UNITED ST ATES PA TENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ELI LILLY AND COMPANY,
`Petitioner
`
`V.
`
`TEVA PHARMACEUTICALS INTERNATIONAL GMBH,
`Patent Owner
`
`Patent No. 11,028,161
`
`DECLARATION OF DR. EVERS
`
`I declare that all statements made herein of my knowledge are true, that all
`
`statements made herein on information and belief are believed to be true, and that
`
`these statements were made with the knowledge that willful false statements and
`
`the like so made are punishable by fine or imprisonment, or both, under Section
`
`1001 of Title 18 ~
`
`e United States Code.
`
`By: I ~ ~ Date:
`
`

`

`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION ....................................................................................... 1
`
`II.
`
`QUALIFICATIONS .................................................................................... 1
`
`III. U.S. PATENT LAW CONCEPTS ............................................................... 3
`
`IV. BACKGROUND AND STATE OF THE ART ........................................... 6
`
`A. Migraine Classifications and Treatment ............................................. 6
`
`B.
`
`C.
`
`Limitations of the Standard of Care in Migraine Prevention .............10
`
`Anti-CGRP Antibodies Were Known and Tested in the Art..............13
`
`D.
`
`The Prior Art References ..................................................................18
`
`1.
`
`2.
`
`3.
`
`Dodick (EX1003) ....................................................................18
`
`Sun (EX1006) .........................................................................20
`
`Sharma (EX1007) ...................................................................23
`
`V.
`
`LEVEL OF ORDINARY SKILL IN THE ART .........................................24
`
`VI. THE ’161 PATENT ....................................................................................25
`
`A. Overview ..........................................................................................25
`
`B.
`
`C.
`
`The Claims of the ’161 Patent ...........................................................26
`
`Disclosures of the ’161 Patent ...........................................................28
`
`1.
`
`2.
`
`3.
`
`Specification ...........................................................................28
`
`Examples 1-4 ..........................................................................29
`
`Example 5 ...............................................................................30
`
`D.
`
`Claim Construction ...........................................................................31
`
`1.
`
`2.
`
`“subject having refractory migraine” (claim 1) .......................31
`
`“a subject who has been treated with” a medication ................37
`
`i
`
`
`

`

`VII. ANALYSIS OF THE ’180 APPLICATION ...............................................37
`
`VIII. GROUND 1: CLAIMS 1-30 WOULD HAVE BEEN OBVIOUS
`OVER DODICK, SUN, AND SHARMA .....................................................47
`
`A. A POSA would have been motivated to treat patients that
`discontinued at least two preventives because of “no clinically
`meaningful improvement” or “intolerable” side effects.....................48
`
`1.
`
`2.
`
`Sun taught and suggested a “method of treating or
`preventing migraine in a subject having refractory
`migraine, the method comprising: selecting a subject who
`has been treated with two or more different preventative
`migraine treatments wherein at least one of the
`preventative migraine treatments is selected from
`topiramate, carbamazepine, divalproex sodium, sodium
`valproate, valproic acid, divalproex, flunarizine,
`candesartan, pizotifen, amitriptyline, venlafaxine,
`nortriptyline, duloxetine, atenolol, nadolol, metoprolol,
`propranolol, bisopropol, timolol, onabotulinumtoxin A,
`lisinopril, and oxeterone; and administering to the subject
`a therapeutically effective amount of a humanized
`monoclonal anti-calcitonin gene-related peptide (CGRP)
`antagonist antibody,” as claimed .............................................51
`
`Dodick and Sharma taught “administering to the subject
`a therapeutically effective amount of a humanized
`monoclonal anti-calcitonin gene-related peptide (CGRP)
`antagonist antibody comprising the amino acid sequence
`of the heavy chain variable region set forth in SEQ ID
`NO: 63 and the amino acid sequence of the light chain
`variable region set forth in SEQ ID NO: 62,” as claimed ........66
`
`3.
`
`A POSA would have been motivated to use
`galcanezumab in the methods of treatment taught by Sun .......72
`
`B.
`
`Reasonable Expectation of Success ...................................................80
`
`1.
`
`Anti-CGRP mAbs had demonstrated efficacy in patients
`that failed prior preventives ....................................................82
`
`ii
`
`
`

