Paper No. ____
`Date Filed: September 16, 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 3
`
`
`Date Filed: September 16, 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 3
`
`
`
`Description
`
`Abbreviation
`
`Exhibit
`
`2001
`
`2002
`
`2003
`
`Mason J., “Cyclosporins Past, Present,
`and Future,” Transplant. Proc. 24(4)
`(Suppl. 2):61-63 (1992)
`
`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
`
`Borel
`
`Rozycki
`
`’503 patent
`
`’276 patent
`
`’816 patent
`
`’511 patent
`
`2004
`
`Borel, J., “The Cyclosporins,”
`Transplant. Proc. 21(1):810-15 (1989)
`
`2005
`
`Rozycki, J. et al., “New Cyclosporin A
`Analogue: Synthesis and
`Immunosuppressive Activity,” Molecular
`Immunology 29(9):1043-47 (1992)
`
`2006
`
`U.S. Patent No. 4,764,503
`
`2007
`
`U.S. Patent No. 4,885,276
`
`2008
`
`U.S. Patent No. 5,116,816
`
`2009
`
`U.S. Patent No. 5,122,511
`
`1
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2010
`
`2011
`
`2012
`
`Rosen, M. & Schreiber, S., “Natural
`Products as Probes of Cellular Function:
`Studies of Immunophilins,” Angew.
`Chem. Int. Ed. Engl. 31:384-400 (1992)
`
`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)
`
`Keeffe, E. B., “Liver Transplantation—
`Challenges for the Future,” Western
`Journal of Medicine 155(5):541-44
`(1991)
`
`2013
`
`U.S. Patent No. 5,068,323
`
`2014
`
`U.S. Patent No. 4,980,466
`
`2015
`
`U.S. Patent No. 5,143,918
`
`2016
`
`U.S. Patent No. 4,929,611
`
`2017
`
`U.S. Patent No. 5,011,844
`
`2018
`
`EP 0 427 680
`
`2
`
`Rosen
`
`Fagiuoli
`
`Keeffe
`
`’323 patent
`
`’466 patent
`
`’918 patent
`
`’611 patent
`
`’844 patent
`
`EP 680
`
`
`
`Exhibit
`
`2019
`
`2020
`
`2021
`
`2022
`
`2023
`
`Description
`
`Abbreviation
`
`Carpenter, C. B., “Immunosuppression in
`Organ Transplantation,” New Eng. J.
`Med. 322(17):1224-26 (1990)
`
`Parlevliet, K. J. & Schellekens, P. T. A.,
`“Monoclonal Antibodies in Renal
`Transplantation: A Review,” Transplant.
`Int. 5(4):234-46 (1992)
`
`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)
`
`Carpenter
`
`Parlevliet
`
`Cramer
`
`Bartlett
`
`Sollinger
`
`3
`
`
`
`Exhibit
`
`2024
`
`Description
`Mita K. et al., “Advantages of Mizoribine
`Over Azathioprine in Combination
`Therapy With Cyclosporine for Renal
`Transplantation,” Transplant. Proc.
`22(4):1679-81 (1990)
`
`2025
`
`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)
`
`2026
`
`U.S. Patent No. 4,952,579
`
`2027
`
`U.S. Patent No. 5,061,787
`
`2028
`
`U.S. Patent No. 5,137,917
`
`2029
`
`EP 0 181 592
`
`2030
`
`U.S. Patent No. 4,847,381
`
`2031
`
`U.S. Patent No. 4,968,701
`
`2032
`
`Aulton, M. E. (Ed.), Chapters 3, 6, 8, 14,
`Pharmaceutics: The Science of Dosage
`Form Design (1988)
`
`Abbreviation
`
`Mita
`
`Iino
`
`’579 patent
`
`’787 patent
`
`’917 patent
`
`EP 592
`
`’381 patent
`
`’701 patent
`
`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)
`
`2037
`
`U.S. Patent No. 4,916,138
`
`2038
`
`U.S. Patent No. 5,120,726
`
`2039
`
`U.S. Patent No. 5,102,876
`
`2040
`
`U.S. Patent No. 5,138,051
`
`2041
`
`U.S. Patent No. 5,091,389
`
`2042
`
`U.S. Patent No. 5,164,399
`
`5
`
`Takada
`
`’138 patent
`
`’726 patent
`
`’876 patent
`
`’051 patent
`
`’389 patent
`
`’399 patent
`
`
`
`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)
`
`2048
`
`Afinitor® Package Insert
`(Revised: 01/2015)
`
`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)
