`
`Filed: June 7, 2019
`
`Filed on behalf of: Eli Lilly and Company
`
`
`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 IPR2018-01422 (Patent No. 9,340,614)
`Case IPR2018-01423 (Patent No. 9,266,951)
`Case IPR2018-01424 (Patent No. 9,346,881)
`Case IPR2018-01425 (Patent No. 9,890,210)
`Case IPR2018-01426 (Patent No. 9,890,211)
`Case IPR2018-01427 (Patent No. 8,597,649)1
`
`
`_____________________
`
`PETITIONER’S SECOND OBJECTIONS
`TO PATENT OWNER’S EVIDENCE
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`1
`The word-for-word identical paper is filed in each proceeding identified in the
`
`caption.
`
`
`
`

`

`IPR2018-01422, -01423, -01424, -01425, -01426, -01427
`
`
`The Federal Rules of Evidence (“FRE”) generally apply to proceedings
`
`
`
`before the Board. 37 C.F.R. § 42.62(a). Pursuant to 37 C.F.R. § 42.64(b)(1) and
`
`the FRE, Petitioner Eli Lilly and Company (“Lilly” or “Petitioner”) submits the
`
`following objections to certain exhibits submitted by Patent Owner Teva
`
`Pharmaceuticals International GMBH (“Teva” or “Patent Owner”). These
`
`objections apply equally to Patent Owner’s reliance on these exhibits in any
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`subsequently filed documents. These objections are timely filed and served within
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`five business days of service. 37 C.F.R. § 42.64(b)(1).
`
`A. Objection Key
`Lilly objects to the exhibit because it lacks proper foundation or authenticity
`
`A:
`
`under FRE 901 and 902.
`
`B: Lilly objects to the exhibit under the Best Evidence Rule (FRE 1001-1003).
`
`H:
`
`To the extent Teva relies on the content of the exhibit for the truth of the
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`matter asserted, Lilly objects to the exhibit as inadmissible hearsay (see FRE
`
`801 and 802) that does not fall under any exceptions, including FRE 803,
`
`804, 805, and 807.
`
`Lilly objects to the exhibit as an incomplete document (FRE 106).
`
`To the extent Teva relies upon the exhibit to show the state of the art, Lilly
`
`objects to the exhibit as not relevant, confusing, unfairly prejudicial, and
`
`wasting time because the exhibit has not been shown to qualify as prior art
`1
`
`I:
`
`R:
`
`
`
`

`

`IPR2018-01422, -01423, -01424, -01425, -01426, -01427
`
`(FRE 401-403).
`
`S:
`
`Lilly objects to the exhibit as not relevant, confusing, unfairly prejudicial,
`
`and wasting time because it has not been cited in one or more of Teva’s
`
`Patent Owner Responses (FRE 401-403).
`
`T:
`
`Lilly objects to the exhibit as not relevant, confusing, unfairly prejudicial,
`
`and wasting time because it is not relevant to any issue in these IPR
`
`proceedings (FRE 401-403).
`
`X:
`
`Lilly objects to the exhibit because it was improperly filed under 37 C.F.R.
`
`§ 42.6(c).
`
`Z:
`
`Lilly objects to the exhibit because it was improperly filed as redacted
`
`without any protective order, in violation of the Board’s Scheduling Order
`
`(Paper 15 at 2).
`
`B.
`
` Objections
`
`Teva Description
`
`Objections
`
`Teva
`Exhibit No.
`20522
`
`Inman, S., “Anti-CGRP Monoclonal Antibodies
`Transforming Migraine Treatment,” (Oct. 22, 2018),
`NeurologyLive
`https://www.neurologylive.com/conferences/ana-
`2018/anticgrp-mon oclonal-antibodies-transforming-
`migraine-treatment, (last visited May 20, 2019)
`
`2
`Lilly timely objected to these documents during the deposition of Dr.
`
`A, H, R, T
`
`Charles. 37 C.F.R. § 42.64(a); Ex. 2192, 61:4-17, 186:6-11.
`
`
`
`2
`
`

