Case 1:18-cv-12029-ADB Document 439 Filed 07/27/22 Page 1 of 39
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF MASSACHUSETTS
`
`
`TEVA PHARMACEUTICALS
`INTERNATIONAL GMBH and
`TEVA PHARMACEUTICALS
`USA, INC.,
`
`Plaintiffs,
`
`
`v.
`
`ELI LILLY AND COMPANY,
`Defendant.
`
`
`
`
`
`Civil Action No.
`1:18-cv-12029-ADB
`
`
`
`
`
`
`
`FILED UNDER SEAL
`LEAVE TO FILE GRANTED
`05/06/2022 (ECF NO. 340)
`
`LEAVE TO FILE EXCESS
`PAGES GRANTED 02/22/2022
`(ECF NO. 272)
`
`
`PLAINTIFFS’ OPPOSITION TO ELI LILLY AND COMPANY’S MOTION FOR
`SUMMARY JUDGMENT OF INVALIDITY FOR LACK OF ENABLEMENT
`
`

`

`I.
`II.
`
`III.
`
`IV.
`
`V.
`
`
`
`Case 1:18-cv-12029-ADB Document 439 Filed 07/27/22 Page 2 of 39
`
`
`
`TABLE OF CONTENTS
`
`INTRODUCTION .............................................................................................................. 1
`FACTUAL BACKGROUND ............................................................................................. 3
`A.
`The Person of Ordinary Skill in the Art. ................................................................. 3
`B.
`Making Humanized Anti-CGRP Antagonist Antibodies Was Predictable and
`Routine ................................................................................................................................ 3
`C.
`CGRP Was Well-Characterized and Tied to Most Headaches that Required
`Treatment. ........................................................................................................................... 6
`LEGAL STANDARD ......................................................................................................... 7
`A.
`Summary Judgment ................................................................................................ 7
`B.
`Enablement ............................................................................................................. 8
`ARGUMENT .................................................................................................................... 10
`A.
`Lilly’s Motion Papers Violate Local Rule 56.1. ................................................... 11
`B.
`The Court Should Reject Lilly’s Argument that the Patents Do Not Enable the
`“Claimed Antibodies.” ...................................................................................................... 13
`1. The patents claim methods of using human and humanized anti-CGRP
`antagonist antibodies to treat headache, not the antibodies themselves................ 14
`2. Lilly has not established that it would require undue experimentation to make
`and use the “full scope” of the claimed methods. ................................................. 19
`3. Making the claimed antibodies was routine and predictable. ........................ 21
`C.
`Using Humanized Anti-CGRP Antagonist Antibodies to Treat Headache Does
`Not Require Undue Experimentation................................................................................ 24
`1. The vast majority of “headaches” encountered in clinical practice are
`associated with CGRP........................................................................................... 24
`2. Testing in humans is not required for Teva’s claims to be enabled. .............. 26
`D.
`Lilly Has Not Satisfied Its Burden of Proof With Respect to Dependent Claims or
`the Claims of the ’907 and ’908 Patents. .......................................................................... 29
`CONCLUSION ................................................................................................................. 30
`
`
`
`i
`
`

