Case 1:18-cv-12029-ADB Document 440 Filed 07/27/22 Page 1 of 271
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF MASSACHUSETTS
`
`
`
`
`TEVA PHARMACEUTICALS
`INTERNATIONAL GMBH and
`TEVA PHARMACEUTICALS
`USA, INC.,
`
`
`Civil Action No.
`1:18-cv-12029-ADB
`
`
`
`
`
`
`
`
`Plaintiffs,
`
`
`v.
`
`ELI LILLY AND COMPANY,
`
`
`Defendant.
`
`
`
`
`
`L.R. 56.1 RESPONSIVE STATEMENT OF MATERIAL FACTS IN SUPPORT OF
`PLAINTIFFS’ OPPOSITION TO DEFENDANT’S MOTION FOR SUMMARY
`JUDGMENT FOR LACK OF ENABLEMENT
`
`
`
`

`

`Case 1:18-cv-12029-ADB Document 440 Filed 07/27/22 Page 2 of 271
`
`TABLE OF CONTENTS
`
`
`
`IV.
`
`V.
`
`TABLE OF ABBREVIATIONS ................................................................................................... iii
`PLAINTIFFS’ PRELIMINARY STATEMENT ............................................................................ 1
`PLAINTIFFS’ RESPONSIVE MATERIAL FACTS ..................................................................... 3
`I.
`IPR PROCEEDINGS .............................................................................................. 3
`II.
`LEVEL OF ORDINARY SKILL IN THE ART .................................................... 7
`III.
`THE INVENTIONS OF THE PATENTS IN SUIT AND SCOPE OF THE
`ASSERTED CLAIMS ............................................................................................ 8
`STATE OF THE PRIOR ART AND PREDICTABILITY OF THE ART .......... 10
`A.
`CGRP and Headache................................................................................. 10
`B.
`Antibodies, Including Anti-CGRP Antagonist Antibodies ....................... 15
`C.
`Animal Models of Headache .................................................................... 19
`A POSA’S UNDERSTANDING OF THE TEACHINGS OF THE
`SPECIFICATION ................................................................................................. 21
`A.
`Disclosures of Anti-CGRP Antagonist Antibodies................................... 21
`B.
`Disclosures Regarding CGRP and Use of Anti-CGRP Antagonist
`Antibodies to Treat Headache ....................................................... 25
`Animal Assays Demonstrating Effectiveness ............................... 25
`1.
`Use of anti-CGRP Antagonist Antibodies .................................... 28
`2.
`A POSA WOULD HAVE BEEN ABLE TO PRACTICE THE CLAIMED
`METHODS WITHOUT UNDUE EXPERIMENTATION .................................. 30
`VII. COMPARISON OF GALCANEZUMAB AND ANTIBODIES USED IN THE
`ASSERTED CLAIMS .......................................................................................... 33
`VIII. DEVELOPMENT OF GALCANEZUMAB ........................................................ 34
`IX.
`THE INVENTOR’S DEVELOPMENT OF ANTI-CGRP ANTAGONIST
`ANTIBODIES....................................................................................................... 35
`TEVA’S CLUSTER HEADACHE TRIAL .......................................................... 36
`X.
`THE PARTIES’ EXPERTS .................................................................................. 37
`XI.
`XII. DR. RAVETCH’S PGR DECLARATION .......................................................... 38
`XIII.
` ......................................................................... 39
`XIV.
` ..................................................... 41
`PLAINTIFFS’ RESPONSES TO DEFENDANT’S STATEMENT OF MATERIAL FACTS ... 41
`I.
`PROCEDURAL POSTURE ................................................................................. 41
`II.
`CGRP AND HEADACHE DISORDERS ............................................................ 50
`III.
`ANTIBODY DIVERSITY.................................................................................... 58
`
`VI.
`
`i
`
`

