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`Filed: July 11, 2019
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`Filed on behalf of: Eli Lilly and Company
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`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 IPR2018-01710 (Patent No. 8,586,045)
`Case IPR2018-01711 (Patent No. 9,884,907)
`Case IPR2018-01712 (Patent No. 9,884,908)1
`
`_____________________
`
`PETITIONER’S SECOND OBJECTIONS
`TO PATENT OWNER’S EVIDENCE
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`1
`The word-for-word identical paper is filed in each proceeding identified in the
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`caption.
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`
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`IPR2018-01710, -01711, -01712
`
`
`The Federal Rules of Evidence (“FRE”) generally apply to proceedings
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`
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`before the Board. 37 C.F.R. § 42.62(a). Pursuant to 37 C.F.R. § 42.64(b)(1) and
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`the FRE, Petitioner Eli Lilly and Company (“Lilly” or “Petitioner”) submits the
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`following objections to certain exhibits submitted by Patent Owner Teva
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`Pharmaceuticals International GMBH (“Teva” or “Patent Owner”). These
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`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
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`A:
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`under FRE 901 and 902.
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`B: Lilly objects to the exhibit under the Best Evidence Rule (FRE 1001-1003).
`
`H:
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`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
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`801 and 802) that does not fall under any exceptions, including FRE 803,
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`804, 805, and 807.
`
`Lilly objects to the exhibit as an incomplete document (FRE 106).
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`To the extent Teva relies upon the exhibit to show the state of the art, Lilly
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`objects to the exhibit as not relevant, confusing, unfairly prejudicial, and
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`wasting time because the exhibit has not been shown to qualify as prior art
`1
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`I:
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`R:
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`IPR2018-01710, -01711, -01712
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`(FRE 401-403).
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`S:
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`Lilly objects to the exhibit as not relevant, confusing, unfairly prejudicial,
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`and wasting time because it has not been cited in one or more of Teva’s
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`Patent Owner Responses (FRE 401-403).
`
`T:
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`Lilly objects to the exhibit as not relevant, confusing, unfairly prejudicial,
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`and wasting time because it is not relevant to any issue in these IPR
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`proceedings (FRE 401-403).
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`Z:
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`Lilly objects to the exhibit because it was improperly filed as redacted
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`without any protective order, in violation of the Board’s Scheduling Order
`
`(Paper 15 at 2).
`
`B.
`
` Objections
`
`Teva
`Exhibit No.
`20522
`
`20532
`
`Teva Description
`
`Inman, S., “Anti-CGRP Monoclonal Antibodies
`Transforming Migraine Treatment,” (Oct. 22, 2018),
`NeurologyLive
`https://www.neurologylive.com/conferences/ana-
`2018/anticgrp-monoclonal-antibodies-transforming-
`migraine-treatment, (last visited May 20, 2019)
`“Pain Like No Other,” UCLA Health David Geffen
`School of Medicine 38(2): 18-25 (2018)
`
`Objections
`
`A, H, R, T
`
`A, H, R, T
`
`
`2
`Lilly timely objected to these documents during the deposition of Dr.
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`Charles. 37 C.F.R. § 42.64(a); Ex. 2192, 61:4-17, 186:6-11.
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`
`
`2
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`
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`IPR2018-01710, -01711, -01712
`
`Teva Description
`
`Objections
`
`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)
`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 143(8): 1066–1073 (2004)
`
`H, S
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`H, S
`
`H, T
`
`H
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`H, T
`
`H, T
`
`H, I, T
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`H, I, T
`
`H, I, T
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`H, T
`
`3
`
`Teva
`Exhibit No.
`2056
`
`2057
`
`2058
`
`2059
`
`2060
`
`2061
`
`2062
`
`2063
`
`2064
`
`2065
`
`
`
`
`
`IPR2018-01710, -01711, -01712
`
`Teva Description
`
`Objections
`
`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)
`4
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`H, S, T
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`H, S, T
`
`H
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`H, S, T
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`H, R, S, T
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`H, R, S, T
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`H, S, T
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`H, S, T
`
`H, T
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`H, S, T
`
`H, T
`
`Teva
`Exhibit No.