`
`6
`
`Franz
`
`Afinitor® PI
`
`Goldin
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2050
`
`2051
`
`2052
`
`2053
`
`2054
`
`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)
`
`Merck Index, Immunosuppressants for
`Human Therapeutic Use, available from
`Royal Society of Chemistry (02/2016)
`
`Rapamune® Package Insert
`(Revised 05/2015)
`
`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)
`
`2055
`
`Zortress® Package Insert
`(Revised 11/2015)
`
`Marsoni
`
`Xuong
`
`Merck Index
`
`Rapamune® PI
`
`Kahan
`
`Zortress® PI
`
`7
`
`
`
`Exhibit
`
`2056
`
`2057
`
`Description
`Podder, H. et al., “Pharmacokinetic
`Interactions Augment Toxicities of
`Sirolimus/Cyclosporine Combinations,”
`J. Am. Soc. Nephrology 12:1059-71
`(2001)
`
`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)
`
`2061
`
`Yao, J. et al., “Everolimus for Advanced
`Pancreatic Neuroendocrine Tumors,”
`New Eng. J. Med. 364(6):514-23 (2011)
`
`Abbreviation
`
`Podder
`
`GB 220
`
`Motzer
`
`Bissler
`
`Yao
`
`8
`
`
`
`Exhibit
`
`2062
`
`Description
`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)
`
`Abbreviation
`
`Yardley
`
`2063
`
`2064
`
`2065
`
`2066
`
`2067
`
`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)
`
`Merimsky, O. & Chaitchik, S., “Our
`Experience with interferon Alpha: Renal
`Cell Carcinoma,” Mol. Biother. 4(3):130-
`34 (1992)
`
`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)
`
`9
`
`Wersäll
`
`Stahl
`
`Merimsky
`
`Moertel
`
`Sledge
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2068
`
`2069
`
`Greenberg, E. J., “The Treatment of
`Metastatic Breast Cancer,” CA-A Cancer
`Journal for Clinicians 41(4):242-56
`(1991)
`
`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
`
`Greenberg
`
`Yagoda
`
`Adams
`
`Chustecka
`
`
`
`Exhibit
`
`2074
`
`Description
`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)
`
`Abbreviation
`
`Fedele
`
`2075
`
`U.S. Patent No. 5,194,447
`
`’447 patent
`
`Donald
`
`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)
`
`Haliburton Energy Servs., Inc. v.
`Dynamic 3D Geosolutions LLC,
`IPR2014-1186, Paper 18 (P.T.A.B. Feb.
`18, 2015)
`
`Apotex Inc. v. Merck Sharp & Dohme
`Corp., IPR2015-00419, Paper 14
`(P.T.A.B. June 25, 2015)
`
`2076
`
`2077
`
`2078
`
`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
`
`2081
`
`Description
`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)
`
`Abbreviation
`
`2082
`
`2083
`
`2084
`
`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)
`
`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
`
`
`
`Abbreviation
`
`Jorgensen
`Dep.
`
`Klibanov
`
`Roush
`
`Exhibit
`
`2087
`
`Description
`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)
`
`2088
`
`2089
`(served
`but not
`filed)
`
`2090
`(served
`but not
`filed)
`
`2091
`
`2092
`
`2093
`
`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
`
`Transcript of the August 9, 2016
`Deposition of William L. Jorgensen (with
`attached errata)
`
`Declaration of Professor Alexander M.
`Klibanov
`
`Expert Declaration of William R. Roush,
`Ph.D.
`
`13
`
`
`
`Exhibit
`
`2094
`
`2095
`
`2096
`
`2097
`
`2098
`
`Description
`Curriculum Vitae of William R. Roush,
`Ph.D.
`
`Abbreviation
`
`Roush C.V.
`
`Declaration of Howard A. Burris, III,
`M.D.
`
`Burris
`
`Curriculum Vitae of Howard A. Burris,
`III, M.D.
`
`Burris C.V.
