`
`
`
`
`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`
`ELI LILLY AND COMPANY
`Petitioner,
`
`v.
`
`TEVA PHARMACEUTICALS INTERNATIONAL GMBH
`Patent Owner
`
`_____________________
`
`Case IPR2018-01427
`Patent 8,597,649 B2
`_____________________
`
`DECLARATION OF DR. MICHEL D. FERRARI, M.D., PH.D.
`
`
`
`
`
`EX2141
`Eli Lilly & Co. v. Teva Pharms. Int'l GMBH
`IPR2018-01427
`
`

`

`
`
`
`
`
`
`Inter Partes Review of USPN 8,597,649
`Declaration of Michel D. Ferrari, M.D., Ph.D. (EX2141)
`
` TABLE OF CONTENTS
`
`
`Introduction ...................................................................................................... 1 
`I. 
`II.  My Background and Qualifications ................................................................. 2 
`III.  Summary of Opinions ...................................................................................... 5 
`IV.  List of Documents I Considered in Formulating My Opinions ...................... 6 
`V. 
`Person of Ordinary Skill in the Art ................................................................ 12 
`VI.  The ’649 Patent Claims ................................................................................. 13 
`VII.  My Understanding of Obviousness ............................................................... 14 
`VIII.  Before November 2005, the field was focused on treating acute migraine
`with small molecule therapeutics with short half-lives ........................................... 15 
`IX.  Dr. Charles and Dr. Vasserot ignored the potentially life-threatening side
`effects of long-term antagonism of CGRP’s normal function ................................. 19 
`A. 
`Problems in the vascular system can lead to life-threatening situations.... 20 
`B. 
`Because of CGRP’s potent vasodilatory properties, a POSA would have
`expected that sequestering CGRP would risk serious negative consequences to a
`patient’s vascular health ....................................................................................... 23 
`1.  CGRP plays important protective roles in maintaining vascular health .... 25 
`2.  A POSA would have expected that sequestering CGRP would risk serious
`ischemic episodes .............................................................................................. 28 
`3.  A POSA would have expected that sequestering CGRP would lead to high
`blood pressure and its associated risk of heart disease and stroke ................... 32 
`C.  Anti-CGRP antibodies would have presented an even greater risk for
`migraineurs because of an established comorbidity of migraine with stroke and
`cardiac infarcs ....................................................................................................... 37 
`D. 
`Tan 1995 did not demonstrate that a full length antibody could be safe or
`effective for clinical use in patients. ..................................................................... 39 
`
`
`
`
`- i -
`
`

`

`
`
`
`
`Inter Partes Review of USPN 8,597,649
`Declaration of Michel D. Ferrari, M.D., Ph.D. (EX2141)
`
`Lassen did not demonstrate that an anti-CGRP antibody could be safe or
`E. 
`effective for clinical use in patients ...................................................................... 42 
`Experiments with BIBN4096BS had not demonstrated that anti-CGRP
`X. 
`antibodies were suitable for or safe in human patients ............................................ 43 
`XI.  Contrary to Dr. Charles’s and Dr. Vasserot’s assertions, CGRP antibodies
`were not known treatment options for CGRP-mediated diseases prior to November
`14, 2005 .................................................................................................................... 46 
`XII.  Dr. Charles’s and Dr. Vasserot’s arguments are particularly flawed with
`respect to claims 8 and 9 .......................................................................................... 51 
`XIII.  Anti-CGRP antibodies demonstrated unexpectedly superior results ............ 53 
`XIV.  Humanized anti-CGRP antibodies faced industry skepticism ...................... 55 
`
`
`
`
`- ii -
`
`

`

`
`
`
`I, Michel D. Ferrari, M.D., Ph.D., hereby declare as follows.
`
`Inter Partes Review of USPN 8,597,649
`Declaration of Michel D. Ferrari, M.D., Ph.D. (EX2141)
`
`I.
`
`Introduction
`1.
`
`I have been retained as an expert witness on behalf of Teva
`
`Pharmaceuticals International GMBH (“Teva”) for the above-captioned inter
`
`partes review (IPR). I am being compensated for my time in connection with this
`
`IPR at my standard consulting rate, but my compensation is not contingent upon
`
`my opinions or the outcome of this or any other proceeding.
`
`2.
`
`I understand that this Declaration accompanies Teva’s response to an
`
`IPR petition involving U.S. Patent No. 8,597,649 (“the ’649 patent”) (EX1001). I
`
`understand that the petition was filed by Eli Lilly and Company (“Lilly”). I
`
`understand that the ’649 patent resulted from U.S. Patent Application No.
`
`13/870,871 (“the ’871 application”). I understand that the ’871 application is a
`
`continuation application that relates to a series of previous applications. I also
`
`understand that the earliest possible priority date of the ’649 patent is the
`
`November 14, 2005 filing date of U.S. Patent Application No. 60/736,623, and I
`
`refer to this date throughout this declaration. The ’649 patent issued on December
`
`3, 2013.
`
`3.
`
`In preparing this Declaration, I have reviewed the ’649 patent and
`
`each of the documents cited herein from the perspective of a person of ordinary
`
`
`
`- 1 -
`
`

