Paper No. ____
`Date Filed: October 20, 2016
`
`
`
`
`Filed On Behalf Of:
`Novartis AG
`
`By:
`Nicholas N. Kallas
`NKallas@fchs.com
`ZortressAfinitorIPR@fchs.com
`(212) 218-2100
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`PAR PHARMACEUTICAL, INC.,
`
`Petitioner,
`
`v.
`
`NOVARTIS AG,
`
`Patent Owner.
`
`
`
`Case IPR2016-00084
`
`Patent No. 5,665,772
`
`
`
`
`
`
`
`
`PATENT OWNER’S EXHIBIT LIST 5
`
`
`
`Date Filed: October 20, 2016
`
`
`
`
`Filed On Behalf Of:
`Novartis AG
`
`By:
`Nicholas N. Kallas
`NKallas@fchs.com
`ZortressAfinitorIPR@fchs.com
`(212) 218-2100
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`PAR PHARMACEUTICAL, INC.,
`
`Petitioner,
`
`v.
`
`NOVARTIS AG,
`
`Patent Owner.
`
`
`
`Case IPR2016-00084
`
`Patent No. 5,665,772
`
`
`
`
`
`
`
`
`PATENT OWNER’S EXHIBIT LIST 5
`
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`
`
`2001
`
`Mason J., “Cyclosporins Past, Present,
`and Future,” Transplant. Proc. 24(4)
`(Suppl. 2):61-63 (1992)
`
`2002
`
`2003
`
`Wenk, M. et al., “Pharmacokinetics of
`Cyclosporine G in Patients with Renal
`Failure,” Transplantation 45(3):558-61
`(1988)
`
`Traber, R. et al., “Cyclosporins—New
`Analogues by Precursor Directed
`Biosynthesis,” Journal of Antibiotics
`42(4):591-97 (1989)
`
`Mason
`
`Wenk
`
`Traber
`
`2004
`
`Borel, J., “The Cyclosporins,”
`Transplant. Proc. 21(1):810-15 (1989)
`
`Borel
`
`2005
`
`Rozycki, J. et al., “New Cyclosporin A
`Analogue: Synthesis and
`Immunosuppressive Activity,” Molecular
`Immunology 29(9):1043-47 (1992)
`
`Rozycki
`
`2006 U.S. Patent No. 4,764,503
`
`’503 patent
`
`2007 U.S. Patent No. 4,885,276
`
`’276 patent
`
`2008 U.S. Patent No. 5,116,816
`
`’816 patent
`
`2009 U.S. Patent No. 5,122,511
`
`’511 patent
`
`
`
`1
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2010
`
`Rosen, M. & Schreiber, S., “Natural
`Products as Probes of Cellular Function:
`Studies of Immunophilins,” Angew.
`Chem. Int. Ed. Engl. 31:384-400 (1992)
`
`2011
`
`Fagiuoli, S. et al., “FK 506: A New
`Immunosuppressive Agent for Organ
`Transplantation. Pharmacology,
`Mechanism of Action and Clinical
`Applications,” Ital. J. Gastrolenterol.
`24(6):355-60 (1992)
`
`2012
`
`Keeffe, E. B., “Liver Transplantation—
`Challenges for the Future,” Western
`Journal of Medicine 155(5):541-44
`(1991)
`
`Rosen
`
`Fagiuoli
`
`Keeffe
`
`2013 U.S. Patent No. 5,068,323
`
`’323 patent
`
`2014 U.S. Patent No. 4,980,466
`
`’466 patent
`
`2015 U.S. Patent No. 5,143,918
`
`’918 patent
`
`2016 U.S. Patent No. 4,929,611
`
`’611 patent
`
`2017 U.S. Patent No. 5,011,844
`
`’844 patent
`
`2018
`
`EP 0 427 680
`
`EP 680
`
`
`
`2
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2019
`
`Carpenter, C. B., “Immunosuppression in
`Organ Transplantation,” New Eng. J.
`Med. 322(17):1224-26 (1990)
`
`Carpenter
`
`2020
`
`2021
`
`2022
`
`2023
`
`Parlevliet, K. J. & Schellekens, P. T. A.,
`“Monoclonal Antibodies in Renal
`Transplantation: A Review,” Transplant.
`Int. 5(4):234-46 (1992)
`
`Parlevliet
`
`Cramer, D. V. et al., “The Effect of a
`New Immunosuppressive Drug,
`Brequinar Sodium, on Heart, Liver, and
`Kidney Allograft Rejection in the Rat,”
`Transplantation, 53(2):303-08 (1992)
`
`Bartlett, R. R. et al., “Leflunomide
`(HWA 486), a Novel Immunomodulating
`Compound for the Treatment of
`Autoimmune Disorders and Reactions
`Leading to Transplantation Rejection,”
`Agents and Actions 32(1/2):10-21 (1991)
`
`Sollinger, H. W. et al., “RS-61443
`(Mycophenolate Mofetil): A Multicenter
`Study for Refractory Kidney Transplant
`Rejection,” Ann. Surg. 216(4):513-19
`(1992)
`
`Cramer
`
`Bartlett
`
`Sollinger
`
`
`
`3
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2024
`
`2025
`
`Mita K. et al., “Advantages of Mizoribine
`Over Azathioprine in Combination
`Therapy With Cyclosporine for Renal
`Transplantation,” Transplant. Proc.
`22(4):1679-81 (1990)
`
`Iino, Y. et al., “Improvement of Renal
`Function in Transplanted Kidneys with a
`New Immunosuppressive Drug, 15-
`Deoxyspergualin: Treatment of Chronic
`Rejection,” Transplant. Proc.