`

`Case 1:18-cv-12029-ADB Document 439 Filed 07/27/22 Page 3 of 39
`
`TABLE OF AUTHORITIES
`
`
`
`
`
`Page(s)
`
`Cases
`
`In re ’318 Patent Infringement Litig.,
`583 F.3d 1317 (Fed. Cir. 2009)..........................................................................................18, 26
`
`2018 WL 3586271, at *6–*7 (D.N.J. July 26, 2018) .....................................................................15
`
`Abbott Biotechnology Ltd. v. Centocor Ortho Biotech, Inc.,
`35 F. Supp. 3d 163 (D. Mass. 2014) ........................................................................................21
`
`Alcon Research Ltd. v. Barr Lab’ys, Inc.,
`745 F.3d 1180 (Fed. Cir. 2014)................................................................................................21
`
`Allergan, Inc. v. Sandoz Inc.,
`796 F.3d 1293 (Fed. Cir. 2015)..........................................................................................23, 26
`
`Alsina-Ortiz v. Laboy,
`400 F.3d 77 (1st Cir. 2005) ......................................................................................................12
`
`Amgen Inc. v. Hoechst Marion Roussel, Inc.,
`314 F.3d 1313 (Fed. Cir. 2003)......................................................................................9, 13, 28
`
`Amgen Inc. v. Sanofi,
`872 F.3d 1367 (Fed. Cir. 2017)................................................................................................16
`
`Amgen Inc. v. Sanofi, Aventisub LLC,
`987 F.3d 1080 (Fed. Cir. 2021)....................................................................................15, 16, 19
`
`Anderson v. Liberty Lobby, Inc.,
`477 U.S. 242 (1986) ...............................................................................................................7, 8
`
`Baxalta Inc. v. Genentech, Inc.,
`2022 WL 420479 (D. Del. Jan. 13, 2022) ..........................................................................15, 16
`
`In re Biogen ‘755 Patent Litig.,
`335 F. Supp. 3d 688 (D.N.J. 2018) ..........................................................................................14
`
`In re Brana,
`51 F.3d 1560 (Fed. Cir. 1995)..................................................................................................27
`
`Brown v. Armstrong,
` 957. F. Supp. 1293 (D. Mass. 1997), aff’d, 129 F.3d 1252 (1st Cir. 1997) ............................12
`
`ii
`
`

`

`Case 1:18-cv-12029-ADB Document 439 Filed 07/27/22 Page 4 of 39
`
`
`
`Camona v. Toledo,
`215 F.3d 124 (1st Cir. 2000) ....................................................................................................13
`
`Cephalon, Inc. v. Watson Pharms., Inc.,
`707 F.3d 1330 (Fed. Cir. 2013)..................................................................................................9
`
`CFMT, Inc. v. Yieldup Intern. Corp.,
`349 F.3d 1333 (Fed Cir. 2003).....................................................................................13, 18, 23
`
`Chiron Corp. v. Genentech, Inc.,
`363 F.3d 1247 (Fed. Cir. 2004)................................................................................................13
`
`CMI Capital Market Inv., LLC v. González-Toro,
`520 F.3d 58 (1st Cir. 2008) ......................................................................................................12
`
`In re Depomed Pat. Litig.,
`2016 WL 7163647 (D.N.J. Sept. 30, 2016), aff’d, 919 F.3d 1333 (Fed. Cir.
`2019) ........................................................................................................................................19
`
`Edwards Lifesciences AG v. CoreValve, Inc.,
`699 F.3d 1305 (Fed. Cir. 2012)........................................................................................2, 3, 27
`
`Eli Lilly & Co. v. Actavis Elizabeth LLC,
`435 F. App’x 917 (Fed. Cir. 2011) ....................................................................................28, 29
`
`Erfindergemeinschaft UroPep GbR v. Eli Lilly & Co.,
`276 F. Supp. 3d 629 (E.D. Tex. 2017), aff’d, 739 F. App’x 643 (Fed. Cir.
`2018) ................................................................................................................................ passim
`
`Falko-Gunter Falkner v. Inglis,
`448 F.3d 1357 (Fed. Cir. 2006)..................................................................................................9
`
`Feliciano v. Rhode Island,
`160 F.3d 780 (1st Cir. 1998) ................................................................................................8, 12
`
`Geneva Pharms., Inc. v. GlaxoSmithKline PLC,
`349 F.3d 1373 (2003) ...............................................................................................................26
`
`Idenix Pharms. LLC v. Gilead Scis. Inc.,
`941 F.3d 1149 (Fed. Cir. 2019)....................................................................................17, 18, 21
`
`Invitrogen Corp. v. Clontech Labs., Inc.,
`429 F.3d 1052 (Fed. Cir. 2005)............................................................................................8, 29
`
`Johns Hopkins Univ. v. CellPro, Inc.,
`152 F.3d 1342 (Fed. Cir. 1998)..................................................................................................8
`
`iii
`
`