`

`
`
`
`
`Inter Partes Review of USPN 8,597,649
`Declaration of Michel D. Ferrari, M.D., Ph.D. (EX2141)
`
`skill in the art, in light of general knowledge in the art before November 14, 2005.
`
`In formulating my opinions, I have relied upon my experience, education, and
`
`knowledge in the relevant art. In formulating my opinions, I have also considered
`
`the viewpoint of a person of ordinary skill in the art (“POSA”) (i.e., a person of
`
`ordinary skill in the field of the ’649 patent, as defined further below in Section V)
`
`prior to November 14, 2005.
`
`II. My Background and Qualifications
`4. My qualifications and credentials are more fully set forth in my
`
`curriculum vitae, provided as EX2142. I am an expert in the field of clinical
`
`neurology, and have been since approximately 1985. I have been actively working
`
`in the field of neurology, with a focus on migraine, since 1980, and have gained
`
`significant experience in this field while both performing clinical research and
`
`treating patients since I graduated from medical school.
`
`5.
`
`I studied medicine at the University of Leiden and received my
`
`Doctor of Medicine Degree in 1980. I subsequently decided to specialize in
`
`Neurology and Neuroscience and received specialty certificates in Neurology and
`
`Clinical Neurophysiology in 1985. I was awarded a Ph.D. cum laude in 1992 and
`
`the title of my thesis was “Serotonin and Migraine,”
`
`6.
`
`I have dedicated much of my career to the study of migraine and other
`
`primary headaches and the focus of my research has been aimed at unravelling the
`
`
`
`- 2 -
`
`

`

`Inter Partes Review of USPN 8,597,649
`Declaration of Michel D. Ferrari, M.D., Ph.D. (EX2141)
`
`mechanisms for all aspects of these conditions from triggering and initiation to
`
`treatment of acute attacks and prevention. As of 2005, I would have described
`
`myself as a Clinician, Clinical Researcher and Clinical Neurologist to reflect the
`
`various roles that I undertook (and continue to undertake to this day). As a result
`
`of my research, I am an author on over 450 peer reviewed publications. My
`
`research efforts have included investigation of the possibility of therapeutically
`
`targeting the CGRP signaling pathway, including developing and conducting
`
`clinical trials of therapeutics targeting the CGRP pathway. These efforts began in
`
`the early 2000’s.
`
`7.
`
`I am currently Professor of Neurology, Chair of the Leiden Center for
`
`Translational Neuroscience, and a member of the Permanent Science Committee
`
`at Leiden University Medical Center (LUMC). I am also President of the Dutch
`
`Headache Society and past President of the International Headache Society (IHS),
`
`having been the President of this society in the period from 2001 to 2003.
`
`8. My role in Leiden involves (and involved in 2005) me being
`
`responsible for the care of many thousands of patients suffering from migraine
`
`and cluster headache. The Leiden University Medical Center (LUMC) Headache
`
`Clinic was and is the central reference center for headache patients in the
`
`Netherlands, although I care for migraine and cluster headache patients from other
`
`parts of the world as well.
`
`- 3 -
`
`
`
`
`
`
`
`

