Reference #127.
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`(Ex. 31 [Hale Resp.] at Exhibit 1.) It estimates that “more than 2000 scientists, physicians, nurses,
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`and lawyers have been involved in the characterization and development” of one humanized
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`therapeutic antibody. (Ex. 77 [Hale Ex. 9] at 262.)
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`Case 1:18-cv-12029-ADB Document 291 Filed 03/28/22 Page 36 of 108
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`wm6~06NQNN—_—ee_—_—
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`Case 1:18-cv-12029-ADB Document 291 Filed 03/28/22 Page 38 of 108
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`135.
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`In 2005-2006, one could also attempt to make fully “human”antibodies, whichare
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`antibodies derived entirely from human sequences, using transgenic animals, e.g., transgenic mice.
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`(Ex. 31 [Hale Resp.] at §§ 92-93; Ex. 15 [McDonnell Op.] at § 64.)
`
`136. Dr. McDonnell has opined that “[{a]lthough the technology for making human
`
`antibodies was generally known, its use in the pharmaceutical industry was relatively new,” and
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`“Tals of 2005, only one therapeutic antibody approved in the US and Europe was a human
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`antibody.” (Ex. 15 [McDonnell Op.] at § 65.)
`
`137. OnJune 29, 202Mm wasdeposed in herpersonal
`capacity and as Teva’s corporate designeePo
`
`
`Po In that depositionshe testified as follows:
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`(Ex. 88 [Daugherty] at 690; see also Ex. 15 [McDonnell Op.] at ¶¶ 70-71, 290.)
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`V.
`
`The Patents-in-Suit
`
`A.
`
`Shared Specification of the Patents-in-Suit
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`35
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`36
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`154.
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`The specification of the Patents-in-Suit lists 84 related variants of Antibody G1,
`
`referred to as M1-M84, which vary by 10 or fewer amino acids from Antibody G1. (Ex. 1 [’045
`
`patent] at Table 6; Ex. 15 [McDonnell Op.] at ¶¶ 140-141; Ex. 13 [Hale Tr.] at 186:15-20.)
`
`155.
`
`Teva has admitted that the humanized antibody amino acid sequences listed in the
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`specification of the patents-in-suit have comparative “percentage sequence identity” values of
`
`greater than 95% when calculated according to the method set forth in the ’045 patent at 45:5-20.
`
`(Ex. 32 [Teva Response to RFA No. 18].)
`
`156.
`
`Teva has admitted that light chain CDR3, heavy chain CDR1, and heavy chain
`
`CDR3 of antibodies M1-M84 are identical to those of Antibody G1. (Ex. 32 [Teva Response to
`
`RFA No. 8]; Ex. 13 [Hale Tr.] at 187:10-188:8.)
`
`157.
`
`The specification of the Patents-in-Suit reports binding affinity for antibodies M1-
`
`M84, measured by Biacore surface plasmon resonance at 37°C. (Ex. 1 [’045 patent] at Table 6;
`
`Ex. 13 [Hale Tr.] at 189:13-19; Ex. 15 [McDonnell Op.] at ¶ 279.)
`
`37
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`Case 1:18-cv-12029-ADB Document 291 Filed 03/28/22 Page 43 of 108
`Case 1:18-cv-12029-ADB Document 291 Filed 03/28/22 Page 43 of 108
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`160.
`
`Inhis January 25, 2022 deposition, Dr. Haletestified as follows:
`
`Q All of the murine monoclonalantibodies tested in the patents-in-suit bound to
`the C-terminal region in CGRP,correct?
`A That seemsto be what they reported,yes.
`
`(Ex. 13 [Hale Tr.] at 175:2-6.)
`
`161.
`
`Inhis January 25, 2022 deposition, Dr. Hale testified as follows:
`
`Q Turing to column 67, line 19, the ’045 patent reports that “Antibody G1 binds
`to a C-terminal epitope with F37 and G33 being the most important residues,”
`correct?
`A Yes, that’s what it says. And I see that that is the same as the epitopes they
`have described for the murine antibodies.
`
`(Ex. 13 [Hale Tr.] at 183:22-184:4.)
`
`162.
`
`In his August 5, 2021 deposition, named inventor Kristian T. Poulsen testified as
`
`follows:
`
`
`
`163.
`
`Inhis August 20, 2021 deposition, named inventor JaumePonstestified as follows
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`a «2:
`
`Civ. P.