`

`Case 1:18-cv-12029-ADB Document 439 Filed 07/27/22 Page 5 of 39
`
`
`
`Kirk v. Raymark Indus., Inc.,
`61 F.3d 147 (3d Cir. 1995).......................................................................................................13
`
`McRO, Inc. v. Bandai Namco Games Am. Inc.,
`959 F.3d 1091 (Fed. Cir. 2020)................................................................................................29
`
`Merck Sharp & Dohme Corp. v. Genentech,
`PGR2021-00036 (July 24, 2021) (Ex. CZ) ..............................................................................15
`
`Montfort-Rodriguez v. Rey-Hernandez,
`504 F.3d 221 (1st Cir. 2007) ......................................................................................................8
`
`MorphoSys AG v. Janssen Biotech, Inc.,
`358 F. Supp. 3d 354 (D. Del. 2019) ...................................................................................16, 19
`
`Ortho-McNeil Pharm., Inc. v. Mylan Lab’ys, Inc.,
`2006 WL 2865469 (D.N.J. Oct. 5, 2006), aff'd, 520 F.3d 1358 (Fed. Cir.
`2008) ........................................................................................................................................28
`
`Pfizer Inc. v. Teva Pharms. USA, Inc.,
`555 F. App’x 961 (Fed. Cir. 2014) ............................................................................................9
`
`PPG Indus., Inc. v. Guardian Indus. Corp.,
`75 F.3d 1558 (Fed. Cir. 1996)....................................................................................................9
`
`Resolution Trust Corp. v. Fidelity & Deposit Co.,
`1998 WL 2030798 (D.N.J. Jan. 27, 1998) ...............................................................................12
`
`Rosco, Inc. v. Mirror Lite Co.,
`304 F.3d 1373 (Fed. Cir. 2002)..........................................................................................29, 30
`
`SanDisk Corp. v. Kingston Tech. Co., Inc.,
`863 F. Supp. 2d 815 (W.D. Wis. 2012) ...................................................................................13
`
`Sandt Tech., Ltd. v. Resco Metal & Plastics Corp.,
`264 F.3d 1344 (Fed. Cir. 2001)..........................................................................................29, 30
`
`Soitec, S.A. v. Silicon Genesis Corp.,
`2002 WL 34453284 (D. Mass. Feb. 25, 2002) ........................................................................13
`
`In re Varrasso,
`37 F.3d 760 (1st Cir. 1994) ........................................................................................................8
`
`In re Wands,
`858 F.2d 731 (Fed. Cir. 1988)......................................................................................1, 8, 9, 16
`
`Wyeth & Cordis Corp. v. Abbott Lab’ys,
`720 F.3d 1380 (Fed. Cir. 2013)................................................................................................17
`
`iv
`
`

`

`Case 1:18-cv-12029-ADB Document 439 Filed 07/27/22 Page 6 of 39
`
`
`
`Statutes
`
`21 U.S.C. § 355 ..............................................................................................................................18
`
`35 U.S.C. § 112 ................................................................................................................................8
`
`35 U.S.C. § 282 ..............................................................................................................................29
`
`Other Authorities
`
`Fed. R. Civ. P. 56(c) ........................................................................................................................7
`
`Local Rule 56.1 ....................................................................................................................4, 11, 12
`
`
`
`
`
`v
`
`