`

`Inter Partes Review of USPN 8,597,649
`Declaration of Michel D. Ferrari, M.D., Ph.D. (EX2141)
`
`9.
`
`I am an Elected Fellow of the American Neurological Association
`
`(FANA) and the Royal College of Physicians (FRCP), and an Honorary Member
`
`of the Colombian Neurology Society and the International (IHS), Danish and
`
`Italian Headache Societies. In 2004, I was awarded the Vici Innovational
`
`Research Personal Incentive Schema Award from the Netherlands Organization
`
`for Scientific Research and in 2005 I received the Winkler Medallion for
`
`Excellence in Neurological Research from the Dutch Neurological Association. In
`
`2009, I was awarded the Spinoza Life Time Achievement Premium which is the
`
`highest science prize in the Netherlands. In 2017, I received the 10-year Gravity
`
`Award “Brain on a Chip” as part of the “Netherlands Organ on a Chip Initiative”.
`
`In 2011, I was the recipient of the triennial Hartmann Müller Prize for Biomedical
`
`Research from the University & ETH (Eidgenössische Technische Hochschule –
`
`Swiss Federal Institute of Technology) in Zurich, Switzerland.
`
`10. Throughout the course of my career I have acted as a scientific
`
`advisor and/or consultant to many pharmaceutical companies investigating
`
`possible treatments for migraine, cluster headache and other primary headaches.
`
`This includes acting as an advisor and/or serving on the advisory board for
`
`Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb,
`
`Wellcome, Merck, Pfizer, Eli Lilly, GlaxoSmithKline, Teva, Novartis, Sandoz,
`
`J&J
`
`(including Janssen), SmithKlineBeecham, Menarini, Medtronic and
`
`- 4 -
`
`
`
`
`
`
`
`

`

`
`
`
`
`Inter Partes Review of USPN 8,597,649
`Declaration of Michel D. Ferrari, M.D., Ph.D. (EX2141)
`
`Electrocore. These advisory roles included sitting on the advisory board of three
`
`companies developing CGRP receptor antagonists.
`
`11. Among other things, my various advisory and/or consultancy roles
`
`around November 2005 involved the development and testing of CGRP receptor
`
`antagonists (such as BIBN4096BS and related small molecules, which I discuss
`
`below), including practical experience in conducting clinical trials. In particular, I
`
`played an instrumental role in the clinical design and testing of BIBN4096BS for
`
`its efficacy and safety in treating acute migraine. Earlier, I also played an
`
`instrumental role in the clinical design and testing of the class of drugs known as
`
`triptans for their use in treating acute migraine starting in the late 1980’s.
`
`III. Summary of Opinions
`12.
`In preparing this Declaration, I have reviewed the expert declarations
`
`of Dr. Andrew C. Charles, M.D. (EX1002) and Dr. Alain P. Vasserot, Ph.D.
`
`(EX1003). As detailed below, I disagree with Dr. Charles’s and Dr. Vasserot’s
`
`arguments regarding the ’649 patent because their declarations neglected to
`
`address or take into account the significant concerns a POSA would have had
`
`regarding the potentially life-threatening side effects of inhibiting CGRP activity.
`
`CGRP is one of the most potent microvascular vasodilator substances identified to
`
`date, and a POSA would have expected that sequestering CGRP risked causing
`
`deleterious side effects on the vascular system via prevention of CGRP-mediated
`
`
`
`- 5 -
`
`

`

`
`
`
`
`Inter Partes Review of USPN 8,597,649
`Declaration of Michel D. Ferrari, M.D., Ph.D. (EX2141)
`
`vasodilation to rescue viable penumbra tissue in cardiac and cerebral ischemic
`
`events. This concern would have been particularly problematic for anti-CGRP
`
`antibodies because the long half-life of antibodies meant that any side effects
`
`would have been expected to persist for long periods of time. But therapeutic anti-
`
`CGRP antibodies were not even on the radar of investigators prior to November
`
`2005, and it is only with the hindsight of more recent results that one can look
`
`back at the disclosures of the time to argue that a person of ordinary skill in the art
`
`would have had reason to generate humanized anti-CGRP antibodies for
`
`therapeutic use.
`
`
`IV. List of Documents I Considered in Formulating My Opinions
`13.
`In formulating my opinions, I have reviewed all the references and
`
`documents cited herein, including those listed below.
`
`Exhibit #
`1001
`
`Description
`U.S. Patent No. 8,597,649 (“the ’649 Patent”)
`
`1002
`1003
`1022
`
`1024
`
`Declaration of Andrew Charles, M.D. (U.S. Patent No. 8,597,649)
`Declaration of Alain P. Vasserot (U.S. Patent No. 8,597,649)
`Tan et al., “Calcitonin Gene-Related Peptide as an Endogenous
`Vasodilator: Immunoblockade Studies in vivo with an Anticalcitonin
`Gene-Related Peptide Monoclonal Antibody and its Fab’ fragment,”
`Clinical Science (1995) 89: 565-573
`Doods et al., “Pharmacological Profile of BIBN4096BS, the First
`Selective Small Molecule CGRP Antagonist,” Br. J. Pharmacol.
`(2000) 129: 420-423
`
`
`
`- 6 -
`
`

