UNITED STATES PATENT AND TRADEMARK OFFICE
`
`______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________________
`
`
`APOTEX INC., APOTEX CORP., ARGENTUM PHARMACEUTICALS LLC,
`ACTAVIS ELIZABETH LLC, TEVA PHARMACEUTICALS USA, INC., SUN
`PHARMACEUTICAL INDUSTRIES, LTD., SUN PHARMACEUTICAL
`INDUSTRIES, INC., and SUN PHARMA GLOBAL FZE,
`
`Petitioners,
`
`v.
`
`NOVARTIS AG,
`
`Patent Owner.
`
`______________________
`
`Case IPR2017-008541
`
`U.S. Patent No. 9,187,405
`______________________
`
`PATENT OWNER’S SECOND UPDATED EXHIBIT LIST
`
`Mail Stop Patent Board
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
` 1 Cases IPR2017-01550, IPR2017-01946, and IPR2017-01929 have been joined
`with this proceeding.
`
`
`
`
`

`

`
`
`Exhibit
`2001
`
`2002
`
`2003
`
`2004
`2005
`
`2006
`2007
`2008
`
`2009
`
`2010
`
`2011
`
`2012
`
`2013
`2014
`
`2015
`
`List of Patent Owner’s Evidence and Exhibits
`Reference
`Declaration of Robert W. Trenchard in Support of Motion for
`Admission Pro Hac Vice
`Order Admitting Robert W. Trenchard Pro Hac Vice, Torrent
`Pharm. Ltd. v. Novartis AG, IPR2014-00784, Paper 8
`Declaration of Fred D. Lublin, M.D. in support of Patent Owner’s
`Preliminary Response
`Curriculum Vitae of Fred D. Lublin, M.D.
`Declaration of William J. Jusko, Ph.D. in support of Patent
`Owner’s Preliminary Response
`Curriculum Vitae of William J. Jusko, Ph.D.
`United States Patent 5,604,229 to Fujita et al.
`Brinkmann et al., The Immune Modulator FTY720 Targets
`Sphingosine 1-Phosphate Receptors, 277 J. Bio. Chem. 24,
`21453–57 (2002)
`Forrest et al., Immune Cell Regulation and Cardiovascular Effects
`of Sphingosine 1-Phosphate Receptor Agonists in Rodents Are
`Mediated via Distinct Receptor Subtypes, 309 J. Pharm. And
`Experimental Therapeutics 2, 758–68 (2004)
`Lublin et al., Defining the clinical course of multiple sclerosis:
`Results of an international survey, 46 Neurology 907–11 (1996)
`Miller et al., How Modeling and Simulation Have Enhanced
`Decision Making in New Drug Development, 32 J.
`Pharmacokinetics and Pharmacodynamics 2, 185–97 (2005)
`Sanna et al., Sphingosine 1-Phosphate (S1P) Receptor Subtypes
`S1P1 and S1P3, Respectively, Regulate Lymphocyte Recirculation
`and Heart Rate, 279 J. Bio. Chem. 14, 13839–48 (2004)
`Public LinkedIn Profile of Tadimeti S. Rao, Ph.D.
`Webb et al., Sphingosine 1-phosphate receptor agonists attenuate
`relapsing-remitting experimental autoimmune encephalitis in SJL
`mice, 153 J. Neuroimmunology 108–21 (2004)
`U.S. Food and Drug Administration Guidance – “Guidance for
`Industry End-of-Phase 2A Meetings,” accessed on March 30, 2009
`at https://www.fda.gov/Error/index.htm.
`
`
`
`_________________
`*Exhibits marked with an asterisk have been served on Petitioner but not filed with the Board as
`of the date of the Certificate of Service herewith.
`
`

`

`
`
`
`
`Exhibit
`2016
`
`2017
`
`2018
`2019
`
`2020
`
`Reference
`U.S. Food and Drug Administration Guidance – “Clinical
`Pharmacology Section of Labeling for Human Prescription Drug
`and Biological Products – Content and Format,” (December 2016)
`Bloomberg Profile of Klemens Budde, M.D., accessed on April
`27, 2017 at http://www.bloomberg.com
`Public LinkedIn Profile of Janet Karlix
`Bibliographic Data of Application No. 06/633,481, accessed on
`May 1, 2017 at portal.uspto.gov/pair/PublicPair
`Transcript of August 25, 2017, conference call between the parties
`and the Board regarding Patent Owner’s List of Proposed
`Motions.
`Email from Jane M. Love, Ph.D. to Michael Rosato regarding
`“IPR2017-00854 – Request for Conference Call,” sent August 8,
`2017.
`Declaration of Lawrence Steinman, M.D.
`Curriculum Vitae of Lawrence Steinman, M.D.
`Second Declaration of William J. Jusko, Ph.D.
`Second Declaration of Fred D. Lublin, M.D.
`Declaration of Christian Schnell
`American Autoimmune Related Diseases Association, Inc.
`Autoimmune Disease List, accessed on October 5, 2017 at
`www.aarda.org/diseaselist
`Boehler T, et al. FTY720 exerts differential effects on CD4+ and
`CD8+ T-lymphocyte subpopulations expressing chemokine and
`adhesion receptors. Nephrol Dial Transplant. 2004
`Mar;19(3):702-13.
`Bouérat L, et al. Indolin-2-ones with high in vivo efficacy in a
`model for multiple sclerosis. J Med Chem. 2005 Aug
`25;48(17):5412-4.
`Budde K, et al. FTY720 (fingolimod) in renal transplantation.
`Clin Transplant. 2006;20 Suppl 17:17-24.
`Chavez, Daniel. "FTY720 For Relapsing Multiple Sclerosis Phase
`II Data Shows Sustained Efficiency And Good Tolerability."
`Medical News Today. MediLexicon, Intl., 10 Apr. 2006. Web. 13
`November 2017.
`<http://www.medicalnewstoday.com/releases/41281.php>
`_________________
`*Exhibits marked with an asterisk have been served on Petitioner but not filed with the Board as
`of the date of the Certificate of Service herewith.
`
`
`2021*
`
`
`2022
`2023
`2024
`2025
`2026
`2027
`
`2028
`
`2029
`
`2030
`
`2031
`
`
`
`
`
`