`

`Case 1:18-cv-12029-ADB Document 439 Filed 07/27/22 Page 7 of 39
`
`
`
`TABLE OF ABBREVIATIONS
`
`
`Description
`U.S. Patent No. 8,586,045 (Ex. E)
`U.S. Patent No. 9,884,907 (Ex. AL)
`U.S. Patent No. 9,884,908 (Ex. AO)
`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
`Calcitonin gene-related peptide
`Transcript of Dr. Andrew Charles (Jan. 27, 2022) (Ex. R)
`Food and Drug Administration
`Final Written Decision of IPR2018-01427 (Feb. 18, 2020) (Ex. C)
`Inter partes review
`ECF No. 316, Local Rule 56.1 Statement of Undisputed Material
`Facts in Support of Plaintiffs’ Motion for Summary Judgment
`Regarding Judicial Estoppel
`Eli Lilly and Company
`ECF No. 290 (Eli Lilly and Company’s Memorandum in Support of
`its Motion for Summary Judgment of Invalidity for Lack of
`Enablement)
`ECF No. 320 (Plaintiffs’ Memorandum in Support of its Motion to
`Exclude the Expert Testimony of Dr. Diane Mould)
`U.S. Patent Nos. 8,586,045; 9,884,907; and 9,884,908
`Person of ordinary skill in the art
`Patent Trial and Appeal Board
`United States Patent and Trademark Office
`ECF No. 295 (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 for Written Description)
`Concurrently-filed Plaintiffs’ Responsive Statement of Material Facts
`Teva Pharmaceuticals International GmbH and Teva Pharmaceuticals
`USA, Inc.
`
`Abbreviation
`’045 patent
`’907 patent
`’908 patent
`Abdiche Decl.
`
`CGRP
`Charles Tr.
`FDA
`FWD
`IPR
`ECF No. 316,
`Judicial Estoppel
`SUMF
`Lilly
`Mot.
`
`Mould Daubert
`Mem.
`Patents-in-suit
`POSA
`PTAB
`PTO
`SOF
`
`RMF
`Teva
`
`
`
`
`
`
`vi
`
`

`

`Case 1:18-cv-12029-ADB Document 439 Filed 07/27/22 Page 8 of 39
`
`
`
`I.
`
`INTRODUCTION
`
`Lilly’s Motion for Summary Judgment of Invalidity for Lack of Enablement (ECF
`
`No. 290) (“Mot.”) and its accompanying 101-page, 411-paragraph statement of material facts
`
`(ECF No. 291) (“SOF”) only reinforces why the Court should grant Teva’s co-pending Motion for
`
`Summary Judgment of Judicial Estoppel (ECF No. 314). The one-sided narrative Lilly advances
`
`in its motion completely contradicts the facts it persuaded the Patent Trial and Appeal Board
`
`(“PTAB”) to adopt in the inter partes review (“IPR”) proceedings when the PTAB canceled Teva’s
`
`composition of matter patents. The “extensive” prior art describing anti-CGRP antagonist
`
`antibodies in “several publications” from the IPRs, is now “limited” and describes “[o]nly a small
`
`number of murine antibodies.” What were “common way[s] to measure antagonist activity” using
`
`“conventional means” such as “routine and conventional assays” in the IPRs, are now only good
`
`for producing “inconsistent, experiment- and condition-dependent results.” Techniques for
`
`making humanized anti-CGRP antagonist antibodies that were “routine” and “conventional” in the
`
`IPRs now create “extensive obstacles and layers of unpredictability.” Lilly goes so far as to assert
`
`in its motion that a person of ordinary skill in the art (“POSA”)—the exact same POSA the PTAB
`
`adopted in the IPRs—would have “no experience with . . . anything resembling the claimed
`
`methods” and would be working from a “blank canvas.” Lilly’s complete reversal in position on
`
`the skill level of the POSA, predictability of the science, and knowledge in the field to advance
`
`different defenses in this Court is precisely why the doctrine of judicial estoppel exists.
`
`To prevail on its enablement defense, Lilly must prove by clear and convincing evidence
`
`that it would take “undue experimentation” to practice the invention claimed in Teva’s patents.
`
`“Whether undue experimentation is needed is not a single, simple factual determination, but rather
`
`is a conclusion reached by weighing many factual considerations.” In re Wands, 858 F.2d 731,
`
`1
`
`