`

`Case 1:18-cv-12029-ADB Document 440 Filed 07/27/22 Page 3 of 271
`
`
`
`IV.
`
`V.
`
`VI.
`VII.
`VIII.
`
`THE TRIAL-AND-ERROR COMPLEXITY OF MAKING THERAPEUTIC
`ANTIBODIES....................................................................................................... 74
`THE PATENTS-IN-SUIT .................................................................................. 107
`A.
`Shared Specification of the Patents-in-Suit ............................................ 107
`B.
`Claims of the ’045 Patent ........................................................................ 137
`C.
`Claims of the ’907 Patent ........................................................................ 140
`D.
`Claims of the ’908 Patent ........................................................................ 145
`A PERSON OF ORDINARY SKILL IN THE ART .......................................... 150
`SCOPE OF THE CLAIMS ................................................................................. 151
`
` .. 157
`
`X.
`
`IX.
`
` DEVELOPMENT OF EMGALITY®
`LILLY’S
`(GALCANEZUMAB) ........................................................................................ 181
`NO PRIOR EXPERIENCE WITH THE CLAIMED ANTIBODIES IN THIS
`NEW FIELD ....................................................................................................... 205
`TEVA EXPERTS’ ENABLEMENT ANALYSIS ............................................. 250
`XI.
`XII. OTHER ASSERTED CLAIMS .......................................................................... 253
`
`
`
`
`
`
`
`ii
`
`

`

`Case 1:18-cv-12029-ADB Document 440 Filed 07/27/22 Page 4 of 271
`
`TABLE OF ABBREVIATIONS
`
`
`
`Short Cite
`’045 patent
`
`’210 patent
`
`’211 patent
`
`’614 patent
`
`’649 patent
`
`’881 patent
`
`’907 patent
`
`’908 patent
`
`’951 patent
`
`Abdiche Decl.
`
`Abdiche Tr.
`
`
`
`Description & Other Names/References
`Patent-in-suit. U.S. Patent No. 8,586,045 to Joerg Zeller et al., issued
`November 19, 2013, entitled “Methods of Using Anti-CGRP Antagonist
`Antibodies” currently assigned to Teva Pharmaceuticals International
`GmbH
`U.S. 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
`U.S. 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
`U.S. 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
`U.S. 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 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
`U.S. 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
`Declaration of Yasmina Abdiche, Ph.D. in support of Teva’s Oppositions
`to Lilly’s Motions for Summary Judgment of Invalidity for (1) Lack of
`Enablement, and (2) Lack of Written Description
`Transcript of deposition of Yasmina Noubia Abdiche, named inventor of
`the patents-in-suit, dated August 17, 2021
`
`
`
`
`
`iii
`
`

`

`Case 1:18-cv-12029-ADB Document 440 Filed 07/27/22 Page 5 of 271
`
`
`
`Short Cite
`BBB
`
`
`
`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.
`
`Description & Other Names/References
`Blood-brain barrier
`
`
`
`
`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 January 10, 2022
`Responsive Expert Report of Andrew Blumenfeld, M.D. Regarding
`Validity, on behalf of Teva, served November 1, 2021
`Transcript of deposition of expert Andrew Blumenfeld, M.D., on behalf of
`Teva, dated January 26, 2022
`Calcitonin Gene-Related Peptide
`Opening 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 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
`
`
`
`
`Documents from the public docket filed through the CM/ECF system.
`Unless otherwise noted, citations are to the public docket of Case No.
`1:18-cv-12029-ADB, D. Mass.
`Exhibits to concurrently-filed Attorney Declaration
`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 GmbH
`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 Inter 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
`
`iv
`
`

`

`Case 1:18-cv-12029-ADB Document 440 Filed 07/27/22 Page 6 of 271
`
`
`
`Short Cite
`Hale Supp.
`
`Hale Tr.
`
`Harnish Tr.
`
`Hill Reb.
`
`Hill Tr.
`
`ICHD-II
`IPR
`
`IPR2018-1710
`Vasserot Decl.
`
`IPR2018-1711
`Vasserot Decl.
`
`IPR2018-1712
`Vasserot Decl.
`
`Lilly’s
`Memorandum; or
`Mot.
`L.R.
`McDonnell Op.
`
`McDonnell Reb.
`
`McDonnell Reply
`
`McDonnell Supp.
`
`
`
`Mould Op.
`
`Mould Reply
`
`Description & Other Names/References
`Supplemental Responsive Expert Report of Geoffrey Hale, Ph.D.,
`Regarding Validity, on behalf of Teva, served January 7, 2022
`Transcript of deposition of expert Geoffrey Hale, Ph.D., on behalf of
`Teva, dated January 25, 2022
`Transcript of deposition of fact witness Douglas Harnish, Ph.D., defended
`by Teva counsel, dated July 29, 2021
`Rebuttal Expert Report of Raymond Hill, 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
`International Classification of Headache Disorders, 2nd edition
`Inter partes review proceedings at 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 GmbH
`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’l GmbH
`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’l GmbH
`Eli Lilly and Company’s Memorandum in Support of its Motion for
`Summary Judgment of Invalidity for Lack of Enablement, ECF No. 290,
`March 28, 2022
`Local Rule
`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
`Noninfringement of 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
`
`
`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
`December 7, 2021
`
`
`
`v
`
`