`

`2.
`
`3.
`
`Targeting CGRP was reasonably expected to treat
`refractory patients ...................................................................87
`
`Planned clinical trials indicate a reasonable expectation
`of success ................................................................................92
`
`C.
`
`A POSA would have been motivated to treat patients that were
`contraindicated for two or more migraine preventives with
`galcanezumab ...................................................................................94
`
`D. Dependent Claims 2-30 .....................................................................96
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`Claim 2 ...................................................................................97
`
`Claims 3, 4, 5, 6, and 7 ...........................................................97
`
`Claim 8 ...................................................................................98
`
`Claims 9 and 10 ......................................................................98
`
`Claims 11 and 12 ....................................................................99
`
`Claims 13, 14, and 16 .............................................................99
`
`Claims 15 and 18 .................................................................. 100
`
`Claim 17 ............................................................................... 100
`
`Claims 19 .............................................................................. 100
`
`10. Claims 20 and 21 .................................................................. 100
`
`11. Claims 22, 23, and 24 ........................................................... 101
`
`12. Claims 25 and 29 .................................................................. 101
`
`13. Claim 26 ............................................................................... 101
`
`14. Claim 27 ............................................................................... 102
`
`15. Claim 28 ............................................................................... 102
`
`16. Claim 30 ............................................................................... 103
`
`iii
`
`
`

`

`IX. GROUND 2: CLAIMS 1-30 WOULD HAVE BEEN OBVIOUS
`OVER DODICK IN VIEW OF SHARMA ................................................. 103
`
`A. A POSA would have been motivated to treat “contraindicated”
`and “select[ed]” patients with anti-CGRP mAbs ............................. 105
`
`1.
`
`2.
`
`Patients with contraindications to two or more preventive
`migraine treatments would have been particularly
`suitable for treatment with anti-CGRP mAbs ........................ 107
`
`Patients previously treated with two or more preventive
`migraine treatments were particularly suitable for
`treatment with anti-CGRP mAbs .......................................... 109
`
`B.
`
`Dodick and Sharma taught and suggested the claimed method
`of using galcanezumab to treat “contraindicated” patients .............. 112
`
`1.
`
`2.
`
`3.
`
`“A method of treating or preventing migraine in a subject
`having refractory migraine” .................................................. 112
`
`“[S]electing a subject who has been treated with two or
`more different preventative migraine treatments wherein
`at least one of the preventative migraine treatments is
`selected from topiramate, carbamazepine, divalproex
`sodium, sodium valproate, valproic acid, divalproex,
`flunarizine, candesartan, pizotifen, amitriptyline,
`venlafaxine, nortriptyline, duloxetine, atenolol, nadolol,
`metoprolol, propranolol, bisopropol, timolol,
`onabotulinumtoxinA, lisinopril, and oxeterone” .................... 116
`
`“[A]dministering to the subject a therapeutically effective
`amount of a humanized monoclonal anti-calcitonin gene-
`related peptide (CGRP) antagonist antibody comprising
`the amino acid sequence of the heavy chain variable
`region set forth in SEQ ID NO: 63 and the amino acid
`sequence of the light chain variable region set forth in
`SEQ ID NO: 62” ................................................................... 119
`
`C.
`
`A POSA would have reasonably expected galcanezumab to
`effectively treat “contraindicated” and “select[ed]” patients ........... 120
`
`D. Dependent Claims 2-30 ................................................................... 124
`
`iv
`
`
`