`

`Case 1:18-cv-12029-ADB Document 439 Filed 07/27/22 Page 9 of 39
`
`
`
`737 (Fed. Cir. 1988). Lilly’s core argument is that it would take undue experimentation to make
`
`and use the “claimed antibodies”—i.e., anti-CGRP antagonist antibodies. This argument misses
`
`the mark because the claims here are for methods of using antibodies to treat headache, not for the
`
`antibodies themselves. Where, as here, the inventions claimed are new methods of using a known
`
`class of molecules, courts evaluate whether the inventive methods are enabled, not the prior art
`
`class of molecules. There is substantial evidence that anti-CGRP antagonist antibodies were well
`
`known and the processes for screening and humanizing them were routine and conventional in the
`
`field of antibody engineering. For the reasons set forth in Teva’s co-pending Motion for Summary
`
`Judgment of Judicial Estoppel, Lilly should be precluded from arguing otherwise. In any event,
`
`disputed issues of fact on every one of the eight factors underpinning the enablement determination
`
`(the so-called “Wands factors”) preclude summary judgment.
`
`Lilly advances a second argument—namely, it would take undue experimentation to
`
`practice the full scope of the “claimed methods.” See Mot. at 23. Although this argument focuses
`
`on the correct invention, it fares no better. Lilly makes much of its own development efforts and
`
`the high bar set by the FDA to obtain regulatory approval for drugs in the United States. Lilly’s
`
`argument boils down to its assertion that “[t]esting in humans was thus essential” to enable an
`
`“effective amount” of anti-CGRP antagonist antibodies that could be used to treat headaches. Id.
`
`Courts have repeatedly rejected arguments that the level of experimentation, testing, and
`
`optimization required for commercial or regulatory purposes sets the bar for enablement. Rather,
`
`“it has long been recognized that when experimentation on human subjects is inappropriate, as in
`
`the testing and development of drugs and medical devices, the enablement requirement may be
`
`met by animal tests or in vitro data.” Edwards Lifesciences AG v. CoreValve, Inc., 699 F.3d 1305,
`
`1309 (Fed. Cir. 2012) (citations omitted). Lilly’s Motion ignores substantial evidence explaining
`
`2
`
`

`

`Case 1:18-cv-12029-ADB Document 439 Filed 07/27/22 Page 10 of 39
`
`
`
`that the animal assays and data reported in the specification of the patents is highly correlated with
`
`and predictive of efficacy in the treatment of migraines, which represent the vast majority of
`
`headache disorders encountered by a POSA. No more is required under patent law. As set forth
`
`below, these many factual disputes and competing expert testimony on these highly scientific
`
`topics make summary judgment inappropriate.
`
`II.
`
`FACTUAL BACKGROUND
`
`A.
`
`The Person of Ordinary Skill in the Art.
`
`The parties agree that the hypothetical POSA has specialized expertise in two fields. First,
`
`the POSA has a “Ph.D. in a relevant field, such as immunology, biochemistry, or pharmacology,
`
`with several years of post-doctoral experience in antibody engineering, pharmacokinetics, and
`
`pharmacodynamics.” SOF ¶¶ 223–24. Second, the POSA has a “M.D. with a residency or
`
`specialty in neurology, and several years of experience studying CGRP or treating patients with a
`
`CGRP-related disease, such as migraine headaches.” Id. Throughout its motion, Lilly attempts to
`
`minimize the skill and knowledge in the art but, as set forth below, the fields of antibody
`
`engineering and CGRP biology were mature and predictable by 2005. RMF ¶¶ P19, P51–P59,
`
`P61–78.
`
`B. Making Humanized Anti-CGRP Antagonist Antibodies Was Predictable and
`Routine
`
`In general, there are three basic steps to make humanized anti-CGRP antagonist antibodies:
`
`(1) generating non-human antibodies that bind to human CGRP; (2) selecting the antibodies that
`
`not only bind to CGRP but also antagonize it; and (3) humanizing those anti-CGRP antagonist
`
`antibodies. RMF ¶ P62. Although the techniques used to perform each of these steps may seem
`
`time-consuming and technical to lay persons, they are conventional and routine to POSAs in the
`
`field of antibody engineering. As Teva explains in more detail in its opposition to Lilly’s Motion
`
`3
`
`