`

`Case 1:18-cv-12029-ADB Document 440 Filed 07/27/22 Page 7 of 271
`
`
`
`Description & Other Names/References
`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’l GmbH
`Transcript of deposition of Jaume Pons, Ph.D., named inventor of the
`patents-in-suit, dated August 20, 2021
`Patent Owner Response in an Inter Partes Review proceeding before the
`United States Patent and Trademark Office Patent Trial and Appeal Board
`Person of ordinary skill in the art
`Transcript of deposition of Kristian T. Poulsen, named inventor of the
`patents-in-suit, dated August 5, 2021
`Patent Trial and Appeal Board of the United States Patent and Trademark
`Office
`Transcript of deposition of fact witness Thomas Edwin Rainey, defended
`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
`Ravetch 2022 Decl. Concurrently-filed Declaration of Jeffrey V. Ravetch, M.D., Ph.D.
`Ravetch
`Declaration of Dr. Jeffrey V. Ravetch in Support of Petition for Post
`Declaration
`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 December 7, 2021
`Request for Admission
`Concurrently-filed Plaintiffs’ Responsive Statement of Material Facts
`
`Short Cite
`Pons Decl.
`
`Pons Tr.
`
`POR
`
`POSA
`Poulsen Tr.
`
`PTAB
`
`Rainey Tr.
`
`Rapoport Tr.
`
`Ravetch CC Decl.
`
`Ravetch CC Tr.
`
`Ravetch Op.
`
`Ravetch Reply
`
`RFA
`RMF
`
`
`
`Stratton Tr.
`
`Tomlinson Decl.
`
`Tomlinson Tr.
`
`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
`Pharms. Int’l GmbH
`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 Jöerg Zeller, named inventor of the patents-in-
`suit, dated August 11, 2021
`
`vi
`
`

`

`Case 1:18-cv-12029-ADB Document 440 Filed 07/27/22 Page 8 of 271
`
`
`
`PLAINTIFFS’ PRELIMINARY STATEMENT
`
`Pursuant to Local Rule 56.1 (“Rule 56.1”), Teva responds to each “statement of fact”
`
`asserted by Lilly in its L.R. 56.1 Statement of Material Facts In Support of Defendant Eli Lilly and
`
`Company’s Motion for Summary Judgment of Invalidity for Lack of Enablement (“Lilly’s 56.1
`
`Statement”). As a preliminary matter, Lilly’s 56.1 Statement violates both the letter and the spirit
`
`of Rule 56.1 and on that basis alone the Court should deny Lilly’s motion. The 101-page Statement
`
`comprising 411 “facts” and attaching 93 exhibits is far from concise. L.R. 56.1 (requiring motions
`
`for summary judgment include a “concise statement of material facts” that the moving party
`
`contends are not subject to a genuine dispute) (emphasis added). Instead, Lilly’s 56.1 Statement
`
`wastefully forces Teva to respond to a myriad of “facts” that are neither material nor undisputed.1,2
`
`
`1 For example, Lilly’s Rule 56.1 Statement fails to acknowledge that the majority of the material
`fact issues it addresses are actually disputed. Lilly instead presents a one-sided view of these issues
`that cites only to evidence that supports Lilly’s view without admitting to the existence of either a
`dispute or contrary evidence in the record. Disputed factual issues discussed but not recognized
`as such by Lilly include, among others: (i) whether generating and humanizing antibodies was
`routine and predictable; (ii) the amount of effort and expense required for a POSA to make and
`identify antibodies for use in the claimed methods, and whether the effort would be “undue”;
`(iii) the size of the class of anti-CGRP antagonist antibodies; (iv) the applicability of the claimed
`methods to headache generally; (v) the need for preclinical testing in non-human primates and
`clinical trials for a POSA to practice the claimed methods, and whether such studies would be
`“undue.” See, e.g., Rule 56.1 Statement ¶¶ 24–27, 75–82, 88, 93–100, 110–17, 118–41, 185–87,
`248–59, 275–92, 343–70.
`
`2 Lilly’s 56.1 statement relies on inadmissible hearsay statements from Teva’s experts in the IPR
`proceedings who are not offering opinions in this case, including from the Antibody IPRs, in which
`Lilly was successful and in which the PTAB adopted the opinions of Lilly’s experts, including Dr.
`Charles, who is also Lilly’s expert in these proceedings. See Lilly’s 56.1 Statement ¶¶ 51, 76, 110,
`115–17, 119, 121, 131–32 (Dr. Tomlinson’s IPR declaration and testimony); id. ¶¶ 324–25 (Dr.
`Ferrari’s IPR declaration); id. ¶¶ 350–51 (Dr. Foord’s IPR testimony); id. ¶¶ 26, 36 (Dr. Rapoport’s
`IPR testimony).
`
`
`
`
`
`1
`
`