`

`Exhibit #
`1025
`
`1026
`1027
`
`1028
`1031
`
`1033
`
`1035
`1040
`
`1042
`
`1047
`
`1059
`1070
`
`1096
`
`2001
`
`2003
`
`
`
`
`
`
`
`Inter Partes Review of USPN 8,597,649
`Declaration of Michel D. Ferrari, M.D., Ph.D. (EX2141)
`
`Description
`Olesen et al., “Calcitonin Gene-Related Peptide Receptor Antagonist
`BIBN 4096 BS for the Acute Treatment of Migraine,” N. Engl. J.
`Med. (2004) 350: 1104-10 Olesen et al., “Calcitonin Gene-Related
`Peptide Receptor Antagonist BIBN 4096 BS for the Acute Treatment
`of Migraine,” N. Engl. J. Med. (2004) 350: 1104-10
`Sveinsson, International Publication No. WO 2004/014351
`Salmon et al., U.S. Patent Application Publication No. US
`2002/0162125
`De Lacharriere et al., U.S. Patent No. 6,344,438
`Arulmani et al., “Calcitonin Gene-related Peptide and Its Role in
`Migraine Pathophysiology,” Eur. J. Pharmacol. (2004) 143: 315-330
`Wong et al., “Monoclonal Antibody to Rat α-CGRP: Production,
`Characterization, and in vivo Immunoneutralization Activity,”
`Hybridoma (1993) 12: 93-106
`Edvinsson and Hargreaves, The Headaches 289-299 (3rd ed. 2006)
`Arulmozhi et al., “Migraine: Current Concepts and Emerging
`Therapies,” Vascular Pharmacol. (2005) 43: 176-187
`Iovino et al., “Safety, Tolerability and Pharmacokinetics of BIBN
`4096 BS, the First Selective Small Molecule Calcitonin Generelated
`Peptide Receptor Antagonist, Following Single Intravenous
`Administration in Healthy Volunteers,” Cephalalgia (2004) 24: 645-
`656
`Lassen et al., “CGRP May Play a Causative Role in Migraine,”
`Cephalagia (2002) 22: 54-61
`Janeway et al., Immunobiology 123-154 (5th ed. 2001)
`Kim et al., “Antibody Engineering for the Development of
`Therapeutic Antibodies,” Mol. Cells (2005) 20: 17-29
`Wimalawansa, “Calcitonin Gene-Related Peptide and Its Receptors:
`Molecular Genetics, Physiology, Pathophysiology, and Therapeutic
`Potentials,” Endocrine Reviews (1996) 17(5): 533-585
`Edvinsson, L., “Calcitonin Gene-Related Peptide (CGRP) in
`Cerebrovascular Disease,” TheScientificWorldJOURNAL, 2:1484–90
`(2002)
`Brain, S. and Grant, A., “Vascular Actions of Calcitonin Gene-
`Related Peptide and Adrenomedullin,” Physiol. Rev., 84:903-34
`(2004)
`
`- 7 -
`
`

`

`Exhibit #
`2004
`
`2006
`
`2008
`
`2009
`
`2011
`
`2012
`
`2014
`
`2015
`
`2016
`
`2017
`
`2019
`
`
`
`
`
`
`
`Inter Partes Review of USPN 8,597,649
`Declaration of Michel D. Ferrari, M.D., Ph.D. (EX2141)
`
`Description
`Chiba, T., et al., “Calcitonin gene-related peptide receptor antagonist
`human CGRP-(8-37),” Am. J. Physiol.:Endocrin. & Metab.,
`19:E331-35 (1989)
`Gegg, Jr., C., et al., “CGRP Peptide Antagonists And Conjugates,”
`U.S. Patent No. 8,168,592 B2 (filed October 19, 2006; issued May 1,
`2012)
`Rist, B., et al., “CGRP 27-37 analogues with high affinity to the
`CGRP1 receptor show antagonistic properties in a rat blood flow
`assay,” Regul. Pept. 79:153-58 (1999)
`Goadsby, P., “Calcitonin Gene-Related Peptide Antagonists as
`Treatments of Migraine and Other Primary Headaches,” Drugs,
`65:2557-67 (2005)
`Supowit, S., et al., “Calcitonin Gene-Related Peptide Protects
`Against Hypertension-Induced Heart and Kidney Damage,”
`Hypertension, 45:109-14 (2005)
`Aiyar, N., et al., “Pharmacology of SB-273779, a Nonpeptide
`Calcitonin Gene-Related Peptide 1 Receptor Antagonist,” The
`Journal of Pharmacology and Experimental Therapeutics, 296:768–
`75 (2001)
`Patchett, A., et al., “Benzimidazolinyl Piperidines as CGRP
`Ligands,” U.S. Patent No. 6,552,043 B1 (filed September 22, 1999;
`issued April 22, 2003)
`Zimmer, O., et al., “Substituted Cyclopentene Compounds,” U.S.
`Patent No. 7,109,214 B2 (filed November 19, 2004; issued
`September 19, 2006)
`Chaturvedula, P., et al., “Constrained Compounds as CGRP-
`Receptor Antagonists,” U.S. Patent No. 7,384,930 B2 (filed October
`11, 2005; issued June 10, 2008)
`Rudolf, K., et al., “Modified Aminoacids, Pharmaceuticals
`Containing These Compounds and Method for Their Production,”
`U.S. Patent No. 6,344,449 B1 (filed September 8, 1997; issued
`February 5, 2002)
`Petersen, K., et al., “The CGRP-antagonist, BIBN4096BS does not
`affect cerebral or systemic haemodynamics in healthy volunteers,”
`Cephalalgia, 25:139–47 (2004)
`
`- 8 -
`
`