`

`Case 1:18-cv-12029-ADB Document 439 Filed 07/27/22 Page 11 of 39
`
`
`
`for summary judgment on written description, the specification discloses these prior art methods
`
`for making, screening, and humanizing the antibodies used in the invention.
`
`Making murine (mouse) anti-CGRP antibodies. By 2005, “murine monoclonal anti-CGRP
`
`antagonist antibod[ies] that bind[] to human CGRP . . . were extensively described in the prior
`
`art.” Local Rule 56.1 Statement of Undisputed Material Facts in Support of Plaintiffs’ Motion for
`
`Summary Judgment Regarding Judicial Estoppel (“ECF No. 316, Judicial Estoppel SUMF”) ¶ 7;
`
`see RMF ¶¶ PP63–64. As Lilly explained to the PTAB, Teva’s patents “acknowledge[] the routine
`
`nature of generating anti-CGRP antagonist antibodies, stating that ‘anti-CGRP antagonist
`
`antibodies may be made by any method known in the art’” and, by 2005, there were “established
`
`and conventional techniques for antibody stimulation and production.” ECF No. 316, Judicial
`
`Estoppel SUMF ¶ 8. The process for generating anti-CGRP antagonist antibodies against human
`
`CGRP would have been “straightforward” because, among other things “researchers had already
`
`generated anti-CGRP antagonist antibodies against human CGRP” and “human CGRP was readily
`
`available for use in the laboratory, and in fact was commercially available.” Judicial Estoppel
`
`SUMF ¶ 10; see RMF ¶ PP64. The “techniques for making” “murine monoclonal anti-CGRP
`
`antagonist antibod[ies] that bind[] to human CGRP” have been “extensively described in the prior
`
`art.” ECF No. 316, Judicial Estoppel SUMF ¶ 10; see RMF ¶¶ PP65–67.
`
`Identifying anti-CGRP antagonists. Not all antibodies that bind to CGRP are “anti-CGRP
`
`antagonist antibodies.” Rather, the Court’s construction requires the antibodies used in the claimed
`
`methods to both “[1] bind to CGRP and [2] inhibit CGRP biological activity and/or downstream
`
`pathway(s) mediated by CGRP signaling.” See ECF No. 101 at 11. Teva’s patents describe the
`
`use of a high-throughput, automated method to identify anti-CGRP antagonist antibodies, referred
`
`to as the “cAMP activation assay.” RMF ¶¶ PP70–72, P98–99. By 2005, “measuring inhibition
`
`4
`
`

`

`Case 1:18-cv-12029-ADB Document 439 Filed 07/27/22 Page 12 of 39
`
`HIGHLY CONFIDENTIAL – OUTSIDE COUNSEL ONLY
`
`of cAMP activation [was] a conventional means of evaluating whether an anti-CGRP antagonist
`
`antibody is, in fact, an anti-CGRP antagonist” and was recognized to be a “common way to
`
`measure antagonistic activity.” ECF No. 316, Judicial Estoppel SUMF ¶ 27. The assay was so
`
`widely used within the field that it was commercially available as a kit, called the HitHunterTM
`
`Enzyme Fragment Complementation Assay. RMF ¶¶ P71–72. By 2004, these assays were
`
`adapted to 384-well and 1,536-well formats. Id. The high-throughput, automated nature of these
`
`assays allowed labs to screen hundreds of thousands of compounds to be tested simultaneously
`
`over the course of a few days. Id. Thus, screening for and confirming an antibody’s ability “to
`
`bind[] to human aCGRP [and] inhibit[] it from binding to its receptor and thereby suppress[] cAMP
`
`activation in cells . . . would have been a natural and routine course of antibody engineering.” ECF
`
`No. 316, Judicial Estoppel SUMF ¶ 36.
`
`Humanizing anti-CGRP antagonist antibodies. “[H]umanization was a well-established
`
`and routine procedure by 2005.” Id. ¶ 44; see RMF ¶ P73. The prior art “describe[d] routine and
`
`conventional humanization technologies that had been recognized as the ‘gold standard’ years
`
`before 2005.” ECF No. 316, Judicial Estoppel SUMF ¶ 45. Using those prior art methods, a
`
`POSA “would have readily been able to” humanize an antibody “while maintaining or even
`
`improving the binding specificity and affinity for human CGRP.” ECF No. 316, Judicial Estoppel
`
`SUMF ¶ 46; see RMF ¶ P74. Thus, “[b]y 2005, routine humanization techniques were well-known
`
`to result in humanized monoclonal antibodies that maintained the binding affinities of donor
`
`murine antibodies . . . .
`
` Indeed, humanization had become commonplace in antibody
`
`engineering.” ECF No. 316, Judicial Estoppel SUMF ¶ 46. The PTAB found as a factual matter
`
`that “a person of ordinary skill would have considered it routine and would have had a reasonable
`
`expectation to make the claimed antibody.” Id. ¶ 19.
`
`5
`
`