`

`Case 1:18-cv-12029-ADB Document 440 Filed 07/27/22 Page 9 of 271
`
`
`
`Lilly’s inclusion of dozens of facts that are clearly not material also masks what material facts are
`
`in dispute.3
`
`This type of “needle in a haystack” statement is exactly what the rules prohibit because it
`
`does not clarify the disputed issues, and impermissibly shifts the burden to organize evidence from
`
`Lilly to both Teva, which must respond to every fact regardless of its materiality, and to this Court,
`
`which would be saddled with judging each and every one of Teva’s responses to Lilly’s assertions.
`
`See, e.g., Cataldo v. Moses, 361 F. Supp. 2d 420, 426 (D.N.J. 2004) (faulting plaintiff for violating
`
`the spirit of an analogous rule by “submitting wholesale immaterial information” in the form of “a
`
`106-page statement with 363 paragraphs of ‘undisputed material facts.’”); Resol. Tr. Corp. v. Fid.
`
`& Deposit Co., 1998 WL 2030798, at *1 n.3 (D.N.J. Jan. 27, 1998) (reprimanding plaintiff for
`
`submitting a 130-page statement of facts that provides “much information irrelevant to this
`
`motion” including “reproduce[ing] pages of deposition testimony already provided to the Court”).
`
`The First Circuit has upheld courts that have struck Rule 56.1 statements for less egregious
`
`violations. In Alsina-Ortiz v. Laboy, for example, the First Circuit affirmed the District Court for
`
`striking a moving parties’ statement of material facts when it spanned “60 pages and 130 facts—
`
`many being irrelevant, repetitive or unsupported by record citation” and therefore failed to comply
`
`with a local rule analogous to Rule 56.1 in this jurisdiction. 400 F.3d 77, 80–81 (1st Cir. 2005).
`
`Even recognizing that “a case could have a great many material contested facts,” the court found
`
`that the moving party “simply dumped an undigested record on the judge, expecting him to do
`
`
`3 Lilly’s 56.1 statement contains many “facts” that are not material, and in many instances are cited
`only in string cites for assertions that are, at most, tangentially related. For example, for the simple
`factual assertion that “[n]or does [the specification] disclose galcanezumab,” Lilly cites 19
`paragraphs of its 56.1 Statement, most of which are cited for nothing else and do not relate at all
`to the contents of the specification. Mot. at 6 (citing Lilly’s 56.1 Statement ¶¶ 167–68, 294–309,
`314).
`
`2
`
`