`

`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`Claim 2 ................................................................................. 124
`
`Claims 3, 4, 5, 6, and 7 ......................................................... 127
`
`Claim 8 ................................................................................. 130
`
`Claims 9 and 10 .................................................................... 131
`
`Claims 11 and 12 .................................................................. 134
`
`Claims 13, 14, and 16 ........................................................... 136
`
`Claim 17 ............................................................................... 138
`
`Claims 15 and 18 .................................................................. 140
`
`Claim 19 ............................................................................... 141
`
`10. Claims 20 and 21 .................................................................. 143
`
`11. Claims 22, 23, and 24 ........................................................... 145
`
`12. Claims 25 and 29 .................................................................. 147
`
`13. Claim 26 ............................................................................... 148
`
`14. Claim 27 ............................................................................... 152
`
`15. Claim 28 ............................................................................... 154
`
`16. Claim 30 ............................................................................... 155
`
`v
`
`
`

`

`I. INTRODUCTION
`
`1.
`
`I, Stefan Evers, M.D., Ph.D. have been retained by Finnegan,
`
`Henderson, Farabow, Garrett & Dunner, LLP, counsel for Petitioner Eli Lilly and
`
`Company (“Lilly”), as an independent expert in the field of neurology, including
`
`the treatment of migraine, with a research focus on calcitonin gene-related peptide
`
`(“CGRP”).
`
`2.
`
`I am being compensated for the time I spend on this matter, but my
`
`compensation is not contingent upon my opinions or the outcome of this or any
`
`other proceeding.
`
`II. QUALIFICATIONS
`
`3.
`
`I studied medicine at the University of Münster, Germany, and
`
`received my degree of doctor of medicine (M.D.) from the University of Münster
`
`in 1992. I received a study grant from the Protestant Church of Germany.
`
`Thereafter, I trained in neurology at the University Hospital in Münster and also
`
`trained one year in psychiatry and became certified Board Member of Neurology
`
`in 1999. I received a certified sub-specialization in Pain Therapy (1999), in
`
`Intensive Care Medicine (2004), and in Sleep Medicine (2015). I became a
`
`consultant in Neurology at the University Hospital of Münster in 2002 and
`
`received a Professorship in Neurology and Clinical Neurophysiology in 2005. In
`
`1
`
`
`

`

`2012, I moved to Lindenbrunn Hospital where I am working now as Head of the
`
`Department of Neurology.
`
`4.
`
`From the beginning on, my clinical work and my research interest had
`
`a focus on pain medicine, in particular on headache research. I stayed one year
`
`(1998) at the Institute of Neurology, University College of London under the
`
`supervision of Professor Goadsby and did research on neuropeptides in cluster
`
`headache. From 2003 to 2007, I was President of the German Migraine and
`
`Headache Society (DMKG), and from 2003 to 2010, I was chair of the Headache
`
`Panel of the European Federation of Neurological Societies (EFNS), and from
`
`2016 to 2020, I was chair of the Headache Panel of the European Academy of
`
`Neurology (EAN). I am a Fellow of the EAN (FEAN).
`
`5. My main activities in the last 10 years were due to my position as
`
`General Secretary of the International Headache Society (IHS) which ended in
`
`September 2021 as the maximum turn was over. In this position, I was responsible
`
`for the administration and the organization of all activities of IHS.
`
`6.
`
`I published in total (December 2021) 272 original papers with peer
`
`review, 208 review papers, 10 books, and 116 book chapters. The total number of
`
`my congress contributions is 693. In 2020, I was a “highly cited researcher” in the
`
`Clarivate Web of Science.
`
`2
`
`
`