`

`Exhibit #
`2058
`
`2061
`
`2068
`
`2070
`
`2071
`
`2078
`
`2079
`
`2082
`
`2086
`
`2088
`
`2089
`
`2122
`
`2125
`
`
`
`
`
`
`
`Inter Partes Review of USPN 8,597,649
`Declaration of Michel D. Ferrari, M.D., Ph.D. (EX2141)
`
`Description
`Uren, N.G., et al., “Effect of intravenous calcitonin gene related
`peptide on ischaemia threshold and coronary stenosis severity in
`humans,” Cardiovascular Research 27: 1477- 1481 (1993)
`Franco-Cereceda, A. and Liska, J., “Potential of Calcitonin Gene-
`Related Peptide in Coronary Heart Disease,” Pharmacology 60:1–8
`(2000)
`Hay, D.L. and Poyner, D. “The Preclinical Pharmacology
`of BIBN4096BS, a CGRP Antagonist,” Cardiovascular Drug
`Reviews 23(1): 31-42 (2005)
`Wimalawansa, S.J., “Circadian variation of plasma calcitonin gene-
`related peptide in man,” Journal of Neuroendocrinology 3(3): 319-
`322 (1991)
`Burgey, C., et al., “CGRP Receptor Antagonists,” PCT International
`Publication No. WO 2004/092166 (filed April 9, 2004; published
`October 28, 2004)
`Juul, R., et al., “Calcitonin gene-related peptide-LI in subarachnoid
`haemorrhage in man. Signs of activation of the trigemino-
`cerebrovascular system?,” Br. J. Neurosurgery 4: 171-180 (1990)
`Gennari, C., et al., “Improved cardiac performance with human
`calcitonin gene related peptide in patients with congestive heart
`failure,” Cardiovascular Research 24: 239-241 (1990)
`Humbert, M., et al., “Treatment of pulmonary arterial hypertension,”
`N. Engl. J. Med. 351:1425-1436 (2004)
`Parnetti, L., et al., “Headache and ischemic stroke,” J. Headache
`Pain 3(1):15–20 (2002)
`Etminan, M., et al., “Risk of ischaemic stroke in people with
`migraine: systematic review and meta-analysis of observational
`studies,” Brit. Med. J. 330: 63-65 (2005)
`Wimalawansa, S.J., “Age-related changes in tissue contents of
`immunoreactive calcitonin gene-related peptide,” Aging Clin . Exp.
`Res. 4(1): 211-217 (1992)
`Oh-hashi, Y., et al., “Elevated Sympathetic Nervous Activity in Mice
`Deficient in αCGRP,” Circ Res. 89(11):983-990 (2001)
`Gangula, P.R.R., et al., “Increased Blood Pressure in α-Calcitonin
`Gene–Related Peptide/Calcitonin Gene Knockout Mice,”
`Hypertension 35(part 2): 470-475 (2000)
`
`- 9 -
`
`