`

`IPR2018-01422, -01423, -01424, -01425, -01426, -01427
`
`Teva Description
`
`“Pain Like No Other,” UCLA Health David Geffen
`School of Medicine 38(2): 18-25 (2018)
`Hay, D.L., et al., “A comparison of the actions of
`BIBN4096BS and CGRP8-37 on CGRP and
`adrenomedullin receptors expressed on SK-N-MC, L6,
`Col 29 and Rat 2 cells,” British Journal of
`Pharmacology 137(1): 80 - 86 (2002)
`Hay, D.L., et al., “CL/RAMP2 and CL/RAMP3 produce
`pharmacologically distinct adrenomedullin receptors: a
`comparison of effects of adrenomedullin22–52, CGRP8–37
`and BIBN4096BS,” British Journal of Pharmacology
`140(3): 477–486 (2003)
`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)
`Geppetti, P., et al., “CGRP and migraine: neurogenic
`inflammation revisited,” Journal of Headache & Pain
`6(2):61–70 (2005)
`Hay, D., et al., “Pharmacological discrimination of
`calcitonin receptor: receptor Activity-modifying protein
`complexes,” Molecular Pharmacology 67(5): 1655–1665
`(2005)
`Franco-Cereceda, A. and Liska, J., “Potential of
`Calcitonin Gene-Related Peptide in Coronary Heart
`Disease,” Pharmacology 60:1–8 (2000)
`The Biochemical Basis of Neuropharmacology, Chapter
`4: Receptors, 65-84, (Jack R. Cooper et al. eds., 8th ed.
`2003)
`Excerpt from Rang, H., et al., Pharmacology, p. 15, 5th
`ed., Elsevier Science Limited, (2003)
`Molecular Cell Biology, Chapter 13: Signaling
`molecules and cell-surface receptors, 537-538, (Harvey
`Lodish et al. eds., 5th ed. 2003)
`Sheykhzade, M., et al., “Noncompetitive antagonism of
`BIBN4096BS on CGRP-induced responses in human
`subcutaneous arteries,” British Journal of Pharmacology
`3
`
`Objections
`
`A, H, R, T
`
`H, S
`
`H, S
`
`H, T
`
`H
`
`H, T
`
`H, T
`
`H, I, T
`
`H, I, T
`
`H, I, T
`
`H, T
`
`Teva
`Exhibit No.
`20532
`
`2056
`
`2057
`
`2058
`
`2059
`
`2060
`
`2061
`
`2062
`
`2063
`
`2064
`
`2065
`
`
`
`

`

`Teva
`Exhibit No.
`
`IPR2018-01422, -01423, -01424, -01425, -01426, -01427
`
`Teva Description
`
`Objections
`
`143(8): 1066–1073 (2004)
`Gallai, V., et al., “Vasoactive peptide levels in the
`plasma of young migraine patients with and without aura
`assessed both interictally and ictally,” Cephalalgia
`15(1):384-390 (1995)
`Sarchielli, P., et al., “Nitric oxide metabolites,
`prostaglandins and trigeminal vasoactive peptides in
`internal jugular vein blood during spontaneous migraine
`attacks,” Cephalalgia, 20(10): 907-918 (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)
`Hendrikse, E.R., et al., “Molecular studies of CGRP and
`the CGRP family of peptides in the central nervous
`system,” Cephalalgia 39(3):403–419 (2019)
`Concise Dictionary of Biomedicine and Molecular
`Biology, pp. 40, 80 (Juo, P-S., ed.)
`Jain, R., “Physiological barriers to delivery of
`monoclonal antibodies and other macromolecules in
`tumors,” Cancer Research (Suppl.) 50: 814s-819s (1990)
`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)
`Tjen-A-Looi, S., et al., “CGRP and somatostatin
`modulate chronic hypoxic pulmonary hypertension,” Am.
`J. Physiol. 263(3): H681-H690 (1992)
`
`H, S, T, X
`
`H, S, T, X
`
`H
`
`H, S, T
`
`H, R, S, T
`
`H, R, S, T
`
`H, S, T
`
`H, S, T
`
`H, T
`
`H, S, T
`
`H, T
`
`4
`
`2066
`
`2067
`
`2068
`
`2070
`
`2073
`
`2075
`
`2077
`
`2078
`
`2079
`
`2082
`
`2084
`
`
`
`