`

`7.
`
`I am a member, among others, of the following organizations: German
`
`Migraine and Headache Society; International Headache Society; International
`
`Association for the study of Pain; German Society of Neurology; European
`
`Academy of Neurology; and local medical Ethics Committee.
`
`8.
`
`Beside medicine, I studied musicology at the University of Münster
`
`and received a doctor of philosophy (Ph.D.) in 2003. A copy of my curriculum
`
`vitae is provided in Appendix A.
`
`III. U.S. PATENT LAW CONCEPTS
`
`9.
`
`The opinions I express in this declaration involve the application of
`
`my technical knowledge and experience to evaluating certain prior art with respect
`
`to the ’161 Patent. In preparing this declaration, certain patent law concepts have
`
`been explained to me by legal counsel, including the legal standard for interpreting
`
`claims, as well as those for assessing written description, enablement, and
`
`obviousness.
`
`10.
`
`I understand that patentability must be analyzed from the perspective
`
`of “a person of ordinary skill in the art” (“POSA”) in the same field as the
`
`challenged patent as of the “effective filing date” of the claims. I understand that a
`
`POSA is a hypothetical individual presumed to know the relevant art as of the
`
`“effective filing date” of the claims and has the same level of skill as the ordinary
`
`practitioner of the art at issue.
`
`3
`
`
`

`

`11.
`
`I understand that the Patent Trial and Appeal Board (“PTAB”)
`
`interprets claims based on their ordinary meaning as understood by a POSA at the
`
`time of the “effective filing date” in light of the claim language, patent
`
`specification, and prosecution history.
`
`12.
`
`I understand that the “effective filing date” is evaluated on a claim by
`
`claim basis and that it is (1) the actual filing date of the patent or the application
`
`containing a claim to the invention; or (2) the filing date of the earliest priority
`
`application that provides “written description” and “enables” the subject matter of
`
`the claim.
`
`13.
`
`I understand that a patent claim is not entitled to a filing date of a
`
`priority application as its “effective filing date” if the disclosure in the priority
`
`application lacks written description support for the claim, that is, if the claim is
`
`not sufficiently supported by the disclosure in the earlier filed application. I
`
`understand that the basic inquiry for written description is whether the
`
`specification describes the claimed subject matter such that a POSA would
`
`understand that the inventor actually invented what is claimed.
`
`14.
`
`I understand that a patent claim also cannot benefit from the filing
`
`date of an application if the disclosure in the application lacks enablement, that is,
`
`if the patent specification does not enable a POSA to make and use the full scope
`
`of the claimed subject matter without undue experimentation.
`
`4
`
`
`

`

`15.
`
`I understand that a patent claim is unpatentable for obviousness if any
`
`subject matter within the scope of the claim would have been obvious to a POSA
`
`as of the effective filing date. I understand this entails considering (a) the scope
`
`and content of the prior art, (b) the differences between the prior art and the
`
`claimed invention, (c) the level of ordinary skill in the art, and (d) any secondary
`
`considerations of non-obviousness, such as unexpected results, commercial success
`
`of products or processes using the invention, long-felt need for the invention,
`
`failure of others to make the invention, industry acceptance of the invention, and
`
`copying of the invention by others.
`
`16.
`
`I further understand that a claim may be obvious based on multiple
`
`references combined with one another, as well as based on the knowledge and skill
`
`of a POSA. I also understand there must have been a motivation or other reason
`
`that would have prompted a POSA to combine the features of the prior art. I also
`
`understand that a POSA must have reasonably expected that the combination will
`
`work; that is, obviousness requires a “reasonable expectation of success” in
`
`achieving the claimed subject matter.
`
`17.
`
`I have also been informed that when a claim recites a value, if prior
`
`art discloses a narrow range covering the value, the claimed value is presumed
`
`obvious absent evidence to the contrary.
`
`5
`
`
`