`24(4):1381-82 (1992)
`
`Mita
`
`Iino
`
`2026 U.S. Patent No. 4,952,579
`
`’579 patent
`
`2027 U.S. Patent No. 5,061,787
`
`’787 patent
`
`2028 U.S. Patent No. 5,137,917
`
`’917 patent
`
`2029
`
`EP 0 181 592
`
`EP 592
`
`2030 U.S. Patent No. 4,847,381
`
`’381 patent
`
`2031 U.S. Patent No. 4,968,701
`
`’701 patent
`
`2032
`
`Aulton, M. E. (Ed.), Chapters 3, 6, 8, 14,
`Pharmaceutics: The Science of Dosage
`Form Design (1988)
`
`Aulton
`
`
`
`4
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2033
`
`2034
`
`Silverman, R.B., Chapter 8,“Prodrugs
`and Drug Delivery Systems,” The
`Organic Chemistry of Drug Design and
`Drug Action (1992)
`
`Ansel, H. & Popovich, N., Chapter 4,
`“Dosage Form Design: Biopharmaceutic
`Considerations,” Pharmaceutical Dosage
`Forms and Drug Delivery Systems, 5th
`Edition (1990)
`
`Silverman
`
`Ansel
`
`2035 U.K. Patent Application GB 2 222 770 A
`
`GB 770
`
`2036
`
`Takada, K. et al., “Development of a
`New Carrier for Cyclosporine A With
`Selectivity for Lymphatics,” Transplant.
`Proc. 19(1):1711-12 (1987)
`
`Takada
`
`2037 U.S. Patent No. 4,916,138
`
`’138 patent
`
`2038 U.S. Patent No. 5,120,726
`
`’726 patent
`
`2039 U.S. Patent No. 5,102,876
`
`’876 patent
`
`2040 U.S. Patent No. 5,138,051
`
`’051 patent
`
`2041 U.S. Patent No. 5,091,389
`
`’389 patent
`
`2042 U.S. Patent No. 5,164,399
`
`’399 patent
`
`
`
`5
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2043
`
`2044
`
`2045
`
`Brookhaven Protein Databank Entry
`1FKB (produced by Par in the related
`litigation) (Release Date October 31,
`1993)
`
`Pauling, L., “7-4 Aromatic
`Hydrocarbons, Benzene,” General
`Chemistry Dover Edition (1988)
`
`PDB Entry
`
`Pauling
`
`Lemke, T., Chapters 10, 11, 12, Review of
`Organic Functional Groups Second
`Edition (1988)
`
`Lemke Ch. 10-12
`
`2046 U.S. Patent No. 5,118,677
`
`’677 patent
`
`2047
`
`Franz, D. et al., “Efficacy and Safety of
`Everolimus for Subependymal Giant Cell
`Astrocytomas Associated with Tuberous
`Sclerosis Complex (EXIST-1): A
`Multicentre, Randomised, Placebo-
`Controlled Phase 3 Trial,” Lancet
`381:125–32 (2013)
`
`Franz
`
`2048
`
`Afinitor® Package Insert
`(Revised: 01/2015)
`
`Afinitor® PI
`
`2049
`
`Goldin, A. et al., “Current Results of the
`Screening Program at the Division of
`Cancer Treatment, National Cancer
`Institute,” Europ. J. Cancer 17:129-42
`(1981)
`
`Goldin
`
`
`
`6
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2050
`
`2051
`
`Marsoni, S. & R., Wittes, “Clinical
`Development of Anticancer Agents – A
`National Cancer Institute Recipients,”
`Cancer Treatment Reports 68(1):77-85
`(1984)
`
`Xuong, N. et al., “Use of the Multiwire
`Area Detector Diffractometer as a
`National Resource for Protein
`Crystallography,” Acta Cryst. B41:267-
`69 (1985)
`
`Marsoni
`
`Xuong
`
`2052
`
`Merck Index, Immunosuppressants for
`Human Therapeutic Use, available from
`Royal Society of Chemistry (02/2016)
`
`Merck Index
`
`2053
`
`Rapamune® Package Insert
`(Revised 05/2015)
`
`Rapamune® PI
`
`2054
`
`Kahan, B. et al., “A Phase I Study of a 4-
`week Course of SDZ-RAD (RAD) in
`Quiescent Cyclosporine-Prednisone-
`Treated Renal Transplant Recipients,”
`Transplantation 68(8):1100-06 (1999)
`
`Kahan
`
`2055
`
`Zortress® Package Insert
`(Revised 11/2015)
`
`Zortress® PI
`
`
`
`7
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2056
`
`Podder, H. et al., “Pharmacokinetic
`Interactions Augment Toxicities of
`Sirolimus/Cyclosporine Combinations,”
`J. Am. Soc. Nephrology 12:1059-71
`(2001)
`
`2057
`
`GB Application 9221220 (October 9,
`1992) from certified file history of U.S.
`Patent App. No. 08/416 673
`
`2058
`
` Reserved
`
`2059
`
`2060
`
`Motzer, R. et al., “Efficacy of Everolimus
`in Advanced Renal Cell Carcinoma: A
`Double-Blind, Randomised, Placebo-
`Controlled Phase III Trial,” Lancet
`372:449-56 (2008)
`
`Bissler, J. et al., “Everolimus for
`Angiomylipoma Associated with
`Tuberous Sclerosis Complex Or Sporadic
`Lymphangioleimyomatosis (EXIST-2): A
`Multicenter, Randomized, Double-Blind,
`Placebo-Controlled Trial,” Lancet
`381:817-24 (2013)
`
`Podder
`
`GB 220
`
`
`
`Motzer
`
`Bissler
`
`2061
`
`Yao, J. et al., “Everolimus for Advanced
`Pancreatic Neuroendocrine Tumors,”
`New Eng. J. Med. 364(6):514-23 (2011)
`
`Yao
`
`
`
`8
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2062
`
`2063
`
`2064
`
`2065
`
`2066
`
`2067
`
`Yardley, D. et al., “Everolimus Plus
`Exemestane in Postmenopausal Patients
`with HR+ Breast Cancer: BOLERO-2
`Final Progression-Free Survival
`Analysis,” Adv. Ther. 30:870-84 (2013)
`
`Wersäll, P. “Interleukin-2 and Interferon
`in Renal Cell Carcinoma,” Med.