`

`Case 1:18-cv-12029-ADB Document 440 Filed 07/27/22 Page 10 of 271
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`
`
`counsel’s job.” Id.; see also Brown v. Armstrong, 957 F. Supp. 1293, 1297 (D. Mass. 1997), aff’d,
`
`129 F.3d 1252 (1st Cir. 1997) (explaining that the rule is intended to “expedite the process of
`
`determining which facts are genuinely in dispute, so that the court may turn quickly to the usually
`
`more difficult task of determining whether the disputed issues are material”); CMI Capital Market
`
`Inv., LLC v. González-Toro, 520 F.3d 58, 62 (1st Cir. 2008) (describing that Rule 56.1, also known
`
`as an “anti-ferret” rule, is intended to “relieve the district court of any responsibly to ferret through
`
`the record to discern whether any material fact is genuinely in dispute”). Here, it is impossible to
`
`tell from Lilly’s 56.1 Statement which facts Lilly considers material to its Motion and, of those,
`
`which are genuinely undisputed. Accordingly, the Court should deny the motion that relies on
`
`Lilly’s 56.1 Statement.
`
`PLAINTIFFS’ RESPONSIVE MATERIAL FACTS
`
`Pursuant to Local Rule 56.1, Plaintiffs submit the below Responsive Material Facts in
`
`Support of its Opposition to Defendant’s Motion for Summary Judgment of Invalidity for Lack of
`
`Enablement (“RMF”), showing that there are genuine issues of fact to be tried.
`
`I.
`
`IPR PROCEEDINGS
`
`P1.
`
`Lilly filed petitions for Inter Partes Review (“IPR”) of six “composition of matter”
`
`patents related to the patents in suit. Ex. BH (’1422 Petition); Ex. BI (’1424 Petition). The
`
`“composition of matter” patents had claims directed to classes of anti-CGRP antagonist antibodies.
`
`In the IPRs, Lilly argued that the claims were invalid because they were obvious in view of the art
`
`existing at the time of the invention. Ex. B (’1422 FWD) at 11–12, 20; Ex. C (’1424 FWD) at 11–
`
`12, 20; (Eli Lilly & Co. v. Teva Pharms. Int’l GmbH, 2020 WL 806932 (PTAB Feb. 18, 2020); Eli
`
`Lilly & Co. v. Teva Pharms. Int’l GmbH, 2020 WL 808240 (PTAB Feb. 18, 2020))
`
`P2.
`
`The central issues in the Composition of Matter IPRs were whether a POSA would
`
`have been motivated to combine prior art references that disclosed non-human anti-CGRP
`
`3
`
`