`
`The Merck Index, 11th Edition
`(Budavari, S. ed., 1989), Entries 2013,
`3832, 4786, 6596, 7074, 7075, 7076,
`7206, and 7226
`
`Merck Index, 11th
`Edition
`
`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
`
`Physicians’ Desk Reference (Medical
`Economics Data 46th ed. 1992), Entries
`for Today® and Semecid®
`
`’337 Patent
`
`1992 PDR(a)
`
`2100
`
`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
`
`
`
`Abbreviation
`
`Szász
`
`Lemke Ch. 6
`
`Carey
`
`1991 PDR
`
`Partridge Trial
`
`Exhibit
`
`Description
`
`2103
`
`2104
`
`2105
`
`2106
`
`2107
`
`Szász, G. & Budvári-Bárány, Z., Chapter
`5, “β-Adrenergic Antagonists (β-
`Blockers),” Pharmaceutical Chemistry of
`Antihypertensive Agents (1991)
`
`Lemke, T., Chapter 6, “Alcohols,”
`Review of Organic Functional Groups
`Second Edition (1988)
`
`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
`
`2109
`
`Description
`Venkataramanan, R. et al.,
`“Pharmacokinetics of FK 506 in
`Transplant Patients,” Transplant. Proc.
`23(6):2736-40 (1991)
`
`Abbreviation
`
`Venkataramanan
`
`2110
`
`Reserved
`
`2111
`
`2112
`
`Sinkula, A.A. & Yalkowsky, S.H.,
`“Rationale for Design of Biologically
`Reversible Drug Derivatives: Prodrugs,”
`J. of Pharm. Sci. 64(2):181- 210 (1975)
`
`Bundgaard, H., “Novel chemical
`approaches in prodrug design,” Drugs of
`the Future 16(5):443-458 (1991)
`
`2113 WO 92/21341
`
`2114
`
`Physicians’ Desk Reference (Medical
`Economics Data 46th ed. 1992), Entries
`for Various Commercial Formulations
`Containing Amides, Esters, or Carboxylic
`Acids
`
`Sinkula &
`Yalkowsky
`
`Bundgaard
`
`WO ’341
`
`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
`
`
`
`Abbreviation
`
`’264 patent
`
`’333 patent
`
`’203 patent
`
`’772 patent
`
`’670 patent
`
`’299 patent
`
`PDB File 1FKB
`
`Oldenziel
`
`Scott 1984
`
`Exhibit
`
`Description
`
`2117
`
`U.S. Patent No. 5,023,264
`
`2118
`
`U.S. Patent No. 5,162,333
`
`2119
`
`U.S. Patent No. 5,177,203
`
`2120
`
`U.S. Patent No. 5,665,772 (updated to
`include February 2016 Certificate of
`Correction)
`
`2121
`
`U.S. Patent No. 5,221,670
`
`2122
`
`U.S. Patent No. 5,260,299
`
`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)
`
`17
`
`
`
`Exhibit
`
`Description
`
`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)
`
`Farina, V. et al., “The Stille Reaction,”
`Org. React., 50:1-652 (1997)
`
`Abbreviation
`
`Stille
`
`Scott 1988
`
`Farina
`
`2126
`
`2127
`
`2128
`
`2129
`
`2130
`
`2131
`
`2132
`
`2133
`
`U.S. Patent Application No. 07/598,270
`File History
`
`’270 Application
`File History
`
`’678 patent
`
`Par Invalidity
`Contentions
`
`Tullius Trial
`
`Vlaminck
`
`U.S. Patent No. 5,118,678
`
`Excerpts from Defendant Par
`Pharmaceutical, Inc.’s Initial Invalidity
`Contentions dated March 26, 2015
`
`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)
`
`18
`
`
`
`Exhibit
`
`Description
`
`2134
`
`2135
`
`2136
`
`2137
`
`2138
`
`2139
`
`2140
`
`2141
`
`2142
`
`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)
`
`U.S. Patent No. 5,130,307
`
`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)
`
`U.S. Patent No. 4,868,153
`
`U.S. Patent No. 4,861,776
`
`U.S Patent No. 5,233,036 File History
`
`19
`
`Abbreviation
`
`De Simone
`
`Fischer
`
`’307 patent
`
`Whiting
`
`Merck Manual
`
`Sollinger 1992(a)
`
`’153 patent
`
`’776 patent
`
`Hughes File
`History
`
`
`
`Exhibit
`
`2143
`
`Description
`
`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)
`
`Abbreviation
`
`’263 patent
`
`Collier
`
`Ratain Trial
`
`Proleukin® PDR
`
`Belldegrun
`
`Intron® A PDR
`
`Skillings
`
`20
`
`
`
`Exhibit
`
`Description
`
`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)
`
`2152
`
`2153
`
`2154
`
`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)
`
`Novartis press release dated July 20, 2012
`(available at
`http://www.multivu.com/players/English/
`56006-novartis-afinitor-fda-approval/,
`accessed 1/14/2016)
`
`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)
`
`Abbreviation
`
`FDA Guidance
`
`Afinitor®
`February 2016
`Label
`
`Ratain Dep.