`Oncology & Tumor Pharmacother.,
`9(4):71-76 (1992)
`
`Stahl, M. et al., “Cytokines and Cytotoxic
`Agents in Renal Cell Carcinoma: A
`Review,” Seminars in Oncology,
`19(2)(suppl. 4):70-79 (1992)
`
`Yardley
`
`Wersäll
`
`Stahl
`
`Merimsky, O. & Chaitchik, S., “Our
`Experience with interferon Alpha: Renal
`Cell Carcinoma,” Mol. Biother. 4(3):130-
`34 (1992)
`
`Merimsky
`
`Moertel, C. et al., “Streptozocin-
`Doxorubicin, Streptozocin-Fluorouracil,
`or Chlorozotocin in the Treatment of
`Advanced Islet-Cell Carcinoma,” New
`Engl. J. Med. 326(8):519-23 (1992)
`
`Sledge, G. & Antman, K., “Progress in
`Chemotherapy for Metastatic Breast
`Cancer,” Seminars in Oncology
`19(3):317-32 (1992)
`
`Moertel
`
`Sledge
`
`
`
`9
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`Greenberg, E. J., “The Treatment of
`Metastatic Breast Cancer,” CA-A Cancer
`Journal for Clinicians 41(4):242-56
`(1991)
`
`Greenberg
`
`2068
`
`2069
`
`Yagoda, A. et al., “Chemotherapy for
`Advanced Renal-Cell Carcinoma: 1983-
`1993,” Seminars in Oncology 22(1):42-
`60 (1995)
`
`2070
`
`Summary of Afinitor® Sales
`
`2071
`
`Excerpts from Novartis’ 2009-2015 Form
`20-F
`
`Adams, S., “Breast Cancer Drug
`Everolimus ‘Biggest Advance in Years,’”
`Telegraph, September 18, 2012.
`available at
`http://www.telegraph.co.uk/news/health/n
`ews/9548828/Breast-cancer-drug-
`everolimus-biggest-advance-in-
`years.html (accessed 01/22/2016)
`
`Chustecka, Z., ‘“Strongest Ever Data’ in
`Breast Cancer With Everolimus,”
`Medscape Medical News, September 26,
`2011. available at
`http://www.medscape.com/viewarticle/75
`0365 (accessed 01/25/2016)
`
`2072
`
`2073
`
`
`
`10
`
`Yagoda
`
`
`
`
`
`Adams
`
`Chustecka
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2074
`
`Fedele, P. et al., “Recent Advances in the
`Treatment of Hormone Receptor Positive
`HER2 Negative Metastatic Breast
`Cancer,” Critical Reviews in
`Oncology/Hematology 94:291-301 (2015)
`
`Fedele
`
`2075 U.S. Patent No. 5,194,447
`
`’447 patent
`
`Donald, D.K. et al., “C10 N-Acyl
`Modified FK-506: A Possible Hybrid
`Analogue of the Transition State Of
`Peptidyl-Prolyl Cis-Trans Isomerization,”
`Tetr. Letters 32(10):1375-78 (1991)
`
`Donald
`
`Haliburton Energy Servs., Inc. v.
`Dynamic 3D Geosolutions LLC,
`IPR2014-1186, Paper 18 (P.T.A.B. Feb.
`18, 2015)
`
`
`
`
`
`
`
`
`
`2076
`
`2077
`
`2078
`
`Apotex Inc. v. Merck Sharp & Dohme
`Corp., IPR2015-00419, Paper 14
`(P.T.A.B. June 25, 2015)
`
`2079
`
`Pfizer Inc. v. Teva Pharms. USA, Inc.,
`555 F. App’x 961 (Fed. Cir. 2014)
`
`2080
`
`Mylan Pharms. Inc. v. AstraZeneca AB,
`IPR2015-01340, Paper 12 (P.T.A.B. Dec.
`9, 2015)
`
`
`
`11
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2081
`
`2082
`
`2083
`
`Janssen Pharm. N.V. v. Mylan Pharms.,
`Inc., 456 F. Supp. 2d 644 (D.N.J. 2006),
`aff’d, 223 Fed. App’x 999 (Fed. Cir.
`2007)
`
`Pfizer Inc. v. Mylan Pharms. Inc., 71 F.
`Supp. 3d 458 (D. Del. 2014), aff’d, No.
`2015-1131, 2016 WL 147840 (Fed. Cir.,
`Jan. 13, 2016)
`
`AstraZeneca Pharms. LP v. Anchen
`Pharms., Inc., No. 10-CV-1835 JAP TJB,
`2012 WL 1065458 (D.N.J. Mar. 29,
`2012) aff’d, 498 F. App’x 999 (Fed. Cir.
`2013)
`
`2084
`
`Lupin Ltd. v. Vertex Pharms. Inc.,
`IPR2015-00405, Paper 13 (P.T.A.B. July
`9, 2015)
`
`2085
`
`Neupak Inc. v. Ideal Mfg. & Sales Corp.,
`41 Fed. App’x 435, 440 (Fed. Cir. 2002)
`
`2086
`
`Janssen Pharm. N.V. v. Mylan Pharms.,
`Inc., 223 Fed. App’x 999 (Fed. Cir. 2007)
`affirming 456 F. Supp. 2d 644 (D.N.J.
`2006)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`12
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`Pfizer Inc. v. Mylan Pharms. Inc., No.