`

`IV. BACKGROUND AND STATE OF THE ART
`
`A. Migraine Classifications and Treatment
`
`18. Migraine is one of the three major primary headache disorders (the
`
`other two being Tension-Type Headache and Cluster Headache). EX1008
`
`(Arulmozhi 2005), 2. Migraine affects approximately 15-ၕ25% of women and 6-ၕ8%
`
`of men, and the literature indicates that its prevalence is increasing. EX1009
`
`(Russo 2015), 5.
`
`19. Migraine patients (“migraineurs”) can be classified into, among
`
`others, episodic migraine (“EM”), defined as fourteen or less headache days per
`
`month and chronic migraine (“CM”), defined as fifteen or more headache days
`
`including at least eight days with migraine headache. EX1010 (Katsarava 2012),
`
`1; EX1009 (Russo 2015), 5. For some patients, migraine attacks include a
`
`complex of focal neurological symptoms, known as aura. EX1009 (Russo 2015),
`
`2.
`
`20. Migraine patients that fail to respond to preventive pharmacological
`
`treatments are known as refractory migraine patients. EX1011 (Martelletti 2014),
`
`2; EX1027 (Goldberg 2015), 2 (“Although it is difficult to determine the exact
`
`number of patients who are refractory to conventional treatment, such patients are
`
`not rare and represent a wake-up call for the development of new compounds in
`
`migraine therapy”). While there was (and is) no accepted definition of
`
`6
`
`
`

`

`“refractory,”1 it was generally recognized to describe patients that failed at least
`
`three drugs belonging from four effective preventive treatment pharmacological
`
`classes (beta blockers, anticonvulsants, calcium antagonists, tricyclic
`
`antidepressants). EX1012 (Paemeleire 2014), 13; EX1011 (Martelletti 2014), 2.2
`
`21. Moreover, definitions of “refractory migraine” include various other
`
`criteria such as the severity of a patient’s migraine symptoms, impact on quality of
`
`
`1 “Refractory” in quotations refers to the colloquial understanding of refractory
`
`migraine, also known as “treatment resistant” or “intractable” migraine. EX1011
`
`(Martelletti 2014), 2; EX1013 (Schulman 2008), 1-2. A POSA would have
`
`recognized that all three of these referred to patients that had previously failed at
`
`least three classes of migraine preventives.
`
`2 While at least one proposed definition for refractory migraine required two
`
`preventive failures in combination with acute treatment failures (EX1013
`
`(Schulman 2008), 3), many deemed this threshold too low. EX1014 (Schulman
`
`2009), 5 (“The most frequently desired change [in the RM definition], reported by
`
`41% of respondents, was to increase the required number of failed preventative
`
`medication classes. The criteria required failure in 2 classes. Of those who desired
`
`a change, 50% would require 3 failed classes and 26% would require 4 failed
`
`classes.”).
`
`7
`
`
`

`

`life, and failure of acute medications. For instance, one proposal for defining
`
`refractory migraine “agreed that to be refractory, a headache must impair quality of
`
`life” and require failure of “adequate trials of abortive medicines.” EX1013
`
`(Schulman 2008), 1, 2.
`
`22. Thus, patients were not considered “refractory” simply because they
`
`failed 1-2 preventive treatments. Rather, it was common for general migraineurs to
`
`have tried and discontinued, due to efficacy or side effects, multiple types of
`
`preventive medications, highlighting the lack of efficacy of existing treatments.
`
`EX1015 (Blumenfeld 2013), 2-4, Figs. 3-4. In fact, a 2013 study found that EM
`
`patients who sought preventive treatment used an average of approximately three
`
`different preventives, while CM patients used an average of approximately four
`
`different preventives. EX1015 (Blumenfeld 2013), 4.
`
`23. While there was no single defined parameter for evaluating clinical
`
`efficacy of prophylactic treatment as of 2016 or 2017, a preventive drug was
`
`considered clinically successful if it reduced migraine frequency and/or symptoms
`
`by at least 30% or 50%, depending on the criteria used. EX1016 (Silberstein
`
`2015), 3; see also EX1017 (Silberstein 2008), 8 (International Headache Society
`
`(“IHS”) Guidelines defining “responder rates” as “either a ≥ 30% or ≥ 50%
`
`reduction in (i) headache days with moderate or severe intensity, (ii) migraine days,
`
`or (iii) migraine episodes compared with baseline period”). It was often the case,
`
`8
`
`
`