`

`Inter Partes Review of USPN 8,597,649
`Declaration of Michel D. Ferrari, M.D., Ph.D. (EX2141)
`
`Exhibit #
`2126
`
`2127
`
`2139
`
`2142
`2143
`
`2144
`
`2145
`
`2146
`
`2147
`
`2148
`
`2149
`
`2150
`
`2151
`
`2152
`
`Description
`The Seventh Report of the Joint National Committee on Prevention,
`Detection, Evaluation, and Treatment of High Blood Pressure
`(August 2004)
`“Hypertension in America: A National Reading,” Am. J. Manag.
`Care 11(suppl. 13): S383-S385 (2005)
`Juul, R., et al., “Calcitonin gene-related peptide (human α-CGRP)
`counteracts vasoconstriction in human subarachnoid haemorrhage,”
`Neuroscience Letters 170(1) : 67- 70 (1994)
`Curriculum Vitae of Michel D. Ferrari, M.D., Ph.D.
`Collard, C.D. and Gelman, S., “Pathophysiology, Clinical
`Manifestations, and Prevention of Ischemia–Reperfusion Injury,”
`Anesthesiology 94(6): 1133–1138 (2001)
`Solenski, N.J., “Transient Ischemic Attacks: Part I. Diagnosis and
`Evaluation,” Am Fam Physician 69(7): 1665-74,1679-80 (2004)
`Fox, K., et al., “Guidelines on the management of stable angina
`pectoris,” European Heart Journal 27: 1341-1381 (2006)
`Panza, J.A., “Myocardial Ischemia and the Pains of the Heart,” New
`Engl. J. Med. 346(25): 1934-1935 (2002)
`Parker, J.O., “Angina Pectoris: A Review of Current and Emerging
`Therapies,” Am. J. Manag. Care 10(suppl. 11): S332-338 (2004)
`Sobey, C.G. and Faraci, F.M., “Subarachnoid Haemorrhage: What
`Happens To The Cerebral Arteries?,” Clinical and Experimental
`Pharmacology and Physiology 25(11): 867-876 (1998)
`Preibisz, J.J., “Calcitonin Gene-Related Peptide and Regulation of
`Human Cardiovascular Homeostasis,” Am. J. Hypertens.
`6(5 pt. 1): 434-450 (1993)
`Kallner, G. and Franco-Cereceda, A., “Aggravation of Myocardial
`Infarction in the Porcine Heart by Capsaicin-Induced Depletion of
`Calcitonin Gene-Related Peptide (CGRP),” Journal of
`Cardiovascular Pharmacology 32(3): 500-504 (1998)
`Mair, J., et al., “Plasma CGRP in acute myocardial infarction,”
`Lancet 335: 168 (1990)
`Li, Y-J., et al., “Calcitonin gene-related peptide-induced
`preconditioning protects against ischemia-reperfusion injury in
`isolated rat hearts,” Eur. J. Pharmacol. 311(2-3): 163-167 (1996)
`
`- 10 -
`
`
`
`
`
`
`
`

`

`Exhibit #
`2154
`
`2156
`
`2157
`
`2158
`
`2159
`
`2161
`
`2162
`
`2163
`
`2164
`
`2189
`
`2193
`
`
`
`
`
`
`
`Inter Partes Review of USPN 8,597,649
`Declaration of Michel D. Ferrari, M.D., Ph.D. (EX2141)
`
`Description
`Edvinsson, L., et al., “Reduced levels of calcitonin gene-related
`peptide-like immunoreactivity in human brain vessels after
`subarachnoid haemorrhage,” Neuroscience Letters 121: 151-154
`(1991)
`Shawket, S.A. and Brown, M., “Pathogenetic and Therapeutic
`Implications of Calcitonin-Gene-Related Peptide in the
`Cardiovascular System,” Trends Cardiovasc. Med. 1(5): 211-215
`(1991)
`Bousser, M.G. and Welch, K.M.A., “Relation between migraine and
`stroke,” Lancet Neurol. 4(9): 533–42 (2005)
`Carolei, A., et al., “Comorbidities of migraine: a user-friendly
`overview,” J. Headache Pain 4(suppl. 1): S23–S25 (2003)
`Stang, P.E., et al., “Headache, cerebrovascular symptoms, and stroke
`The Atherosclerosis Risk in Communities Study,” Neurology 64(9):
`1573–1577 (2005)
`Dodick, D.W., et al., “Safety and efficacy of LY2951742, a
`monoclonal antibody to calcitonin gene-related peptide, for the
`prevention of migraine: a phase 2, randomised, double-blind,
`placebo-controlled study,” Lancet Neurol. 13: 885–92 (2014)
`Goldberg, S.W., and Silberstein, S., “Targeting CGRP: A New Era
`for Migraine Treatment,” CNS Drugs 29:443–452 (2015)
`Pellesi, L., et al., “Spotlight on Anti-CGRP Monoclonal Antibodies
`in Migraine: The Clinical Evidence to Date,” Clinical Pharmacology
`in Drug Development 6(6) 534–547 (2017)
`Li, Y-J. and Peng, J., “The cardioprotection of calcitonin gene-
`related peptide-mediated preconditioning,” European Journal of
`Pharmacology 442: 173– 177 (2002)
`Bender, K., “Promise and Pitfalls of Preventing
`Migraine With CGRP Inhibitors,” (July 10, 2018), MD Magazine ,
`https://www.mdmag.com/journals/md-magazine-
`neurology/2018/july-neuro-2018/promise-and-pitfalls-of-preventing-
`migraine-with-cgrp-inhibitors, (last visited March 20, 2019)
`Prudenzano, M.P., et al., “The comorbidity of migraine and
`hypertension. A study in a tertiary care headache centre,” J.
`Headache Pain 6(4): 220–222 (2005)
`
`- 11 -
`
`