`2015-1131, 2016 WL 147840 (Fed. Cir.,
`Jan. 13, 2016) affirming 71 F. Supp. 3d
`458 (D. Del. 2014)
`
`Declaration in Support of Patent Owner
`Novartis’s Motion for Pro Hac Vice
`Admission of Christina Schwarz Under
`37 C.F.R. § 42.10
`
`Deposition Exhibit 2089 from the August
`9, 2016 Deposition of William L.
`Jorgensen
`
`Deposition Exhibit 2090 from the August
`9, 2016 Deposition of William L.
`Jorgensen
`
`2087
`
`2088
`
`2089
`(served
`but not
`filed)
`
`2090
`(served
`but not
`filed)
`
`
`
`
`
`
`
`
`
`2091
`
`Transcript of the August 9, 2016
`Deposition of William L. Jorgensen (with
`attached errata)
`
`Jorgensen
` Dep.
`
`2092 Declaration of Professor Alexander M.
`Klibanov
`
`2093
`
`Expert Declaration of William R. Roush,
`Ph.D.
`
`Klibanov
`
`Roush
`
`
`
`13
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2094
`
`Curriculum Vitae of William R. Roush,
`Ph.D.
`
`Roush C.V.
`
`2095
`
`Declaration of Howard A. Burris, III,
`M.D.
`
`Burris
`
`2096
`
`Curriculum Vitae of Howard A. Burris,
`III, M.D.
`
`Burris C.V.
`
`2097
`
`The Merck Index, 11th Edition
`(Budavari, S. ed., 1989), Entries 2013,
`3832, 4786, 6596, 7074, 7075, 7076,
`7206, and 7226
`
`Merck Index, 11th
`Edition
`
`2098
`
`The Merck Index, 10th Edition
`(Windholz, M. & Budavari, S. eds.,
`1983), Entries 1513, 1532
`
`Merck Index, 10th
`Edition
`
`2099 U.S. Patent No. 4,179,337
`
`’337 Patent
`
`2100
`
`Physicians’ Desk Reference (Medical
`Economics Data 46th ed. 1992), Entries
`for Today® and Semecid®
`
`1992 PDR(a)
`
`2101
`
`Histamine II and Anti-Histaminics,
`Chemistry, Metabolism and Physiological
`and Pharmacological Actions, Ch. II. A.
`I. (Silva, M. ed.,1978), 175-178
`
`Histamine II and
`Anti-Histaminics
`
`2102
`
` Reserved
`
`
`
`
`
`14
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2103
`
`Szász, G. & Budvári-Bárány, Z., Chapter
`5, “β-Adrenergic Antagonists (β-
`Blockers),” Pharmaceutical Chemistry of
`Antihypertensive Agents (1991)
`
`Szász
`
`2104
`
`Lemke, T., Chapter 6, “Alcohols,”
`Review of Organic Functional Groups
`Second Edition (1988)
`
`Lemke Ch. 6
`
`Carey
`
`1991 PDR
`
`Partridge Trial
`
`2105
`
`2106
`
`2107
`
`Carey, F., Chapter 4, §§ 4.1-4.7,
`“Introduction to Functional Groups.
`Alcohols and Alkyl Halides,” Organic
`Chemistry (1987)
`
`Physicians’ Desk Reference (Medical
`Economics Data 45th ed. 1991),Entries
`for Lutrepulse® for Injection and
`Relefact® TRH
`
`Excerpts of Transcript of Trial Testimony
`of J. Partridge, Novartis v. Breckenridge,
`Roxane and Par (C.A. Nos. 14-1043-
`RGA, 14-1196-RGA and 14-1289-RGA),
`(D. Del. August 29, 2016), Pages 1, 54,
`217-18, 228-29, 250-51 (Rough
`Transcript)
`
`2108 U.S. Patent No. 4,388,307
`
`’307 Patent
`
`
`
`15
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2109
`
`Venkataramanan, R. et al.,
`“Pharmacokinetics of FK 506 in
`Transplant Patients,” Transplant. Proc.
`23(6):2736-40 (1991)
`
`Venkataramanan
`
`2110
`
` Reserved
`
`2111
`
`Sinkula, A.A. & Yalkowsky, S.H.,
`“Rationale for Design of Biologically
`Reversible Drug Derivatives: Prodrugs,”
`J. of Pharm. Sci. 64(2):181- 210 (1975)
`
`
`
`Sinkula &
`Yalkowsky
`
`2112
`
`Bundgaard, H., “Novel chemical
`approaches in prodrug design,” Drugs of
`the Future 16(5):443-458 (1991)
`
`Bundgaard
`
`2113 WO 92/21341
`
`WO ’341
`
`2114
`
`Physicians’ Desk Reference (Medical
`Economics Data 46th ed. 1992), Entries
`for Various Commercial Formulations
`Containing Amides, Esters, or Carboxylic
`Acids
`
`1992 PDR(b)
`
`2115
`
`Nonionic Surfactants, Chapters, 1, 4, and
`5, (Schick, M., ed., 1967)
`
`Schick
`
`2116
`
`Physicians’ Desk Reference (Medical
`Economics Data 46th ed. 1992), Entry for
`Sandimmune®
`
`Sandimmune®
`PDR
`
`
`
`16
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2117 U.S. Patent No. 5,023,264
`
`’264 patent
`
`2118 U.S. Patent No. 5,162,333
`
`’333 patent
`
`2119 U.S. Patent No. 5,177,203
`
`’203 patent
`
`2120
`
`U.S. Patent No. 5,665,772 (updated to
`include February 2016 Certificate of
`Correction)
`
`’772 patent
`
`2121 U.S. Patent No. 5,221,670
`
`’670 patent
`
`2122 U.S. Patent No. 5,260,299
`
`’299 patent
`
`2123
`
`2124
`
`2125
`
`Protein Databank File 1FKB, Atomic
`Structure of the Rapamycin Human
`Immunophilin FKBP-12 Complex
`(available at
`https://files.rcsb.org/view/1FKB.pdb,
`accessed 9/9/2016)
`
`Oldenziel, O.H. et al., “A General One-
`Step Synthesis of Nitriles from Ketones
`Using Tosylmethyl Isocyanide.