`2066
`
`2067
`
`2068
`
`2070
`
`2073
`
`2075
`
`2077
`
`2078
`
`2079
`
`2082
`
`2084
`
`
`
`
`
`IPR2018-01710, -01711, -01712
`
`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-launch-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,
`Chapters 1-3 (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))
`
`Objections
`
`A, H, T
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`H, S, T
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`H, S, T
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`H, S, T
`
`H, I, T
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`H, R, S, T
`
`H, I, S, T
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`H, S, T
`
`H, S, T
`
`H, I, S
`
`5
`
`Teva
`Exhibit No.
`2085
`
`2086
`
`2088
`
`2089
`
`2090
`
`2091
`
`2092
`
`2093
`
`2094
`
`2095
`
`
`
`
`
`IPR2018-01710, -01711, -01712
`
`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
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`H, S
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`H, R, S
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`H, S
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`H, S
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`H, S
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`H, T
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`H, T
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`H, R, T
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`H, S, T
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`6
`
`Teva
`Exhibit No.
`2096
`
`2097
`
`2098
`
`2099
`
`2100
`
`2101
`
`2102
`
`2103
`
`2104
`
`2105
`
`
`
`
`
`IPR2018-01710, -01711, -01712
`
`Teva Description
`
`Objections
`
`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)
`
`H, S, T
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`H, S, T
`
`A, H, R, S, T
`
`H, R, S, T
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`H, I, R, T
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`H, S, T
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`H, S, T
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`H, S, T
`
`H, S, T
`
`H, S, T
`
`7
`
`Teva
`Exhibit No.
`2107
`
`2108
`
`2109
`
`2110
`
`2111
`
`2112
`
`2113
`
`2114
`
`2115
`
`2116
`
`
`
`
`
`IPR2018-01710, -01711, -01712
`
`Teva Description
`
`Objections
`
`Maraschiello, C., “The Relevance of Immunogenicity
`in 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
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`H, R, S, T
`
`H, S, T
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`H, R, S, T
`
`H, S, T
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`H, T
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`H, S, T
`
`H, S, T
`
`A, H, S, T
`
`H, S, T
`
`H, T
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`8
`
`Teva
`Exhibit No.
`2117
`
`2118
`
`2119
`
`2120
`
`2121
`
`2122
`
`2124
`
`2125
`
`2126
`
`2127
`
`2128
`
`
`
`
`
`IPR2018-01710, -01711, -01712
`
`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
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`H, T
`
`H, S, T
`
`9
`
`Teva
`Exhibit No.
`2129
`
`2130
`
`2131
`
`2132
`
`2133
`
`2134
`
`2135
`
`2136
`
`2139
`
`
`
`
`
`IPR2018-01710, -01711, -01712
`
`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
`
`
`
`
`
`IPR2018-01710, -01711, -01712
`
`Teva Description
`
`Objections
`
`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-cluster-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,” Lancet Neurol. 13: 885–92 (2014)
`11
`
`H, S, T
`
`A, H, T
`
`H, S, T
`
`H, S, T
`
`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
`
`
`
`
`
`IPR2018-01710, -01711, -01712
`
`Teva Description
`
`Objections
`
`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-promise-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
`
`Teva
`Exhibit No.
`2162
`
`2163
`
`2164
`
`2166
`
`2167
`
`2168
`
`2169
`
`2170
`
`2171
`
`
`
`
`
`IPR2018-01710, -01711, -01712
`
`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)
`
`Objections
`
`A, H, T
`
`H, T
`
`H, T
`
`A, H, S, T
`
`A, H, S, T
`
`A, H, S, T
`
`H, R, S, T
`
`13
`
`Teva
`Exhibit No.
`2172
`
`2173
`
`2174
`
`2175
`
`2176
`
`2177
`
`2178
`
`
`
`
`
`IPR2018-01710, -01711, -01712
`
`Teva Description
`
`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)
`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)
`
`Objections
`
`A, H, T
`
`H, T
`
`H, S, T
`
`H, T
`
`A, H, T
`
`H, S, T
`
`H, S, T
`
`A, H, T
`
`14
`
`Teva
`Exhibit No.
`2179
`
`2180
`
`2181
`
`2182
`
`2183
`
`2184
`
`2185
`
`2186
`
`
`
`
`
`IPR2018-01710, -01711, -01712
`
`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)
`
`Objections
`
`A, H, S, T
`
`A, H, R, T
`
`H, S, T
`
`H, T
`
`H, S, T
`
`A, H, T
`
`A, H, R, S
`
`H, T
`
`15
`
`Teva
`Exhibit No.