`

`IPR2018-01422, -01423, -01424, -01425, -01426, -01427
`
`Teva Description
`
`Sagonowsky, E., “Amgen's quick Aimovig launch boosts
`blockbuster hopes for Lilly, Teva and Alder: analyst,”
`(Aug. 20, 2018) Fierce Pharma,
`https://www.fiercepharma.com/pharma/amgen-s-quick-
`aimovig-laun ch-has-implications-for-lilly-teva-and-
`alder-analyst, (last visited May 29, 2019)
`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)
`David J. King, Applications and Engineering of
`Monoclonal Antibodies, Chapter 1 Preparation,
`Structure and Function of Monoclonal Antibodies, 1-26
`(1998)
`An, Z., “Monoclonal antibodies – a proven and rapidly
`expanding therapeutic modality for human diseases,”
`Protein Cell 1(4): 319–330 (2010)
`Alberts, B., et al., Molecular Biology of the Cell, pp.
`1736-1780, 4th ed., Garland Science, Taylor & Francis
`Group, New York (2002)
`Köhler, G. and Milstein, C., “Continuous cultures of
`fused cells secreting antibody of predefined specificity,”
`Nature 256(5517): 495-497 (1975)
`Berger, M., et al., “Therapeutic Applications of
`Monoclonal Antibodies,” Am. J. Med. Sci. 324(1):14–30
`(2002)
`Siberil, S. and Teillaud, J., Antibodies Volume 2: Novel
`Technologies and Therapeutic Use, Chapter 12: Future
`Prospects In Antibody Engineering And Therapy, pp.
`199-215 (G. Subramanian, ed., Kluwer
`Academic/Plenum Publishers, New York (2004))
`
`5
`
`Objections
`
`A, H, T
`
`H, S, T
`
`H, S, T
`
`H, S, T
`
`H, I, T
`
`H, R, S, T
`
`H, I, S, T
`
`H, S, T
`
`H, S, T
`
`H, I, S
`
`Teva
`Exhibit No.
`2085
`
`2086
`
`2088
`
`2089
`
`2090
`
`2091
`
`2092
`
`2093
`
`2094
`
`2095
`
`
`
`

`

`IPR2018-01422, -01423, -01424, -01425, -01426, -01427
`
`Teva Description
`
`Daugherty, A.L. and Mrsny, R.J., “Formulation and
`delivery issues for monoclonal antibody therapeutics,”
`Advanced Drug Delivery Reviews 58(5-6): 686-706
`(2006)
`Lonberg, N., “Human antibodies from transgenic
`animals,” Nature Biotechnology 23(9): 1117–1125
`(2005)
`Presta, L.G., “Engineering of therapeutic antibodies to
`minimize immunogenicity and optimize function,”
`Advanced Drug Delivery Reviews 58(5-6): 640-656
`(2006)
`Winter, G., and Harris, W.J., “Humanized antibodies,”
`Trends in Pharmacological Sciences 14(5): 139-143
`(1993)
`Caldas, C., et al., “Humanization of the anti-CD18
`antibody 6.7: an unexpected effect of a framework
`residue in binding to antigen,” Molecular Immunology
`39(15): 941–952 (2003)
`Vaughan, T.J. , et al., “Human antibodies by design,” Nat.
`Biotechnol. 16(6): 535-539 (1998)
`Van Dijk, M.A., and Van de Winkel, J.G.J., “Human
`antibodies as next generation therapeutics,” Current
`Opinion in Chemical Biology 5(4):368-374 (2001)
`Jacobovits, A., “The long-awaited magic bullets:
`therapeutic human monoclonal antibodies from
`transgenic mice,” Exp. Opin. Invest. Drugs 7(4):607-614
`(1998)
`Conflict of Interest in Medical Research, Education and
`Practice, Lo, B. and Field, M.J., eds., pp.1-414, The
`National Academies Press, Washington, D.C. (2009)
`Bains, W., “Failure rates in drug discovery and
`development: will we ever get any better?,” Drug
`Discovery World 9-18 (2004)
`
`Objections
`
`H, R, T
`
`H, S
`
`H, R, S
`
`H, S
`
`H, S
`
`H, S
`
`H, T
`
`H, T
`
`H, R, T
`
`H, S, T
`
`6
`
`Teva
`Exhibit No.
`2096
`
`2097
`
`2098
`
`2099
`
`2100
`
`2101
`
`2102
`
`2103
`
`2104
`
`2105
`
`
`
`