`Introduction of a One-Carbon Unit,” J.
`Org. Chem., 42(19):3114–18 (1977)
`
`Scott, W. J. et al., “Palladium-Catalyzed
`Coupling of Vinyl Triflates with
`Organostannanes. A Short Synthesis of
`Pleraplysillin-1,” J. Am. Chem. Soc.,
`106:4630-32 (1984)
`
`PDB File 1FKB
`
`Oldenziel
`
`Scott 1984
`
`
`
`17
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2126
`
`2127
`
`Stille, J. K., “The Palladium-Catalyzed
`Cross-Coupling Reactions of Organotin
`Reagents with Organic Electrophiles,”
`Angew. Chem. Int. Ed. Engl., 25:508-24
`(1986)
`
`Scott, W.J. and McMurry, J.E., “Olefin
`Synthesis via Organometallic Coupling
`Reactions of Enol Triflates,” Acc. Chem.
`Res., 21(2):47-54 (1988)
`
`Stille
`
`Scott 1988
`
`2128
`
`Farina, V. et al., “The Stille Reaction,”
`Org. React., 50:1-652 (1997)
`
`Farina
`
`2129 U.S. Patent Application No. 07/598,270
`File History
`
`’270 Application
`File History
`
`2130 U.S. Patent No. 5,118,678
`
`2131
`
`Excerpts from Defendant Par
`Pharmaceutical, Inc.’s Initial Invalidity
`Contentions dated March 26, 2015
`
`2132
`
`2133
`
`Excerpts of Transcript of Trial Testimony
`of S. Tullius, Novartis v. Breckenridge,
`Roxane and Par (C.A. Nos. 14-1043-
`RGA, 14-1196-RGA and 14-1289-RGA)
`(D. Del. September 1, 2016), Pages 1201,
`1205, 1308, (Rough Tr.)
`
`Vlaminck, H. et al., “Prospective Study
`on Late Consequences of Subclinical
`Non-Compliance with
`Immunosuppressive Therapy in Renal
`Transplant Patients,” Am. J. Transplant.
`4:1509-13 (2004)
`
`’678 patent
`
`Par Invalidity
`Contentions
`
`Tullius Trial
`
`Vlaminck
`
`
`
`18
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2134
`
`2135
`
`De Simone, P., “Everolimus With
`Reduced Tacrolimus Improves Renal
`Function in De Novo Liver Transplant
`Recipients: A Randomized Controlled
`Trial,” Am. J. Transplant. 12:3008-20
`(2012)
`
`Fischer, L., “Three-year Outcomes in De
`Novo Liver Transplant Patients
`Receiving Everolimus With Reduced
`Tacrolimus: Follow-up Results From a
`Randomized Multicenter Study,”
`Transplantation 99(7):1455-62 (2015)
`
`2136 U.S. Patent No. 5,130,307
`
`2137
`
`2138
`
`2139
`
`Whiting, P.H., “Toxicity of Rapamycin—
`A Comparative and Combination Study
`with Cyclosporine at Immunotherapeutic
`Dosage in the Rat,” Transplantation
`52:203-08 (1991)
`
`Merck Manual of Diagnosis and Therapy,
`16th Edition (Berkow, R. & Fletcher, A.J.
`eds., 1992)
`
`Sollinger H.W. et al., “RS-61443—A
`Phase I Clinical Trial and Pilot Rescue
`Study,” Transplantation 53:428-32
`(1992)
`
`2140 U.S. Patent No. 4,868,153
`
`2141 U.S. Patent No. 4,861,776
`
`2142 U.S Patent No. 5,233,036 File History
`
`De Simone
`
`Fischer
`
`’307 patent
`
`Whiting
`
`Merck Manual
`
`Sollinger 1992(a)
`
`’153 patent
`
`’776 patent
`
`Hughes File
`History
`
`
`
`19
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2143 U.S. Patent No. 5,023,263
`
`2144
`
`2145
`
`2146
`
`2147
`
`2148
`
`2149
`
`Collier, D. St. J., “Rapamycin in
`Experimental Renal Allografts in
`Primates,” Transplant. Proc. 23(4):2246-
`47 (1991)
`
`Excerpts of Transcript of Trial Testimony
`of M. Ratain, Novartis v. Breckenridge,
`Roxane and Par (C.A. Nos. 14-1043-
`RGA, 14-1196-RGA and 14-1289-RGA)
`(D. Del. August 31, 2016), Pages 769-72,
`957-58, 967, 971, 990-1003, 1010-15
`
`Physicians’ Desk Reference (Medical
`Economics Data 47th ed. 1993), Entry for
`Proleukin®
`
`Belldegrun, A. et al., “Immunotherapy
`for Renal Cell Carcinoma.” Seminars in
`Urology 10(1):23-27 (1992)
`
`Physicians’ Desk Reference (Medical
`Economics Data 46th ed. 1992), Entry for
`Intron® A
`
`Skillings, J., et al. “A Phase II Study of
`Recombinant Tumor Necrosis Factor in
`Renal Cell Carcinoma: A Study of the
`National Cancer Institute of Canada
`Clinical Trials Group.” J. of Immunology
`11:67-70 (1992)
`
`’263 patent
`
`Collier
`
`Ratain Trial
`
`Proleukin® PDR
`
`Belldegrun
`
`Intron® A PDR
`
`Skillings
`
`
`
`20
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2150
`
`FDA Guidance for Industry “Clinical
`Trial Endpoints for the Approval of
`Cancer Drugs and Biologics.” (May
`2007) (available at
`http://www.fda.gov/downloads/Drugs/.../
`Guidances/ucm071590.pdf, accessed
`1/15/2016)
`
`2151
`
`Afinitor® Package Insert
`(Revised: 02/2016)
`
`Excerpts of Transcript of Deposition of
`M. Ratain, Novartis v. Breckenridge,
`Roxane and Par (C.A. Nos. 14-1043-
`RGA, 14-1196-RGA and 14-1289-RGA)
`(D. Del. Apr. 11, 2016) (with errata
`sheet)
`
`FDA Guidance
`
`Afinitor®
`February 2016
`Label
`
`Ratain Dep.