`

`however, that patients would take preventive treatment based on partial efficacy or
`
`perceived modest improvements in their migraine symptoms or other quality of life
`
`improvements that fell short of the IHS definition, which is still the case today.
`
`EX1018 (Mansfield 2019), 9 (“respondents most valued a major efficacy
`
`improvement (ie, from 10% to 50% reduction in headache days”).
`
`24. A three-month evaluation period was a commonly recommended
`
`minimum duration—i.e., in order to determine whether a given medication “failed”
`
`a patient needed to have taken the medication for at least three months at stable
`
`dose. EX1011 (Martelletti 2014), 3 (“[a] 3-month treatment period is required to
`
`assess efficacy but it may be useful to continue for a further 3-6 months if there
`
`was some improvement during the first 3 months”); EX1019 (DeMaagd 2008 II), 2
`
`(noting that for beta-blockers “[a]n adequate trial of 3 to 12 months with continued
`
`assessment of efficacy and tolerability is recommended”); EX1020 (Evers 2009),
`
`4-5.
`
`25. For example, Dr. Silberstein taught that preventive treatment doses
`
`should be increased “until clinical benefits are achieved in the absence of, or until
`
`limited by, adverse events,” that an “adequate trial… may take 2 to 3 months to
`
`achieve clinical benefit,” and that therapy should be re-evaluated after three to six
`
`9
`
`
`

`

`months. EX1021(Silberstein 2000), 6.3 Similarly, Dr. Bigal noted in 2008 that a
`
`preventive medication should be considered as failed only after it is “used in
`
`adequate doses for at least 3 months” (EX1022 (Bigal 2008), 2) and in 2016
`
`explained that “[o]ral preventive medications must be… administered daily for
`
`approximately 3 months to establish efficacy” (EX1023 (Bigal 2016), 5 (citing
`
`EX1021 (Silberstein 2000))).
`
`B. Limitations of the Standard of Care in Migraine Prevention
`
`26. Pharmacological treatment of migraine is divided into acute and
`
`preventive. Acute medications, e.g., triptans, were considered adequate for
`
`patients with more infrequent migraine, but were often insufficient for patients
`
`with more severe migraine. EX1024 (DeMaagd 2008 I), 2. By the earliest
`
`possible effective date of the ’161 Patent, it was consensus that “[a]ll patients with
`
`chronic migraine should be offered prevention,” but few of them actually receive
`
`it, based on “issues of efficacy, tolerance, safety, adherence, pharmacophobia and
`
`
`3 As discussed below (§ IX.B.1), Dr. Silberstein is the first author of “Evidence-
`
`based guideline update: Pharmacologic treatment for episodic migraine prevention
`
`in adults” that Dodick relies on for its definition of “approved migraine treatments”
`
`in its exclusion criteria. EX1004 (Dodick Appx.), 2; EX1005 (Silberstein 2012), 7.
`
`10
`
`
`

`

`nocebo response, all suggesting the need for better treatments.” EX1025
`
`(Mitsikostas 2015), 1-2.
`
`27. A variety of medications were used as migraine prophylactics,
`
`including “antiepileptic drugs (e.g. topiramate, divalproex sodium),
`
`antihypertensive agents (e.g. beta blockers, calcium channel blockers, angiotensin-
`
`converting enzyme [ACE] inhibitors, aldosterone receptor blockers) and tricyclic
`
`antidepressants (e.g. amitriptyline, nortriptyline).” EX1026 (Negro 2016), 2; see
`
`also EX1019 (DeMaagd 2008 II), 1 (“[T]he commonly used agents that have been
`
`studied and that have reported efficacy include the beta blockers, the tricyclic
`
`antidepressants, and some anticonvulsants.”); EX1005 (Silberstein 2012), 12.
`
`28. The field generally made no distinction with respect to clinical
`
`efficacy between using preventive medications for treating the various subgroups
`
`of migraineurs—i.e., EM, CM, and the presence of certain migraine conditions
`
`such as aura symptoms. EX1016 (Silberstein 2015), 2-3 (“A drug is chosen based
`
`on its efficacy, its adverse event profile, the patient’s preference, and the presence
`
`of any coexistent or comorbid conditions.”). That is, the same preventive
`
`medications were generally used for all patient types, although there may have
`
`been preferences for certain cases.
`
`29. None of the available preventive medications, however, had been
`
`designed specifically for the treatment of migraine and many had not been
`
`11
`
`
`