`

`IPR2018-01422, -01423, -01424, -01425, -01426, -01427
`
`Teva Description
`
`Objections
`
`H, S, T
`
`H, S, T
`
`A, H, R, S,
`T
`
`H, R, S, T
`
`H, I, R, T
`
`H, S, T
`
`Stockwin, L.H. and Holmes, S., “The role of therapeutic
`antibodies in drug discovery,” Biochemical Society
`Transactions 31(2): 433-436 (2003)
`Ravandi, F., et al., “Modulation of Cellular Signaling
`Pathways: Prospects for Targeted Therapy in
`Hematological Malignancies,” Clinical Cancer Research
`9(2): 535–550 (2003)
`European Medicines Agency Guideline On Strategies To
`Identify And Mitigate Risks For First-Inhuman Clinical
`Trials With Investigational Medicinal Products July 2017
`Janssens, N., et al., “The Wnt-dependent signaling
`pathways as target in oncology drug discovery,”
`Investigational New Drugs 24(4): 263–280 (2006)
`British National Formulary, pp.448-445, Vol. 52, BMJ
`Publishing Group Ltd and RPS Publishing (2006)
`Knauf, M.J., et al., “Relationship of Effective Molecular
`Size to Systemic Clearance in Rats of Recombinant
`Interleukin-2 Chemically Modified with Water-soluble
`Polymers,” J. Biol. Chem. 263(29): 15064-15070 (1988)
`Chapman, A.P., et al., “Therapeutic antibody fragments
`with prolonged in vivo half-lives,” Nature Biotechnology
`17(8): 780 – 783 (1999)
`Murray, J.L., “Monoclonal Antibody Treatment of Solid
`Tumors: A Coming of Age,” Seminars in Oncology 27(6
`suppl. 11): 64-70 (2000)
`Fujimori, K., et al., “Modeling Analysis of the Global
`and Microscopic Distribution of Immunoglobulin G,
`F(ab’)2, and Fab in Tumors,” Cancer Research 49(20):
`5656-5663 (1989)
`Leveque, D., et al., “Pharmacokinetics of Therapeutic
`Monoclonal Antibodies Used in Oncology,” Anticancer
`Research 25(3C): 2327-2344 (2005)
`Maraschiello, C., “The Relevance of Immunogenicity in H, R, S, T
`
`H, S, T
`
`H, S, T
`
`H, S, T
`
`H, S, T
`
`7
`
`Teva
`Exhibit No.
`2107
`
`2108
`
`2109
`
`2110
`
`2111
`
`2112
`
`2113
`
`2114
`
`2115
`
`2116
`
`2117
`
`
`
`

`

`Teva
`Exhibit No.
`
`IPR2018-01422, -01423, -01424, -01425, -01426, -01427
`
`Teva Description
`
`Objections
`
`Preclinical Development,” J. Bioanal. Biomed. 6:1-4
`(2014)
`Hamuro, L., et al., “Perspectives on Subcutaneous Route
`of Administration as an Immunogenicity Risk Factor for
`Therapeutic Proteins,” J. Pharm. Sci., 106: 2946-2954
`(2017)
`Schunk, M.K. and Macullum, G.E., “Applications and
`Optimization of Immunization Procedures,” ILAR
`Journal 46(3): 241-247 (2005)
`Fallowfield, L., et al., “ Patients’ preference for
`administration of endocrine treatments by injection or
`tablets: results from a study of women with breast
`cancer,” Annals of Oncology 17(2): 205–210 (2006)
`Chowdhury, P.S. and Wu, H., “Tailor-made antibody
`therapeutics,” Methods 36(1): 11-24 (2005)
`Oh-hashi, Y., et al., “Elevated Sympathetic Nervous
`Activity in Mice Deficient in αCGRP,” Circ Res.
`89(11):983-990 (2001)
`Wimalawansa, S.J., “Age-Related Increase of Calcitonin
`Gene-Related Peptide in Rat Thyroid and Circulation,”
`Peptides 12(5): 1143-1147 (1991)
`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)
`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)
`Ferrara, N., “VEGF as a Therapeutic Target in Cancer,”
`Oncology 69(suppl. 3):11–16 (2005)
`
`H, R, S, T
`
`H, S, T
`
`H, R, S, T
`
`H, S, T
`
`H, T
`
`H, S, T, X
`
`H, S, T
`
`A, H, S, T
`
`H, S, T
`
`H, T
`
`8
`
`2118
`
`2119
`
`2120
`
`2121
`
`2122
`
`2124
`
`2125
`
`2126
`
`2127
`
`2128
`
`
`
`