`
`2152
`
`2153
`
`(revised
`version
`served
`but not
`filed)
`
`2154
`
`Novartis press release dated July 20, 2012
`(available at
`http://www.multivu.com/players/English/
`56006-novartis-afinitor-fda-approval/,
`accessed 1/14/2016)
`
`Novartis July 2012
`PR
`
`Macheledt, J., et al., “Phase II evaluation
`of interferon added to tamoxifen in the
`treatment of metastatic breast cancer,”
`Breast Cancer Research and Treatment
`18:165-70 (1991)
`
`Macheledt
`
`
`
`21
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2155
`
`2156
`
`2157
`
`2158
`
`2159
`
`2160
`
`Douros, J. & Suffness, M, “New
`antitumor substances of natural origin,”
`Cancer Treatment Reviews 8:63-87
`(1981)
`
`Douros, J. & Suffness, M, “New Natural
`Products Under Development at the
`National Cancer Institute,” New Drugs in
`Cancer Chemotherapy 153-75 (Carter,
`S.K. et al. eds., 1981)
`
`Houchens, D.P. et al., “Human Brain
`Tumor Xenografts In Nude Mice as a
`Chemotherapy Model,” Eur. J. Cancer
`Clin. Oncol. 19(6):799-805 (1983)
`
`Benvenuto, J.A. et al., “Phase II clinical
`and pharmacological study of didemnin B
`in patients with metastatic breast cancer,”
`Invest. New Drugs 10:113-17 (1992)
`
`Schilsky, R. et al., “Phase II study of
`echinomycin in patients with advanced
`breast cancer: A report of cancer and
`leukemia group B protocol 8641,” Invest.
`New Drugs 9:269-72 (1991)
`
`Baumann, G., “Molecular Mechanism of
`Immunosuppressive Agents,”
`Transplant. Proc. 24(4) Suppl. 2:4-7
`(1992)
`
`Douros
`
`Douros II
`
`Houchens
`
`Benvenuto
`
`Schilsky
`
`Baumann
`
`
`
`22
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2161
`
`Penn, I. & Starzl, T.E.,
`“Immunosuppression and Cancer.”
`Transplant Proc. 5(1):943-47 (1973)
`
`2162
`
`2163
`
`2164
`
`Muggia, F.M. & Green, M.D., “New
`anthracycline antitumor antibiotics,”
`Critical Reviews in Oncol./Hematol.
`11:43-64 (1993)
`
`Duran, I. et al., “A phase II trial of
`temsirolimus in metastatic
`neuroendocrine carcinomas (NECs),” J.
`Clin. Oncol. 23(16 Supp.):215s (3096)
`(2005)
`
`Vorobiof, D.A. & Falkson, G., “Phase II
`Study of High-dose 4’-Epidoxorubicin in
`the Treatment of Advanced
`Gastrointestinal Cancer,” Eur. J. Cancer
`Clin. Oncol., 25(3):563-64 (1989)
`
`Penn
`
`Muggia
`
` Duran Abstract
`
`Vorobiof
`
`2165
`
`Physicians’ Desk Reference (Medical
`Economics Co. 44th ed. 1990), Entries
`for Adriamycin® PFS and RDF
`
`Adriamycin® PDR
`
`2166
`
`Rowinsky, E.K., &Donehower, R.C.,
`“The Clinical Pharmacology and Use of
`Antimicrotubule Agents in Cancer
`Chemotherapeutics,” Pharmac. Ther.
`52:35-84 (1991)
`
`Rowinsky
`
`
`
`23
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2167
`
`2168
`
`2169
`
`2170
`
`Foster, B.J. et al., “A strategy for the
`development of two clinically active
`cisplatin analogs: CBDCA and CHIP,”
`Cancer Chemother. Pharmacol. 25:395-
`404 (1990)
`
`Foster
`
`Physicians’ Desk Reference (Medical
`Economics Co. 44th ed. 1990), Entry for
`Leukeran®
`
`Leukeran® PDR
`
`Physicians’ Desk Reference (Medical
`Economics Data 46th ed. 1992), Entry for
`Nolvadex®
`
`Nolvadex® PDR
`
`Pandya, K.J. et al., “A Randomized,
`Phase II Trial of Two Dose Levels of
`Temsirolimus (CCI-779) in Patients with
`Extensive-Stage Small-Cell Lung Cancer
`Who Have Responding or Stable Disease
`after Induction Chemotherapy: A Trial of
`the Eastern Cooperative Oncology Group
`(E1500),” J. of Thoracic Oncology
`2(11):1036-41 (2007)
`
`Pandya
`
`2171
`
`Okuno, S. et al., “A Phase 2 Study of
`Temsirolimus (CCI-779) in Patients With
`Soft Tissue Sarcomas,” Cancer
`117(15):3468-75 (2011)
`
`Okuno
`
`
`
`24
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2172
`
`2173
`
`2174
`
`2175
`
`2176
`
`Chang, S.M. et al., “Phase II study of
`CCI-779 in patients with recurrent
`glioblastoma multiforme,”
`Investigational New Drugs 23:357-61
`(2005)
`
`Gonzalez-Angulo, A.M. et al., “Weekly
`nab-Rapamycin in Patients with
`Advanced Nonhematologic
`Malignancies: Final Results of a Phase I
`Trial,” Clin. Cancer Res. 19(19):5474-84
`(2013)
`
`Chang
`
`Gonzalez-Angulo
`
`Duran, I. et al., “A phase II clinical and
`pharmacodynamic study of temsirolimus
`in advanced neuroendocrine carcinomas,”
`Br. J. Cancer 95(9):1148-54 (2006)
`
`Duran
`
`O’Donnell, P.H. & Ratain, M.J.,
`“Evaluating the activity of temsirolimus
`in neuroendocrine cancer,” Br. J. Cancer
`96:177 (2007)
`
`O’Donnell
`
`Wolff, A.C. et al., “Randomized Phase III
`Placebo-Controlled Trial of Letrozole
`Plus Oral Temsirolimus As First-Line
`Endocrine Therapy in Postmenopausal
`Women With Locally Advanced or
`Metastatic Breast Cancer,” J. of Clin.