`

`formally approved for its treatment. EX1027 (Goldberg 2015), 2; EX1025
`
`(Mitsikostas 2015), 2; EX1023 (Bigal 2016), 5; EX1051 (Schulman 2010), 178.
`
`Owing in part to the lack of specificity in their design, “their use [was] often
`
`limited by an arsenal of side effects or inadequate relief.” EX1027 (Goldberg
`
`2015), 2; see also EX1006 (Sun), [0007]. For instance, topiramate, the most
`
`commonly prescribed migraine prophylactic in the U.S., failed in approximately
`
`fifty percent of patients. EX1006 (Sun), [0007]. The efficacy of other common
`
`medications, e.g., beta-blockers, calcium channel blockers (e.g., flunarizine), and
`
`angiotensin receptor blockers (e.g., candesartan) was supported by similarly
`
`inconsistent or conflicting data. EX1005 (Silberstein 2012), 8 (Table 1).
`
`30.
`
`Intolerable side effects were common to all then-available treatments:
`
`it was known that “one out of five patients treated with any migraine preventive
`
`pharmaceutical agent will discontinue treatment because of tolerability and safety
`
`reasons.” EX1025 (Mitsikostas 2015), 2. Patients that stopped treatment with
`
`certain preventive medications (such as flunarizine or beta-blockers) could develop
`
`increased migraine frequency and were “cautioned” against relapse. EX1016
`
`(Silberstein 2015), 6; EX1015 (Blumenfeld), 9.
`
`31. This poor risk-benefit profile led to inconsistent adherence—“a
`
`critical factor in migraine management” (EX1025 (Mitsikostas 2015), 3)—which
`
`was further exacerbated by the fact that treatments required more frequent, even
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`12
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`multiple times per day, administration. EX1028 (Bigal 2014), 5; EX1029 (Vecsei
`
`2015), 5, 7. A study of the primary classes of prophylactics reported that “73.4 %,
`
`70.2 % and 67.6 % of 4,634 migraineurs who initiated migraine prevention with
`
`antidepressants, anti-epileptics and beta-blockers, respectively, were found non-
`
`adherent 6 months later” (EX1025 (Mitsikostas 2015), 3), while another reported
`
`that “[o]nly one out of four patients complies with treatment in chronic migraine
`
`when it is required for 6 months, and this decreases to one in five when treatment
`
`duration increases to 1 year.” (EX1025 (Mitsikostas 2015), 2) see also EX1023
`
`(Bigal 2016), 2.
`
`32. Given the many preventive options, prescribing of migraine
`
`treatments was generally guided by the evidence supporting their reported efficacy,
`
`though “evidence on how to choose the optimal therapy for a patient [was] still
`
`lacking.” EX1030 (Khalid 2016), 5. Moreover, common comorbidities such as
`
`hypotension and obesity, clinically contraindicated numerous common migraine
`
`prophylactics. EX1016 (Silberstein 2015), 4; EX1005 (Silberstein 2012), 8, Table
`
`1; EX1031 (Wang 2010), 1; EX1032 (Silberstein 2009), 4-5.
`
`C. Anti-CGRP Antibodies Were Known and Tested in the Art
`
`33. By 2016, the CGRP pathway was known to play a pivotal role in
`
`migraine pathophysiology. EX1037 (Tepper 2017), 8 (“there is collective
`
`affirmation that in a broad population of migraine patients, CGRP is important in
`
`13
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`