`

`IPR2018-01422, -01423, -01424, -01425, -01426, -01427
`
`Teva Description
`
`Objections
`
`Yotsumoto, F., et al., “Efficacy of Ligand-based
`Targeting for the EGF System in Cancer,” Anticancer
`Research 29: 4879-4886 (2009)
`Zeller, J., et al., “CGRP function-blocking antibodies
`inhibit neurogenic vasodilatation without affecting heart
`rate or arterial blood pressure in the rat,” Brit. J.
`Pharmacol. 155: 1093-1103 (2008)
`Therapeutic Antibody Engineering, Chapter 12:
`Antibody fragments, 265-297 (William Strohl and Lila
`Strohl, No. 11, 2012)
`Wertheimer, A., et al., “Too Many Drugs? The Clinical
`And Economic Value Of Incremental Innovations,”
`Investing in Health: The Social and Economic Benefits of
`Health Care Innovation 14: 77-118 (2001)
`Watkins, B.A., et al., “Resistance of Human
`Immunodeficiency Virus Type 1 to Neutralization by
`Natural Antisera Occurs through Single Amino Acid
`Substitutions That Cause Changes in Antibody Binding
`at Multiple Sites,” Journal of Virology 70(12): 8431–
`8437 (1996)
`Tulip, W.R., et al., “Crystal Structures of two Mutant
`Neuraminidase-Antibody Complexes with Amino Acid
`Substitutions in the Interface,” J. Mol. Biol. 227(1): 149-
`159 (1992)
`Goldberg, M.E., and Djavadi –Ohaniance, L., “Methods
`for measurement of antibody/antigen affinity based on
`ELISA and RIA,” Current Opinion in Immunology 5(2):
`278-281 (1993)
`Praiter, J.D., “Basic Principles of Radioimmunoassay
`Testing: A Simple Approach,” Journal of Nuclear
`Medicine Technology 13(1): 34-43 (1985)
`Juul, R., et al., “Calcitonin gene-related peptide (human
`α-CGRP) counteracts vasoconstriction in human
`subarachnoid haemorrhage,” Neuroscience Letters
`170(1) : 67- 70 (1994)
`
`H, T
`
`H, R, S
`
`H, I, R, S
`
`H, S, T
`
`H, S, T
`
`H, S, T
`
`H, T
`
`H, T
`
`H, S, T
`
`9
`
`Teva
`Exhibit No.
`2129
`
`2130
`
`2131
`
`2132
`
`2133
`
`2134
`
`2135
`
`2136
`
`2139
`
`
`
`

`

`IPR2018-01422, -01423, -01424, -01425, -01426, -01427
`
`Teva Description
`
`Objections
`
`Christopoulos, G., et al., “Multiple Amylin Receptors
`Arise from Receptor Activity Modifying Protein
`Interaction with the Calcitonin Receptor Gene Product,”
`Molecular Pharmacology, 56(1):235-242 (1999)
`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)
`
`H, T
`
`H, S, T
`
`H, S, T
`
`H, R, S, T
`
`H, S, T
`
`H, S, T
`
`H, S, T
`
`H, S, T
`
`H, T
`
`H, T
`
`10
`
`Teva
`Exhibit No.
`2140
`
`2143
`
`2144
`
`2145
`
`2146
`
`2147
`
`2148
`
`2149
`
`2150
`
`2151
`
`
`
`

`

`IPR2018-01422, -01423, -01424, -01425, -01426, -01427
`
`Teva Description
`
`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)
`Weintraub, A., “Teva abandons Ajovy's cluster headache
`ambitions, clearing a path for Lilly to forge a new
`market,” (April 24, 2019), Fierce Pharma,
`https://www.fiercepharma.com/pharma/teva-ditches-trial-
`ajovy-clust er-headache-clearing-a-path-for-lilly-to-forge-
`a-new-market, (last visited May 29, 2019)
`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)
`Edvinsson, L. and Uddmann, R., “Neurobiology in
`primary headaches,” Brain Research Reviews 48: 438–
`456 (2005)
`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,”
`11
`
`Objections
`
`H, S, T
`
`A, H, T
`
`H, S, T
`
`H, S, T, X
`
`H, S, T
`
`H, T
`
`H, S, T
`
`H, S, T
`
`H, T
`
`Teva
`Exhibit No.
`2152
`
`2153
`
`2154
`
`2155
`
`2156
`
`2157
`
`2158
`
`2159
`
`2161
`
`
`
`

`

`Teva
`Exhibit No.
`
`IPR2018-01422, -01423, -01424, -01425, -01426, -01427
`
`Teva Description
`
`Objections
`
`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)
`Lauritsen, C. and Silberstein, S., “Calcitonin Gene-
`Related Peptide, Monoclonal Antibodies, and Migraine,”
`Practical Neurol. 21-29 (2016)
`Underwood, E., “A Shot at Migraine,” Science
`351(6269): 116-119 (2016)
`Ajovy (fremanezumab-vfrm) prescribing information
`(Jan. 2019) FDA Label
`Maasumi, K., et al., “CGRP and Migraine: The Role of
`Blocking Calcitonin Gene- Related Peptide Ligand and
`Receptor in the Management of Migraine,” Drugs 78:
`913–928 (2018)
`Court, E., “New migraine drugs have promise — and a
`$8,500 price tag,” Market Watch,
`https://www.marketwatch.com/story/new-migraine-
`drugs-have-prom ise-and-a-8500-price-tag-2017-06-
`09/print, (last visited May 16, 2019)
`D’Amico, D. and Tepper, S.J., “Prophylaxis of migraine:
`general principles and patient acceptance,”
`Neuropsychiatric Disease and Treatment 4(6): 1155–
`1167 (2008)
`
`H, T
`
`H, T
`
`H, T
`
`H, T
`
`H, T
`
`A, H, T
`
`H, S, T
`
`A, H, T
`
`H, R, T
`
`12
`
`2162
`
`2163
`
`2164
`
`2166
`
`2167
`
`2168
`
`2169
`
`2170
`
`2171
`
`
`
`