`Oncol. 31(2):195-202 (2013)
`
`Wolff
`
`
`
`25
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2177
`
`2178
`
`2179
`
`2180
`
`Acevedo-Gadea, C. et al., “Sirolimus and
`trastuzumab combination therapy for
`HER2-positive metastatic breast cancer
`after progression on prior trastuzumab
`therapy,” Breast Cancer Res. Treat.
`150:157-67 (2015)
`
`Bhattacharyya, G.S. et al., “Reversal of
`Tamoxifen Resistance (Hormone
`Resistance) by Addition of Sirolimus
`(mTOR Inhibitor) In Metastatic Breast
`Cancer,” Euro. J. Cancer 47:9 (2011)
`
`Hudes, G. et al., “Temsirolimus,
`Interferon Alfa, or Both for Advanced
`Renal-Cell Carcinoma,” N. Engl. J. Med.
`356(22):2271-81 (2007)
`
`Jimeno, A. et al., “Pharmacodynamic-
`Guided Modified Continuous
`Reassessment Method-Based, Dose-
`Finding Study of Rapamycin in Adult
`Patients With Solid Tumors,” J. Clin.
`Oncol. 26(25):4172-79 (2008)
`
`
`
`Acevedo-Gadea
`
`Bhattacharyya
`
`Hudes
`
`Jimeno
`
`
`
`26
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`Wyeth Press Release “Wyeth
`Pharmaceuticals Announces Termination
`of Phase 3 Clinical Program with Oral
`Temsirolimus in Women with Metastatic
`Breast Cancer.” (Mar. 16, 2006)
`(available at
`http://www.prnewswire.com/news-
`releases/wyeth-pharmaceuticals-
`announces-termination-of-phase-3-
`clinical-program-with-oral-temsirolimus-
`in-women-with-metastatic-breast-cancer-
`55380662.html, accessed 3/31/16)
`
`Wyeth Press
`Release
`
`Rapamycin Clinical Trials Summary
`Chart
`
`
`
`Abuchowski, A. & Davis, F.F., Chapter
`13, “Soluble Polymer-Enzyme Adducts,”,
`Enzymes as Drugs, (Holcenberg, J.S. &
`Roberts, J. eds.,1981)
`
`Abuchowski
`
`PDB-101, Guide to Understanding PDB
`Data (available at
`http://pdb101.rcsb.org/learn/guide-to-
`understanding-pdb-data/dealing-with-
`coordinates, accessed 9/14/2016)
`
`PDB Data Guide
`
`2181
`
`2182
`
`(revised
`version
`served
`but not
`filed)
`
`2183
`
`2184
`
`
`
`27
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2185
`
`Excerpts from Novartis’s RCC Tracking
`Reports
`
`RCC Tracking
`Reports
`
`2186
`
`Excerpts from Novartis’s Breast Cancer
`ATUs
`
`Breast Cancer
`ATUs
`
`2187
`(served
`but not
`filed)
`
`Information page for Organic Reactions,
`available at
`http://onlinelibrary.wiley.com/book/10.10
`02/0471264180 (accessed September 28,
`2016)
`
`2188
`(served
`but not
`filed)
`
`Author Guidelines for the American
`Journal of Transplantation, available at
`http://onlinelibrary.wiley.com/journal/10.
`1111/(ISSN)1600-
`6143/homepage/ForAuthors.html
`(accessed September 28, 2016)
`
`2189
`(served
`but not
`filed)
`
`Information page for Transplantation,
`available at
`http://journals.lww.com/transplantjournal
`/pages/aboutthejournal.aspx (accessed
`September 28, 2016)
`
`2190
`(served
`but not
`filed)
`
`Transcript of Trial Testimony of J.
`Partridge, Novartis v. Breckenridge,
`Roxane and Par (C.A. Nos. 14-1043-
`RGA, 14-1196-RGA and 14-1289-RGA),
`(D. Del. August 29, 2016) (Rough Tr.)
`
`
`
`28
`
`
`
`
`
`
`
`
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2191
`(served
`but not
`filed)
`
`Transcript of Trial Testimony of S.
`Tullius, Novartis v. Breckenridge, Roxane
`and Par (C.A. Nos. 14-1043-RGA, 14-
`1196-RGA and 14-1289-RGA) (D. Del.
`September 1, 2016) (Rough Tr.)
`
`2192
`(served
`but not
`filed)
`
`Transcript of Trial Testimony of M.
`Ratain, Novartis v. Breckenridge, Roxane
`and Par (C.A. Nos. 14-1043-RGA, 14-
`1196-RGA and 14-1289-RGA) (D. Del.
`August 31, 2016) (Rough Tr.)
`
`2193
`(served
`but not
`filed)
`
`2194
`(served
`but not
`filed)
`
`2195
`(served
`but not
`filed)
`
`Transcript of Deposition of M. Ratain,
`Novartis v. Breckenridge, Roxane and
`Par (C.A. Nos. 14-1043-RGA, 14-1196-
`RGA and 14-1289-RGA) (D. Del. Apr.