`

`Case 1:18-cv-12029-ADB Document 439 Filed 07/27/22 Page 13 of 39
`
`
`
`Human antibodies. Claims 17, 19, 20, 24, and 27 of the ’045 patent include “human anti-
`
`CGRP antagonist antibodies.” A “human antibody” is an antibody “having an amino acid
`
`sequence corresponding to that of an antibody produced by a human” as opposed to antibody
`
`produced by, for example, a mouse. Ex. E (’045 patent) at 13:26–30. Methods for making “human
`
`antibodies” were well-known and routine to POSAs by 2005. RMF ¶¶ P75–76. The most common
`
`process generally followed the same approach described above, except that commercially available
`
`“transgenic” animals are injected with CGRP. See RMF ¶¶ P76, 97.
`
`C.
`
`CGRP Was Well-Characterized and Tied to Most Headaches that Required
`Treatment.
`
`By 2005, CGRP and its role in headache and migraine had been studied for decades and
`
`was the subject of thousands of peer-reviewed articles. RMF ¶ P53. Researchers had
`
`demonstrated that nerve fibers were known to release CGRP during migraine and cluster headache
`
`and that CGRP levels were elevated during migraine attacks. RMF ¶ P54. Researchers found it
`
`“very clear” that infusion of CGRP “caused headache in virtually all migraine sufferers, whereas
`
`placebo did not.” RMF ¶ P55. Articles in 2001 had concluded that “[e]vidence [wa]s
`
`accumulating that inappropriate release of CGRP [wa]s a potential causative factor in several
`
`diseases, including migraine . . . .” Id. In fact, drugs that disrupted the CGRP pathway were
`
`known to be effective for migraine and other forms of headache and several were in routine clinical
`
`use. RMF ¶ P56. Although researchers as of 2005 were focused principally on the role of CGRP
`
`in migraines due to the need for improved migraine treatments, the role of CGRP was generally
`
`implicated in intracranial pain (i.e., head pain), and it was known that many types of severe
`
`headaches respond to drugs that act on the CGRP pathway. RMF ¶ P57.
`
`Not surprisingly, “[t]he excellent correlation between CGRP release and migraine
`
`headache has long pointed to the potential usefulness of a specific CGRP antagonist in the
`
`6
`
`

`

`Case 1:18-cv-12029-ADB Document 439 Filed 07/27/22 Page 14 of 39
`
`
`
`treatment of primary headache.” RMF ¶ P58. Cell-based assays (in vitro) for evaluating the effect
`
`of experimental compounds on CGRP biological function were well established and in routine use.
`
`RMF ¶ P78. Furthermore, animal models (in vivo) that replicate aspects of migraine
`
`pathophysiology were well established in the prior art. RMF ¶¶ P80–85. Importantly, the “closed
`
`cranial window” model in rats had been used extensively in the prior art and had been shown to
`
`be highly correlated with and predictive of efficacy for treating migraine. RMF ¶¶ P86–88.
`
`At the time, several pharmaceutical companies were known to be developing small
`
`molecule drugs (called “gepants”) that targeted CGRP receptors. RMF ¶ P59. The most advanced
`
`of these drugs was known as BIBN4096BS, which had been tested in humans in two small clinical
`
`trials by 2005. Id. Most significantly, in 2004, a research team led by Jes Olesen published in the
`
`New England Journal of Medicine the results of a trial that evaluated various doses of
`
`BIBN4096BS in 126 patients suffering from migraine. Id. That study was designed to “identify
`
`the lowest dose of a drug that is superior to placebo (the minimal effective dose), as evidenced by
`
`a rate of response of at least 60 percent.” Id. Ultimately Olesen concluded that 2.5 mg was the
`
`minimal effective dose. Id. Studies like Olsen—which are called “dose range studies”—were a
`
`routine part of drug development. Id.
`
`III. LEGAL STANDARD
`
`A.
`
`Summary Judgment
`
`The Court may grant summary judgment only if Lilly shows “that there is no genuine issue
`
`as to any material fact and that the moving party is entitled to judgment as a matter of law.” Fed.
`
`R. Civ. P. 56(c). “[T]he substantive law”—here, the law of enablement—“will identify which
`
`facts are material.” Anderson v. Liberty Lobby, Inc., 477 U.S. 242, 248 (1986). To determine if a
`
`dispute about a material fact is “genuine,” the court must decide whether “the evidence is such that
`
`a reasonable [factfinder] could return a verdict for the nonmoving party.” Id. The Court considers
`
`7
`
`