`
`Novartis July 2012
`PR
`
`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)
`
`22
`
`Douros
`
`Douros II
`
`Houchens
`
`Benvenuto
`
`Schilsky
`
`Baumann
`
`
`
`Exhibit
`
`2161
`
`2162
`
`2163
`
`2164
`
`2165
`
`2166
`
`Description
`
`Abbreviation
`
`Penn, I. & Starzl, T.E.,
`“Immunosuppression and Cancer.”
`Transplant Proc. 5(1):943-47 (1973)
`
`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)
`
`Physicians’ Desk Reference (Medical
`Economics Co. 44th ed. 1990), Entries
`for Adriamycin® PFS and RDF
`
`Rowinsky, E.K., &Donehower, R.C.,
`“The Clinical Pharmacology and Use of
`Antimicrotubule Agents in Cancer
`Chemotherapeutics,” Pharmac. Ther.
`52:35-84 (1991)
`
`23
`
`Penn
`
`Muggia
`
`Duran Abstract
`
`Vorobiof
`
`Adriamycin® PDR
`
`Rowinsky
`
`
`
`Exhibit
`
`2167
`
`2168
`
`2169
`
`2170
`
`Description
`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)
`
`Abbreviation
`
`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
`
`Okuno
`
`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)
`
`24
`
`
`
`Exhibit
`
`2172
`
`Description
`Chang, S.M. et al., “Phase II study of
`CCI-779 in patients with recurrent
`glioblastoma multiforme,”
`Investigational New Drugs 23:357-61
`(2005)
`
`Abbreviation
`
`Chang
`
`2173
`
`2174
`
`2175
`
`2176
`
`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)
`
`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)
`
`O’Donnell, P.H. & Ratain, M.J.,
`“Evaluating the activity of temsirolimus
`in neuroendocrine cancer,” Br. J. Cancer
`96:177 (2007)
`
`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)
`
`25
`
`Gonzalez-Angulo
`
`Duran
`
`O’Donnell
`
`Wolff
`
`
`
`Exhibit
`
`2177
`
`Description
`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)
`
`Abbreviation
`
`Acevedo-Gadea
`
`2178
`
`2179
`
`2180
`
`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)
`
`Bhattacharyya
`
`Hudes
`
`Jimeno
`
`26
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2181
`
`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)
`
`2182
`
`Rapamycin Clinical Trials Summary
`Chart
`
`2183
`
`2184
`
`Abuchowski, A. & Davis, F.F., Chapter
`13, “Soluble Polymer-Enzyme Adducts,”,
`Enzymes as Drugs, (Holcenberg, J.S. &
`Roberts, J. eds.,1981)
`
`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)
`
`Wyeth Press
`Release
`
`Abuchowski
`
`PDB Data Guide
`
`2185
`
`Excerpts from Novartis’s RCC Tracking
`Reports
`
`RCC Tracking
`Reports
`
`27
`
`
`
`Exhibit
`
`Description
`
`2186
`
`2402
`
`2403
`
`2404
`
`Excerpts from Novartis’s Breast Cancer
`ATUs
`
`Curriculum Vitae of Professor Alexander
`M. Klibanov
`
`The Condensed Chemical Dictionary, pp.
`556, 957-58 (10th ed. 1981)
`
`Hildebrand, J.H. & Carter, J.M., “The
`Influence On The Ideal Solution Laws Of
`The Distribution Of Polarity Within The
`Molecule,” 16 P. Natl. Acad. Sci. U.S.A.
`285 (1930)
`
`Abbreviation
`
`Breast Cancer
`ATUs
`
`The Condensed
`Chemical
`Dictionary
`
`Hildebrand
`
`28
`
`
`
`CERTIFICATE OF SERVICE
`
`I certify that a copy of the foregoing Patent Owner’s Exhibit List 3 was
`
`served on September 16, 2016 by causing it to be sent by email to counsel for
`
`Petitioner at the following email addresses:
`
`Daniel G. Brown (daniel.brown@lw.com)
`
`Robert Steinberg (bob.steinberg@lw.com)
`
`Jonathan M. Strang (jonathan.strang@lw.com)
`
`Dated: September 16, 2016
`
`/Nicholas N. Kallas/
`Nicholas N. Kallas
`Registration No. 32,530
`Lead Counsel for Patent Owner
`FITZPATRICK, CELLA, HARPER
`& SCINTO
`1290 Avenue of the Americas
`New York, NY 10104-3800
`Tel. 212-218-2100
`
`29
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