`11, 2016) (with errata sheet)
`
`Revised Expert Declaration of William R.
`Roush, Ph.D.
`
`Declaration of Drew Midwinter Pursuant
`to Fed. R. Evid. 902(11) Regarding
`Exhibits 2153, 2185, and 2186
`
`
`
`
`
`
`
`
`
`
`
`
`
`29
`
`
`
`Description
`
`Abbreviation
`
`Exhibit
`
`2196
`(served
`but not
`filed)
`
`2197
`(served
`but not
`filed)
`
`Declaration of Joseph Posluszny Pursuant
`to Fed. R. Evid. 902(11) Regarding
`Exhibit 2151
`
`Declaration of Nicholas N. Kallas
`Regarding Exhibits 2150, 2170-2174,
`2176, 2177, 2179, 2180, and 2182
`
`
`
`
`
`
`
`
`
`
`
`2198
`(served
`but not
`filed)
`
`Journal of Thoracic Oncology, Author
`Information Pack, available at
`https://www.elsevier.com/wps/find/journ
`aldescription.cws_home/738237?generate
`pdf=true
`
`2199
`(served
`but not
`filed)
`
`Cancer, “Overview”, available at
`http://onlinelibrary.wiley.com/journal/10.
`1002/(ISSN)1097-
`0142/homepage/ProductInformation.html
`
`2200
`(served
`but not
`filed)
`
`Investigational New Drugs, “Ethics and
`Disclosures”, available at
`http://www.springer.com/medicine/intern
`al/journal/10637/PS2?detailsPage=societi
`es
`
`
`
`30
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2201
`(served
`but not
`filed)
`
`Clinical Cancer Research, “Information
`for Authors,” available at
`http://aacrjournals.org/content/authors/ifo
`ra
`
`2202
`(served
`but not
`filed)
`
`British Journal of Cancer, “Aims and
`Scope”, available at
`http://www.nature.com/bjc/about/aims_sc
`ope.html
`
`2203
`(served
`but not
`filed)
`
`Journal of Clinical Oncology, “About
`Journal of Clinical Oncology”, available
`at http://jco.ascopubs.org/site/ifc
`
`2204
`(served
`but not
`filed)
`
`Breast Cancer Research and Treatment,
`“About this Journal”, available at
`http://www.springer.com/medicine/intern
`al/journal/10549
`
`
`
`
`
`
`
`
`
`
`
`31
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2205
`(served
`but not
`filed)
`
`New England Journal of Medicine,
`“Media Center Publication Process”,
`available at
`http://www.nejm.org/page/media-
`center/publication-process
`
`2206
`(served
`but not
`filed)
`
`European Journal of Cancer,
`“Introduction” available at
`http://www.ejcancer.com/content/authori
`nfo
`
`2207
`(served
`but not
`filed)
`
`PLOS Medicine, Criteria for Publication”,
`available at
`http://journals.plos.org/plosmedicine/s/jo
`urnal-information
`
`2208
`(served
`but not
`filed)
`
`Wagner et al, “Clinical Activity of mTOR
`Inhibition With Sirolimus in Malignant
`Perivascular Epithelioid Cell Tumors:
`Targeting the Pathogenic Activation of
`mTORC1 in Tumors,” J. Clin. Oncol.
`28:835-840 (2010)
`
`
`
`
`
`
`
`
`
`
`
`32
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2209
`(served
`but not
`filed)
`
`Piovesan et al., “Response to sirolimus in
`combination to tyrosine kinase inhibitors
`(TKI) in three cases of PDGFRA-D842V
`metastatic gastrointestinal stromal tumor
`(GIST),” J. Clin. Oncol. 27:10565 (2009)
`
`2210
`(served
`but not
`filed)
`
`Choo et al., “A Phase 1 dose-finding and
`pharmacodynamic study of rapamycin in
`combination with bevacizumab in
`patients with unresectable hepatocellular
`carcinoma,” Eur. J. Cancer 49:999-1008
`(2013)
`
`2211
`(served
`but not
`filed)
`
`Cloughesy et al., “Antitumor Activity of
`Rapamycin in a Phase I Trial for Patients
`with Recurrent PTEN-Deficient
`Glioblastoma,” PLoS Medicine 5(1):139-
`151 (2008)
`
`2212
`(served
`but not
`filed)
`
`Marrari et al., “Effect of adding sirolimus
`(s) to imatinib (im) on tumor response
`following secondary resistance to im in
`advanced chordoma,” J. Clin. Oncol.
`26:10541 (2008)
`
`
`
`
`
`
`
`
`
`
`
`33
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2213
`(served
`but not
`filed)
`
`2214
`(served
`but not
`filed)
`
`2215
`
`2216
`
`2217
`
`Stacchiotti et al., “Sirolimus in
`advanced hemangioendothelioma,” J
`Clin. Oncol. 31:10565 (2013)
`
`Stallone et al., “Sirolimus for Kaposi’s
`Sarcoma in Renal-Transplant
`Recipients,” New Engl. J. Med.
`352:1317-1323 (2005)
`
`Declaration in Support of Patent Owner
`Novartis’s Motion for Pro Hac Vice
`Admission of Charlotte Jacobsen Under
`37 C.F.R. § 42.10
`
`Declaration in Support of Patent Owner
`Novartis’s Motion for Pro Hac Vice
`Admission of Susanne L. Flanders Under
`37 C.F.R. § 42.10
`
`Declaration in Support of Patent Owner
`Novartis’s Motion for Pro Hac Vice
`Admission of Jared L. Stringham Under
`37 C.F.R. § 42.10
`
`
`
`
`
`
`
`
`
`
`
`2402
`
`Curriculum Vitae of Professor Alexander
`M. Klibanov
`
`
`
`
`
`34
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2403
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