`

`Case 1:18-cv-12029-ADB Document 439 Filed 07/27/22 Page 15 of 39
`
`
`
`only admissible evidence. See Feliciano v. Rhode Island, 160 F.3d 780, 787 (1st Cir. 1998). “The
`
`evidence of the non-movant is to be believed, and all justifiable inferences are to be drawn in his
`
`favor.” Anderson, 477 U.S. at 255. Moreover, a court may not choose between competing
`
`plausible inferences “under the banner of summary judgment.” In re Varrasso, 37 F.3d 760, 764
`
`(1st Cir. 1994). Where evidence “points in different directions” and “support[s] conflicting
`
`inferences,” summary judgment should be denied. Montfort-Rodriguez v. Rey-Hernandez, 504
`
`F.3d 221, 229 (1st Cir. 2007) (internal quotation omitted). Summary judgment of patent invalidity
`
`is improper if the record contains “conflicting evidence, which requires resolution by a jury” and
`
`is particularly improper where questions of scientific fact are in dispute. See Invitrogen Corp. v.
`
`Clontech Labs., Inc., 429 F.3d 1052, 1068 (Fed. Cir. 2005) (“[u]nsubstantiated attorney argument
`
`regarding the meaning of technical evidence is no substitute for competent . . . expert testimony”
`
`and “cannot[] support [defendant’s] burden on summary judgment”).
`
`B.
`
`Enablement
`
`The enablement requirement of Section 112 requires the specification of a patent to “enable
`
`any person skilled in the art to which it pertains, or with which it is most nearly connected, to make
`
`and use” the invention. 35 U.S.C. § 112. Enablement is a question of law evaluating whether
`
`“undue experimentation would have been needed to practice the invention based upon underlying
`
`factual inquiries. Johns Hopkins Univ. v. CellPro, Inc., 152 F.3d 1342, 1354 (Fed. Cir. 1998).
`
`The seminal enablement case is In re Wands, 858 F.2d 731, 733–34, 740 (Fed. Cir. 1988). In that
`
`case, the Court held that claims directed toward the use of functionally-defined monoclonal
`
`antibodies that had high affinity for a protein associated with the hepatitis B virus were enabled.
`
`Id. at 733–34, 740 (“Reasonably interpreted, Wands’ record indicates that, in the production of
`
`high-affinity IgM antibodies against [the hepatitis B protein], the amount of effort needed to obtain
`
`such antibodies is not excessive.”). In Wands, the Federal Circuit identified a set of eight non-
`
`8
`
`

`

`Case 1:18-cv-12029-ADB Document 439 Filed 07/27/22 Page 16 of 39
`
`
`
`exclusive factual considerations to be considered “in determining whether a disclosure would
`
`require undue experimentation” (referred to as the “Wands factors”): “(1) the quantity of
`
`experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or
`
`absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the
`
`relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the
`
`breadth of the claims.” Id. at 737. Because patents are presumed valid, Lilly bears “the burden of
`
`clearly and convincingly proving facts showing that the claims were not enabled.” See A