`

`Inter Partes Review of USPN 8,597,649
`Declaration of Michel D. Ferrari, M.D., Ph.D. (EX2141)
`
`Exhibit #
`2199
`
`2209
`
`2215
`
`Description
`Marquez de Prado, B. and Russo, A.F., “CGRP receptor antagonists:
`A new frontier of anti-migraine medications,” Drug Discovery Today
`3(4): 593-597 (2006)
`Edvinsson, L., et al., “Modification of vasoconstrictor responses in
`cerebral blood vessels by lesioning of the trigeminal nerve: possible
`involvement of CGRP,” Cephalalgia 15(5): 373-383 (1995)
`Edvinsson. L., “Clinical Data on the CGRP Antagonist BIBN4096BS
`for Treatment of Migraine Attacks,” CNS Drug Reviews 11: 69–76
`(2005)
`
`
`
`
`
`
`
`V. Person of Ordinary Skill in the Art
`14.
`I understand that a person of ordinary skill in the art (“POSA”) is a
`
`hypothetical person who is presumed to be aware of all pertinent art, thinks along
`
`conventional wisdom in the art, and is a person of ordinary creativity. The ’649
`
`patent relates to anti-CGRP antagonist antibodies, pharmaceutical compositions
`
`comprising anti-CGRP antagonist antibodies, and methods of using anti-CGRP
`
`antagonist antibodies to treat diseases such as migraine. I understand that the
`
`Board has concluded that, as it relates to the ’649 patent, a POSA would have (1)
`
`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, or (2) an 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. For the
`
`
`
`- 12 -
`
`

`

`
`
`
`
`Inter Partes Review of USPN 8,597,649
`Declaration of Michel D. Ferrari, M.D., Ph.D. (EX2141)
`
`purposes of this proceeding, I agree with this definition of a POSA because these
`
`are, in my experience, the type of people who would work together on developing
`
`therapeutic antibodies.
`
`VI. The ’649 Patent Claims
`15. The ’649 patent’s claims are directed to isolated human or humanized
`
`anti-CGRP antagonist antibodies. Independent claim 1, the sole independent
`
`claim, requires that the antibodies have a binding affinity of 50 nM or less:
`
`1. An isolated human or humanized anti-CGRP antagonist
`antibody with a binding affinity (KD) to human α-CGRP of 50
`nM or less as measured by surface plasmon resonance at 37° C.
`
`EX1001, 101:38-41.
`
`16. The ’649 patent also contains eight dependent claims, claims 2 to 9.
`
`EX1001, 101:42-102:49. Claims 2 and 3 require binding to a fragment or epitope,
`
`respectively, having CGRP residues 25-37. Claim 4 requires a specific antibody
`
`isotype selected from IgG, an IgM, an IgE, an IgA, or an IgD. Claims 5 and 6
`
`require that the antibody comprise an Fc (claim 5) or an Fc with impaired effector
`
`function (claim 6). Claim 7 requires that the antibody be a humanized antibody.
`
`Claim 8 is directed to a pharmaceutical composition that comprises the isolated
`
`human or humanized anti-CGRP antagonist antibody of claim 1 and a
`
`
`
`- 13 -
`
`