`2188
`
`2189
`
`2190
`
`2193
`
`2194
`
`2195
`
`2196
`
`2197
`
`
`
`
`
`IPR2018-01710, -01711, -01712
`
`Teva Description
`
`Objections
`
`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 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
`medications,” Drug Discovery Today 3(4): 593-597
`(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)
`“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/20180914
`005613/en/ADDING-MULTIMEDIA-Teva-
`Announces-U.S.-Approval-AJOVYTM (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)
`
`H, T
`
`H, R, S, T
`
`H, S, T
`
`A, H, S, T
`
`A, H, S, T
`
`H, S, T
`
`A, H, S, T
`
`16
`
`Teva
`Exhibit No.
`2198
`
`2199
`
`2200
`
`2201
`
`2202
`
`2203
`
`2205
`
`
`
`
`
`IPR2018-01710, -01711, -01712
`
`Teva Description
`
`Objections
`
`Limmroth, V., et al., “Features of medication overuse
`headache following overuse of different acute headache
`drugs,” Neurology 59: 1011–1014 (2002)
`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)
`
`H, S, T
`
`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
`
`17
`
`Teva
`Exhibit No.
`2206
`
`2207
`
`2208
`
`2209
`
`2215
`
`2216
`
`2217
`
`2218
`
`2219
`
`2220
`
`2221
`
`
`
`
`
`IPR2018-01710, -01711, -01712
`
`Teva Description
`
`Objections
`
`Dreier, J.P., et al., “Opening of the blood-barrier
`preceding cortical edema in a severe attach of FHM
`type II,” Neurology 64: 2145-2147 (2005)
`Smith, M., “Hyperperfusion with vasogenic leakage by
`fMRI in migraine with prolonged aura,” Neurology
`58(8): 1308-1310 (2002)
`U.S. Securities and Exchange Commission Form 10-Q
`for Pfizer, Inc. (April 2, 2006)
`Ho, T.W., et al., “CGRP and its receptors provide new
`insights into migraine pathophysiology,” Nat. Rev.
`Neurol. 6: 573–582 (2010)
`Pollack, A., “Pfizer to Buy Rinat, a Biotechnology
`Drug Maker,” The New York Times, April 7, 2006
`“Pfizer Delivers Strong Second-Quarter 2006 Results,
`Driven By Performance Of Major In-Line And New
`Products,” U.S. Securities and Exchange Commission,
`Exhibit 99, July 20, 2006,
`https://www.sec.gov/Archives/edgar/data/78003/00012
`7528706003681/pi6456ex99.txt (last visited June 14,
`2019)
`Clinical Trial NCT01011296, “First In Human Study
`To Evaluate The Safety, Tolerability, Pharmacokinetics
`And Pharmacodynamics Of PF-04427429
`Administered Intravenously To Healthy Adult
`Volunteers”, downloaded from
`https://clinicaltrials.gov/ct2/show/NCT01011296?term
`=PF-04427429&rank=2 (last visited June 27, 2019)
`Clinical Trial NCT01117233, “Study In Healthy Adult
`Volunteers To Evaluate The Safety, Tolerability,
`Pharmacokinetics And Pharmacodynamics Of PF-
`04427429”, downloaded from
`https://clinicaltrials.gov/ct2/show/NCT01117233?term
`=PF-04427429&rank=3 (last visited June 27, 2019)
`
`H, T
`
`H, T
`
`A, H, R, T
`
`H, R, T
`
`H, R, T
`
`A, H, R, T
`
`A, H, R, T
`
`A, H, R, T
`
`18
`
`Teva
`Exhibit No.
`2222
`
`2223
`
`2225
`
`2226
`
`2227
`
`2228
`
`2229
`
`2230
`
`
`
`
`
`IPR2018-01710, -01711, -01712
`
`Teva Description
`
`Clinical Trial NCT01165723, “A Clinical Study
`Evaluating The Safety And Tolerability Of PF-
`04427429 In Healthy Adult Volunteers. The
`Pharmacokinetics And Pharmacodynamics Of PF-
`04427429 Will Also Be Investigated”, downloaded
`from
`https://clinicaltrials.gov/ct2/show/NCT01165723?term
`=PF-04427429&rank=4 (last visited June 27, 2019)
`Clinical Trial NCT01147432, “Acute response
`Capsaicin Flare Study”, downloaded from
`https://clinicaltrials.gov/ct2/show/NCT01147432?term
`=PF-04427429&rank=5 (last visited June 27, 2019)
`Clinical Trial NCT01511497, “Safety,
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