`the pathophysiology of migraine.”); EX1033 (Edvinsson 2015), 2. As one
`
`researcher acknowledged, “[i]t [was] not surprising that drugs designed to
`
`specifically block its action are gaining remarkable attention from researchers in
`
`the field.” EX1027 (Goldberg 2015), 1.
`
`34. The first drugs to target CGRP specifically were the “Gepants”—
`
`small molecule inhibitors which demonstrated proof of principle that inhibiting
`
`CGRP could treat migraine. EX1027 (Goldberg 2015), 4-5; EX1033 (Edvinsson
`
`2015), 2 (“Further support for the role of CGRP is established by the antimigraine
`
`effect of CGRP receptor blockade. This was initially demonstrated using
`
`intravenous olcegepant and subsequently with several other gepants given orally.”)
`
`But while the Gepants were shown to be effective, their development was
`
`hampered by liver toxicity with frequent use. EX1034 (Bigal Jan. 2015), 2;
`
`EX1035 (Pellesi 2017), 3.
`
`35. Owing in part due to these issues with the Gepants, research targeting
`
`the CGRP pathway shifted to monoclonal antibodies (mAbs), which promised
`
`improved side effect profiles, longer elimination half-lives, and improved
`
`adherence compared to the then-available treatments. EX1028 (Bigal 2014), 6;
`
`EX1034 (Bigal Jan. 2015), 2; EX1035 (Pellesi 2017), 3. By 2016, four mAbs that
`
`antagonize the CGRP pathway had shown success in at least one phase II trial and
`
`14
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`were being further investigated in ongoing phase III trials, including in
`
`“refractory” patients:
`
`(1) galcanezumab / LY2951742;
`
`(2) eptinezumab / ALD403;
`
`(3) fremanezumab / TEV-48125 / LBR-101; and
`
`(4) erenumab / AMG 334.
`
`EX1026 (Negro 2016), 6-7; EX1036 (Sun 2016), 8 (“The effects of [erenumab] on
`
`migraine prevention in a more difficult to treat population (patients with chronic
`
`migraine, those in whom up to three preventive therapies were not effective, and
`
`patients with medication overuse headache) is the aim of an ongoing study
`
`(NCT02066415).”)
`
`36. The first three of these compounds targeted the CGRP ligand, whereas
`
`erenumab targets the CGRP receptor. EX1035 (Pellesi 2017), 4. The compounds
`
`targeting the ligand were believed to treat migraine by “remov[ing] the excessive
`
`CGRP that is released at perivascular trigeminal sensory nerve fibres” while those
`
`targeting the receptor “block the receptor from signalling.” EX1034 (Bigal Jan.
`
`2015), 2. Thus, “the expectation” was that “antibodies against both the ligand and
`
`receptor would prevent CGRP-induced activation of sensitized central trigeminal
`
`pathways, therefore decreasing headache frequency over time.” EX1034 (Bigal
`
`Jan. 2015), 2.
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`15
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`37. This “expectation” was confirmed by numerous clinical trials in
`
`which all four of the anti-CGRP mAbs, demonstrated similar efficacy against
`
`migraine. EX1026 (Negro 2016), 6-7; EX1027 (Goldberg 2015), 5 (“Preliminary
`
`data showed positive results for all four mAbs.”); EX1035 (Pellesi 2017), 10 (“The
`
`introduction of mAbs targeting the CGRP neuroactive peptide and/or its main
`
`receptor appears to lay the foundation for a new class of prophylactic drugs that
`
`could finally overcome, even only partially, the efficacy, safety, tolerability, and
`
`adherence issues that often affec