`

`Case 1:18-cv-12029-ADB Document 440 Filed 07/27/22 Page 11 of 271
`
`
`
`antagonist antibodies with other prior art references that discussed humanized antibodies
`
`generally, and whether a POSA would have had a reasonable expectation of successfully making
`
`a humanized antibody that antagonized the biological function of CGRP based on the prior art.
`
`Ex. B (’1422 FWD) at 54–55, 103; Ex. C (’1424 FWD) at 64, 101.
`
`P3.
`
`The challenged claims were directed to the class of antibodies that are used to
`
`perform the claimed methods in the asserted claims. See, e.g., Ex. B (’1422 FWD) at 9 (claim 1
`
`of the ’210 patent); Ex. C (’1424 FWD) at 9 (claim 1 of the ’211 patent).
`
`P4.
`
`The PTAB held that all of the challenged claims in Teva’s six Composition of
`
`Matter patents were unpatentable as obvious. Ex. B (’1422 FWD) at 2; Ex. C (’1424 FWD) at 2.
`
`P5.
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`Lilly argued and the PTAB found that by 2005, antibodies that antagonize CGRP,
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`i.e. anti-CGRP antagonist antibodies, “were well known in the art,” and that the methods of
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`preparing them were “routine.” For these arguments, Lilly relied on the Tan 1995 and
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`Wimalawansa references, among others. Ex. B (’1422 FWD) at 40–41, 55–56, 59, 94–95, 102;
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`Ex. C (’1424 FWD) at 27, 52, 102.
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`P6.
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`The PTAB found that it was “well established” by 2005 that one could determine
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`whether an antibody inhibits the CGRP pathway by a screening process that involved measuring
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`“cAMP activation in SK-N-MC cells.” Ex. B (’1422 FWD) at 29–30.
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`P7.
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`The PTAB found that the step of humanizing anti-CGRP antagonist antibodies
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`would have been “routine” by 2005, and that a POSA could humanize an anti-CGRP antagonist
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`antibody without reducing its ability to bind to its target CGRP. See Ex. B (’1422 FWD) at 95–
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`96, 98; Ex. C (’1424 FWD) at 28, 36, 40, 59–60, 103–04, 105–06.
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`P8.
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`The PTAB adopted Lilly’s argument that “by 2005, conventional humanization
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`techniques were routinely used that preserved the affinity and specificity of the donor antibody.”
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`4
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`Case 1:18-cv-12029-ADB Document 440 Filed 07/27/22 Page 12 of 271
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`Ex. B (’1422 FWD) at 96, 148; Ex. C (’1424 FWD) at 59–60, 104–06; Ex. BH (’1422 Petition) at
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`35.
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`P9.
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`In the IPR proceedings, Lilly argued that a POSA “would have had a reasonable
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`expectation of successfully making a humanized anti-CGRP antagonist antibody.” Ex. B (’1422
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`FWD) at 95, 98; Ex. C (’1424 FWD) at 103–05. The PTAB agreed with Lilly’s argument and
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`adopted it in its findings of fact. Ex. B (’1422 FWD) at 100; Ex. C (’1424 FWD) at 106–06.
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`P10.
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`In the IPR proceedings, Lilly argued that a POSA “would have had a reasonable
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`expectation of successfully making a humanized anti-CGRP antagonist antibody.” Ex. B (’1422
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`FWD) at 95, 98; Ex. C (’1424 FWD) at 103–06. The PTAB agreed with Lilly’s argument and
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`adopted it in its findings of fact. Ex. B (’1422 FWD) at 100; Ex. C (’1424 FWD) at 105–06.
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`P11.
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`In the IPR proceedings, Lilly argued, and the PTAB found, that pharmaceutically
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`acceptable excipients and formulations for human administration of antibodies were known. Ex. B
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`(’1422 FWD) at 150–51; Ex. C (’1424 FWD) at 158–59.
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`P12.
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`Lilly argued that the class of humanized anti-CGRP antagonist antibodies would
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`have been obvious to a POSA and were known in the art, and the PTAB accepted Lilly’s argument.
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`See, e.g., Ex. B (’1422 FWD) at 28–29, 48–49. For example, Lilly argued that the Wimalawansa
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`article “proposed the use of humanized anti-CGRP monoclonal antagonistic antibodies as
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`therapeutic agents for CGRP-related diseases.” Ex. B (’1422 FWD) at 28.
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`P13.
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`In the IPRs, Lilly did not identify any particular anti-CGRP antagonist antibody
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`that was within the scope of any of the challenged claim as being obvious. The PTAB also did not
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`identify any particular embodiment as being obvious, but rather concluded that the claims were
`
`obvious generally. See generally Ex. B (’1422 FWD); Ex. C (’1424 FWD) at 102–03, 106, 149–
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`50. In response to Teva’s argument that Lilly had not identified a particular anti-CGRP antagonist
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`5
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`Case 1:18-cv-12029-ADB Document 440 Filed 07/27/22 Page 13 of 271
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`antibody as obvious, the PTAB relied on a prior art reference that “refers to ‘humanized anti-
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`CGRP monoclonal antibodies’ without limitation to any particular anti-CGRP monoclonal
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`antibody.” Ex. B (’1422 FWD)at 93; Ex. C (’1424 FWD)at 101–02.
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`P14.
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`During the IPRs Lilly did not identify any prior art anti-CGRP antagonist antibodies
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`belonging to the IgG4 class. See generally Ex. BH (’1422 Petition); Ex. BI (’1424 Petition).
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`Lilly’s experts testified that there were no such antibodies in the prior art. Ex. CH (McDonnell
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`Dep. Tr.) 167:2–6, 167:21–168:1.
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`P15.
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`Although Lilly did not identify any disclosure IgG4 anti-CGRP antagonist
`
`antibodies in the prior art, the PTAB held that claims directed to IgG4 class anti-CGRP antagonist
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`antibodies were invalid as obvious over the prior art. Ex. B (’1422 FWD) at 154; Ex. C (’1424
`
`FWD) at 151–52.
`
`P16.
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`Lilly also filed petitions for Inter Partes Review (“IPR”) challenging the validity of
`
`the patents in suit in which Lilly argued that the patents in suit are also obvious over the prior art.
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`Ex. D (’1710 FWD) at 2.
`
`P17.
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`The PTAB found that Lilly had not shown that the challenged claims in the Method
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`of Treatment patents at issue in this case were unpatentable. Ex D (’1710 FWD) at 2. Lilly’s
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`arguments and the PTAB’s findings were based solely on obviousness in view of the prior art. The
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`teachings of the specification of the patents in suit was not considered. Ex D (’1710 FWD) at 13,
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`150–51.
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`P18.
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`The PTAB found that the challenged claims in the Method of Treatment patents
`
`were not obvious because uncertainty about whether antibodies would need to cross the blood-
`
`brain barrier weighed against finding a reasonable expectation of success in using the claimed
`
`6
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`Case 1:18-cv-12029-ADB Document 440 Filed 07/27/22 Page 14 of 271
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`methods. Ex. D (’1710 FWD) at 138–40. The Federal Circuit affirmed the PTAB’s decision. See
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`Eli Lilly & Co. v. Teva Pharms. Int’l GmbH, 8 F. 4th 1331 (Fed. Cir. 2021).
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`II. LEVEL OF ORDINARY SKILL IN THE ART
`
`P19.
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`The level of skill in the art was exceptionally high. Ex. B (’1422 FWD) at 12–13;
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`Ex. C (’1424 FWD) at 12–13; Ex. S (Hale Resp. Rpt.) ¶¶ 19–20, 210, 406–15; Ex. V (Hill Reb.
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`Rpt.) ¶¶ 28–29, 488–89; Ex. L (Blumenfeld Resp. Rpt.) ¶¶ 44, 74–80, 127–28.
`
`P20.
`
`A POSA would have had experience generating antibodies against desired targets,
`
`including CGRP. Ex. S (Hale Resp. Rpt.) ¶¶ 58–61, 115–24, 223–26, 284, 410; Ex. V (Hill Reb.
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`Rpt.) ¶¶ 173–74.
`
`P21.
`
`A POSA would have had experience humanizing antibodies. Ex. S (Hale Resp.
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`Rpt.) ¶¶ 62–76, 242–53, 410; Ex. V (Hill Reb. Rpt.) ¶¶ 175–77.
`
`P22.
`
`A POSA would have had extensive knowledge about CGRP, its role in headache
`
`and migraine, and known effective treatments for headache that target the CGRP pathway. Ex. S
`
`(Hale Resp. Rpt.) ¶¶ 110–14; Ex. L (Blumenfeld Resp. Rpt.) ¶¶ 30–37, 76–79; Ex. V (Hill Reb.
`
`Rpt.) ¶¶ 41–52, 72–84; Ex. B (’1422 FWD) at 35–41, 70–73; Ex. C (’1424 FWD) at 45–51, 60–
`
`62.
`
`P23.
`
`A POSA would have had extensive experience treating headache, including with
`
`drugs that target the CGRP pathway. Ex. L (Blumenfeld Resp. Rpt.) ¶¶ 23–37, 128; Ex. V (Hill
`
`Reb. Rpt.) ¶¶ 85–107; Ex. O (Charles Op. Rpt.) ¶¶ 52–53.
`
`P24.
`
`A POSA would have had experience using therapeutic monoclonal antibodies.
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`Ex. S (Hale Resp. Rpt.) ¶¶ 97–102.
`
`P25.
`
`A POSA would have been experienced with the well-known class of monoclonal
`
`anti-CGRP antagonist antibodies as well as the routine techniques involved in generating and
`
`humanizing antibodies. Ex. E (’045 patent) at 25:59-60 (“Anti-CGRP antagonist antibodies are
`
`7
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`