`

`
`
`
`
`Inter Partes Review of USPN 8,597,649
`Declaration of Michel D. Ferrari, M.D., Ph.D. (EX2141)
`
`pharmaceutically acceptable excipient. And claim 9 requires that the antibody of
`
`claim 1 be formulated for systemic administration.
`
`17.
`
`I understand that terms of the claims are to be given their ordinary and
`
`customary meaning in light of the specification and prosecution history—that is,
`
`the meaning that the term would have to a person of ordinary skill in the art in
`
`question at the time of the invention. Having reviewed the ’649 patent
`
`specification, claims, and prosecution history, I do not view any terms as requiring
`
`specific construction. Accordingly, where not specifically discussed, I have given
`
`all claim terms their plain and ordinary meaning to a POSA consistent with the
`
`specification and prosecution history of the ’649 patent.
`
`VII. My Understanding of Obviousness
`18.
`I understand that an obviousness analysis involves determining the
`
`scope and content of the prior art; comparing the differences between the claimed
`
`invention and the prior art; and resolving the level of ordinary skill in the pertinent
`
`art.
`
`19.
`
`I also understand that combining or modifying the teachings of the
`
`prior art to achieve the claimed invention is one way to establish obviousness. I
`
`understand that where there is a reason to modify or combine the prior art to
`
`achieve the claimed invention, there must also be a reasonable expectation of
`
`success in so doing. I understand that the reason to combine prior art references
`
`
`
`- 14 -
`
`

`

`
`
`
`
`Inter Partes Review of USPN 8,597,649
`Declaration of Michel D. Ferrari, M.D., Ph.D. (EX2141)
`
`can come from a variety of sources, not just the prior art itself or the specific
`
`problem the patentee was trying to solve. And I understand that the references
`
`themselves need not provide a specific hint or suggestion of the alteration needed
`
`to arrive at the claimed invention; the analysis may include recourse to logic,
`
`judgment, and common sense available to a person of ordinary skill that does not
`
`need to be explicit in any reference.
`
`20.
`
`I understand that when considering the obviousness of an invention,
`
`one should also consider whether there is any objective evidence that supports the
`
`non-obviousness of the invention. I understand that objective evidence of non-
`
`obviousness (also known as secondary considerations of non-obviousness)
`
`includes factors such as failure of others, unexpectedly superior results, praise in
`
`the industry, long-felt, but unmet, need, and commercial success.
`
`VIII. Before November 2005, the field was focused on treating acute migraine
`with small molecule therapeutics with short half-lives
`21. Before November 2005, a POSA would have known that clinicians
`
`and researchers were focused on small molecule therapeutics with short half-lives
`
`for the treatment of acute migraine. For example, the triptan family of therapeutics
`
`were the “drugs of choice” for acute migraine treatment in the 2004-2005 time
`
`frame. EX1031, 322; EX1040, 176. The triptans are 5-HT receptor agonists with a
`
`low molecular weight and a half-life ranging from 2-6 hours. EX1040, 180-181.
`
`
`
`- 15 -
`
`

`

`
`
`
`
`Inter Partes Review of USPN 8,597,649
`Declaration of Michel D. Ferrari, M.D., Ph.D. (EX2141)
`
`In 2005, triptans were theorized to “ameliorate migraine headache” by multiple
`
`potential mechanisms, including “by constricting the dilated cranial blood vessels
`
`and by inhibiting the trigeminal CGRP release” from sensory nerves. EX1031,
`
`315. While they were the drugs of choice, triptans were also associated with
`
`“vasoconstrictive risk factors” and “the overall associated cardiovascular risks
`
`continue to limit their use.” EX2162, 443-444.
`
`22. Another small molecule being investigated was BIBN4096BS,1 a
`
`small molecule antagonist of the CGRP receptor. See, e.g., EX1025, 1105.
`
`BIBN4096BS has a half-life of approximately 2.5 hours. EX1042, 645. Olesen et
`
`al. (EX1025; “Olesen”) disclosed using BIBN4096BS to treat acute attacks of
`
`migraine, and reported that it “was effective” in doing so. EX2015, 1104. Olesen
`
`reported an overall rate of adverse events of 25%, and that “no serious adverse
`
`events” were observed. EX2015, 1104. However, Olesen also cautioned that their
`
`study did not assess whether BIBN4096BS has any “vasoconstrictor properties”
`
`because “[its] data base was too small,” and therefore Olesen could not conclude
`
`whether BIBN4096BS was different from the triptans in that regard. EX1025,
`
`1109. Further, Olesen infused BIBN4096BS once for only 10 minutes, which is
`
`too short a time period to have any lasting effects because the BIBN4096BS levels
`
`drop quickly and it is gone within a matter of hours.
`
`1 BIBN4096BS is also referred to as olcegepant.
`
`
`
`- 16 -
`
`

`

`Inter Partes Review of USPN 8,597,649
`Declaration of Michel D. Ferrari, M.D., Ph.D. (EX2141)
`
`23. A POSA also would have been aware of studies done with a truncated
`
`CGRP, containing amino acids 8 to 37 of CGRP—called CGRP8-37. The CGRP8-37
`
`peptide acts as a CGRP receptor antagonist. EX2004, E331; EX1024, 420;
`
`EX2003,