`

`IPR2018-01422, -01423, -01424, -01425, -01426, -01427
`
`Teva Description
`
`Carleton, J., “CGRP Antibodies: A Potential Game
`Changer in Migraine Prevention,” (July 11, 2015),
`Migraine Disorders,
`https://www.migrainedisorders.org/news-and-
`updates/blog/cgrp-anti bodies-a-potential-game-changer-
`in-migraine-prevention, (last visited March 20, 2019)
`McAllister, P., “Monoclonal Antibodies and Migraine:
`What the Neurologist Needs to Know,” Practical
`Neurol. 18-22 (2017)
`Elvidge, S., “Anti-CGRP antibodies for migraine turn
`industry heads,” Nature Biotechnology 32(8): 707 (2014)
`Ning, X., et al., “Long-Term Safety Fremanezumab:
`Results of a 1-Year Study,” poster no. P1.015 at The
`American Academy of Neurology 71st Annual Meeting
`(2019)
`McAllister, P., et al., “Long-Term Impact of
`Fremanezumab on Response Rates, Acute Headache
`Medication Use, and Disability in Patients with Chronic
`Migraine: Results of 1-Year Study,” poster no. P2.015 at
`The American Academy of Neurology 71st Annual
`Meeting (2019)
`Brandes, J.L., et al., “Long-Term Impact of
`Fremanezumab on Response Rates, Acute Headache
`Medication Use, and Disability in Patients with Episodic
`Migraine: Results of 1-Year Study,” poster no. P1.005 at
`The American Academy of Neurology 71st Annual
`Meeting (2019)
`Maassen van den Brink, A.M., et al., “Is CGRP Receptor
`Blockade Cardiovascularly Safe? Appropriate Studies
`are Needed,” Headache 58(8):1257-1258 (2018)
`Dumas, P., “To People With Migraine – What You Need
`To Know,” (June 28, 2017), Migraine Again,
`https://migraineagain.com/cgrp-medications-migraine/,
`(last visited March 20, 2019)
`
`Objections
`
`A, H, T
`
`H, T
`
`H, T
`
`A, H, S, T
`
`A, H, S, T
`
`A, H, S, T
`
`H, R, S, T,
`X
`
`A, H, T
`
`13
`
`Teva
`Exhibit No.
`2172
`
`2173
`
`2174
`
`2175
`
`2176
`
`2177
`
`2178
`
`2179
`
`
`
`

`

`IPR2018-01422, -01423, -01424, -01425, -01426, -01427
`
`Teva Description
`
`Objections
`
`Tso, A.R. and Goadsby, P.J., “Anti-CGRP Monoclonal
`Antibodies: the Next Era of Migraine Prevention?,”
`Curr. Treat. Options Neurol. 19: 27 (2017)
`Silberstein, S.D., et al., “The Effect of Beginning
`Treatment With Fremanezumab on Headache and
`Associated Symptoms in the Randomized Phase 2 Study
`of High Frequency Episodic Migraine: Post-Hoc
`Analyses on the First 3 Weeks of Treatment,” Headache
`59(3): 1-11 (2018)
`Dolgin, E., “Migraine drug race turns its final corner,
`FDA decisions in sight,” Nature Biotechnol. 36(3): 207-
`208 (2018)
`Digre, K., “American Headache Society president:
`‘Exciting, cautious’ time for patients with migraine,”
`(October 11, 2018), www.healio.com,
`https://www.healio.com/family-
`medicine/neurology/news/online/%7Be3e75c0f-21c7-
`4de1-a78c-5e3a2f0ba8d6%7D/american-headache-
`society-president-exciting-cautious-time-for-patients-
`with-migraine, (last visited March 20, 2019)
`Bigal, M. E., et al., “From LBR‑101 to Fremanezumab
`for Migraine,” CNS Drugs 32:1025–1037 (2018)
`Pietrini, U., et al., “Hypertension in headache patients?
`A clinical study,” Acta Neurol. Scand. 112: 259–264
`(2005)
`Cassata, C., “Kristin Chenoweth: Migraine Is More Than
`a Bad Headache,” (April 3, 2019) Healthline,
`https://www.healthline.com/health-news/kristin-chenoweth-
`on-living-with-migraines, (last visited March 30, 2019)
`Poyner, D.R., et al., “International Union of
`Pharmacology. XXXII. The Mammalian Calcitonin
`Gene-Related Peptides, Adrenomedullin, Amylin, and
`Calcitonin Receptors,” Pharmacol. Rev. 54(2):233-246
`(2002)
`
`H, T
`
`H, S, T
`
`H, T
`
`A, H, T
`
`H, S, T
`
`H, S, T
`
`A, H, T
`
`H, T
`
`14
`
`Teva
`Exhibit No.
`2180
`
`2181
`
`2182
`
`2183
`
`2184
`
`2185
`
`2186
`
`2187
`
`
`
`