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`Case 1:18-cv-12029-ADB Document 440 Filed 07/27/22 Page 15 of 271
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`known in the art.”); Ex. S (Hale Resp. Rpt.) ¶¶ 115–24, 222–24; 242–49; Ex. V (Hill Reb. Rpt.)
`
`¶¶ 182–92; Ex. N (Charles ’1427 IPR Decl.) ¶¶ 14, 77, 105, 115–23, 147–49; Ex. CU (Charles
`
`’1710 IPR First Decl.) ¶¶ 118, 164; Ex. CJ (Queen); Ex. AB (Andrew 1990); Ex. AM (Shaw
`
`1992); Ex. AT (Tan 1994); Ex. AP (Tan 1995).
`
`P26.
`
`A POSA would have had experience formulating antibodies and determining
`
`appropriate doses. Ex. B (’1422 FWD) at 150–51; Ex. C (’1424 FWD) at 158–59; Ex. S (Hale
`
`Resp. Rpt.) ¶¶ 103–09; Ex. V (Hill Reb. Rpt.) ¶¶ 320–21, 336; Ex. L (Blumenfeld Resp. Rpt.)
`
`¶¶ 92–95, 115-16; Ex. BE (Daugherty 2006) at 697; Ex. CJ (Queen) at 24:28–37.
`
`III. THE INVENTIONS OF THE PATENTS IN SUIT AND SCOPE OF THE ASSERTED
`CLAIMS
`
`P27.
`
`The inventions of the asserted claims are methods for treating headache or migraine
`
`using human or humanized anti-CGRP antagonist antibodies. Ex. V (Hill Reb. Rpt.) ¶¶ 195–97,
`
`216–17, 222–23; Ex. S (Hale Resp. Rpt.) ¶¶ 127, 194-202; Ex. L (Blumenfeld Resp. Rpt.) ¶¶ 46,
`
`70–72.
`
`P28.
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`The inventions of the asserted claims arise from the inventors’ disco