`

`IPR2018-01422, -01423, -01424, -01425, -01426, -01427
`
`Teva Description
`
`de Turenne, V., “Game Changer,” UCLA Health,
`https://www.uclahealth.org/u-magazine/game-changer-
`1741, (last visited May 20, 2019)
`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/jul y-neuro-2018/promise-and-
`pitfalls-of-preventing-migraine-with-cgrp
`-inhibitors, (last visited March 20, 2019)
`Silbertstein, S.D., “Preventative Migraine Treatment,”
`Continuum (Minneap Minn) 21(4):973–989 (2015)
`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)
`Scher, A. I., et al., “Comorbidity of migraine,” Curr.
`Opin. Neurol. 18(3): 305–310 (2005)
`Chaverneff, F., “Fremanezumab May Help Reduce
`Medication Overuse in Chronic Migraine,” (July 1,
`2018), Neurology Advisor,
`https://www.neurologyadvisor.com/conference-
`highlights/ahs-2018/f remanezumab-may-help-reduce-
`medication-overuse-in-chronic-migraine/, (last visited
`May 21, 2019)
`Mavridis, T., et al., “Anti-Calcitonin Gene-Related
`Peptide Monoclonal Antibodies: Adverse Effects. What
`Do We Really Know? A Literature Review,” EMJ Innov.
`3(1): 64-72 (2019)
`Buhlmann, N., et al., “A Receptor Activity Modifying
`Protein (RAMP)2- Dependent Adrenomedullin Receptor
`Is a Calcitonin Gene-Related Peptide Receptor when
`Coexpressed with Human RAMP1,” Endocrinology
`140(6): 2883-2890 (1999)
`Fraser, N. J., et al., “The Amino Terminus of Receptor
`Activity Modifying Proteins Is a Critical Determinant of
`Glycosylation State and Ligand Binding of Calcitonin
`
`15
`
`Objections
`
`A, H, S, T
`
`A, H, R, T
`
`H, S, T
`
`H, T
`
`H, S, T, X
`
`A, H, T
`
`A, H, R, S
`
`H, T
`
`H, T
`
`Teva
`Exhibit No.
`2188
`
`2189
`
`2190
`
`2193
`
`2194
`
`2195
`
`2196
`
`2197
`
`2198
`
`
`
`

`

`Teva
`Exhibit No.
`
`IPR2018-01422, -01423, -01424, -01425, -01426, -01427
`
`Teva Description
`
`Objections
`
`Receptor-Like Receptor,” Molecular Pharmacology,
`55(6): 1054–1059 (1998)
`Marquez de Prado, B. and Russo, A.F., “CGRP receptor
`antagonists: A new frontier of anti-migraine
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`(2006)
`Allen, D.B., “Limitations of short- term studies in
`predicting long-term adverse effects of inhaled
`corticosteroids,” Allergy 54: 29-34 (1999)
`International Conference on Harmonisation of Technical
`Requirements for Registration of Pharmaceuticals for
`Human Use, "ICH Harmonised Tripartite Guideline: The
`extent of population exposure to assess clinical safety for
`drugs intended for long-term treatment of non-life-
`threatening conditions," (October 1994)
`"ADDING MULTIMEDIA Teva Announces U.S.
`Approval of AJOVY (fremanezumab-vfrm) Injection,
`the First and Only Anti-CGRP Treatment with Both
`Quarterly and Monthly Dosing for the Preventive
`Treatment of Migraine in Adults," BusinessWire,
`https://www.businesswire.com/news/home/2018091400561
`3/en/ (last visited May 30, 2019)
`Foord, S.M. and Craig, R.K., “Isolation and
`characterisation of a human calcitonin-gene-related-
`peptide receptor,” Eur. J. Biochem. 170(1-2): 373 - 379
`(1987)
`Glaser, A., “Emgality approval brings new hope for
`preventing migraines,” Migraine Again,
`https://migraineagain.com/emgality-cluster-migraine/
`(last visited May 23, 2019)
`Limmroth, V., et al., “Features of medication overuse
`headache following overuse of different acute headache
`drugs,” Neurology 59: 1011–1014 (2002)
`
`H, R, S, T
`
`H, S, T
`
`A, H, S, T
`
`A, H, S, T
`
`H, S, T
`
`A, H, S, T
`
`H, S, T
`
`16
`
`2199
`
`2200
`
`2201
`
`2202
`
`2203
`
`2205
`
`2206
`
`
`
`

`

`IPR2018-01422, -01423, -01424, -01425, -01426, -01427
`
`Teva Description
`
`Objections
`
`Benschop, R.J., et al., “Development of a novel antibody
`to calcitonin gene-related peptide for the treatment of
`osteoarthritis-related pain,” Osteoarthritis and Cartilage
`22:578-585 (2014)
`Emgality (galcanezumab-gnlm) Prescribing Information
`(Sept. 2018)
`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)
`Center for Drug Evaluation and Research, "Application
`Number: 761063Orig1s000, Product Quality Review(s),"
`Sept. 27, 2018, Emgality
`Center for Drug Evaluation and Research, "Application
`Number: 761089Orig1s000, Product Quality Review(s),"
`Aug. 16, 2018, Ajovy
`Center for Drug Evaluation and Research, "Application
`Number: 761089Orig1s000, Non-Clinical Review(s),"
`Sept. 14, 2018, Ajovy
`Sheykhzade , M. and Nyborg, N., “Caliber dependent
`calcitonin gene-related peptide-induced relaxation in rat
`coronary arteries: effect of K+ on the tachyphylaxis,”
`European Journal of Pharmacology 351: 53–59 (1998)
`Sidiropoulos, P. I., and Boumpas, D. T., “Lessons
`learned from anti-CD40L treatment in systemic lupus
`erythematosus patients,” Lupus 13: 391–397 (2004)
`Revoltella, R., et al. “Comparison of conventional
`immunoassays (RIA, ELISA) with surface plasmon
`resonance for pesticide detection and monitoring,”
`Biotherapy 11: 135-45 (1998)
`Aimovig (erenumab-aooe) prescribing information (May
`2018) FDA Label
`
`H, S, T
`
`H, T
`
`H, S, T
`
`H, S
`
`A, H, I, S,
`T, Z
`
`A, H, I, S,
`T, Z
`
`A, H, I, S,
`T, Z
`
`H
`
`H, S, T
`
`H, S
`
`A, H, T
`
`17
`
`Teva
`Exhibit No.
`2207
`
`2208
`
`2209
`
`2215
`
`2216
`
`2217
`
`2218
`
`2219
`
`2220
`
`2221
`
`2238
`
`
`
`

`

`IPR2018-01422, -01423, -01424, -01425, -01426, -01427
`
`Teva Description
`
`"8.2 Medication-overuse headache (MOH) – ICHD-
`3,IHS Classification ICHD-3," ICHD-3.org,
`https://www.ichd-3.org/8-headache-attributed-to-a-
`substance-or-its- withdrawal/8-2-medication-overuse-
`headache-moh/, (last visited May 28, 2019)
`Hepp, Z., et al., “Persistence and switching patterns of
`oral migraine prophylactic medications among patients
`with chronic migraine: A retrospective claims analysis,”
`Cephalalgia 37(5): 470–485 (2017)
`“Medication Overuse Headache,” American Migraine
`Foundation,
`https://americanmigrainefoundation.org/resource-
`library/medication- overuse-headache-2/ (last visited
`May 28, 2019)
`Kavulich, M., “Interview with Dr. Goadsby – What to
`Expect to CGRP,” Migraine,
`https://migraine.com/clinical/interview-dr-goadsby-
`expect-cgrp/ (last visited May 30, 2019)
`Wimalawansa, S. J., et al., “Regional Distribution of
`Calcitonin Gene-Related Peptide and Its Specific
`Binding Sites in Rats with Particular Reference to the
`Nervous System,” Neuroendocrinology 46(2): 131-136
`(1987)
`Choksi, T., et al., “Comparison of the expression of
`calcitonin receptor-like receptor (CRLR) and receptor
`activity modifying proteins (RAMPs) with CGRP and
`adrenomedullin binding in cell lines,” British Journal of
`Pharmacology 136(5): 784 - 792 (2002)
`Silberstein, S.D., et al., “Fremanezumab May Reduce
`Medi