`

`
`
`Exhibit
`2032
`2033
`
`2034
`
`2035
`
`2036
`
`2037
`
`2038
`
`2039
`
`2040
`2041
`
`2042
`
`
`
`
`
`Reference
`Fingolimod, Chemical Abstract Registry No. 162359-55-9.
`2-amino-2-[2-(4-oc tylphenyl)ethyl]propane-1,3-
`diol;hydrochloride, Chemical Abstract Registry No. 162359-56-0.
`Chiba K, et al. FTY720, a novel immunosuppressant, induces
`sequestration of circulating mature lymphocytes by acceleration
`of lymphocyte homing in rats. I. FTY720 selectively decreases the
`number of circulating mature lymphocytes by acceleration of
`lymphocyte homing. J Immunol. 1998 May 15;160(10):5037-44.
`Cohen JA, et al. Oral fingolimod or intramuscular interferon for
`relapsing multiple sclerosis. N Engl J Med. 2010 Feb
`4;362(5):402-15.
`Doggrell SA. Is fingolimod an advancement in the treatment of
`multiple sclerosis? Evaluation of: KAPPOS L, ANTEL J, COMI
`G. et al.: Oral fingolimod (FTY720) for relapsing multiple
`sclerosis. N. Engl. J. Med. (2006) 355:1124-1140. Expert Opin
`Pharmacother. 2007 Feb;8(3):383-6.
`FDA Approval and Commitment Letter of NDA 022527, dated
`September 21, 2010.
`Foster CA, et al. Brain penetration of the oral immunomodulatory
`drug FTY720 and its phosphorylation in the central nervous
`system during experimental autoimmune encephalomyelitis:
`consequences for mode of action in multiple sclerosis. J
`Pharmacol Exp Ther. 2007 Nov;323(2):469-75. Epub 2007 Aug 6.
`Deposition Transcript of Barbara S. Giesser, M.D., October 2,
`2017
`Gilenya label
`Chapter 2: Guidelines for Collection and Analysis of
`Pharmacokinetic Data. Applied pharmacokinetics: Principles of
`therapeutic drug monitoring. Second edition. Edited by William
`E. Evans, Jerome J. Schentag, and William J. Jusko. Applied
`therapeutics: Spokane, WA. 1986.
`Calabresi PA et al. Safety and efficacy of fingolimod in patients
`with relapsing-remitting multiple sclerosis (FREEDOMS II): a
`double-blind, randomised, placebo-controlled, phase 3 trial.
`Lancet Neurol. 2014 Jun;13(6):545-56.
`
`_________________
`*Exhibits marked with an asterisk have been served on Petitioner but not filed with the Board as
`of the date of the Certificate of Service herewith.
`
`
`
`
`

`

`
`
`Exhibit
`2043
`
`2044
`
`2045
`
`2046
`
`2047
`
`2048
`
`2049
`
`2050
`
`2051
`
`2052
`
`2053
`
`
`
`
`
`Reference
`Kirk SL and Karlik SJ. VEGF and vascular changes in chronic
`neuroinflammation. J Autoimmun. 2003 Dec;21(4):353-63.
`Kirk S, et al. Angiogenesis in multiple sclerosis: is it good, bad or
`an epiphenomenon? J Neurol Sci. 2004 Feb 15;217(2):125-30.
`Kovarik JM, et al. Multiple-dose FTY720: tolerability,
`pharmacokinetics, and lymphocyte responses in healthy subjects.
`J Clin Pharmacol. 2004 May;44(5):532-7.
`Li H, et al. Pharmacokinetics and cell trafficking dynamics of 2-
`amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride
`(FTY720) in cynomolgus monkeys after single oral and
`intravenous doses. J Pharmacol Exp Ther. 2002 May;301(2):519-
`26.
`MCALPINE’S MULTIPLE SCLEROSIS, 4th Edition, Compston,
`ed (Elsevier, Inc., December 2005).
`Park et al. "Peripheral Blood FTY720
`Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling in Renal
`Transplanted Recipients," Abstract #707, Kidney:
`Pharmacogenetics, Kinetics and New Drug, p. 333-334.
`Pinschewer DD, et al. FTY720 immunosuppression impairs
`effector T cell peripheral homing without affecting induction,
`expansion, and memory. J Immunol. 2000 Jun 1;164(11):5761-70.
`CLINICAL PHARMACOKINETICS: CONCEPTS AND
`APPLICATIONS. By Malcolm Rowland and Thomas N. Tozer.
`Lea & Febiger, 600 Washington Square, Philadelphia, Pa 19106.
`1980.
`Steinman L and Zamvil SS. How to successfully apply animal
`studies in experimental allergic encephalomyelitis to research on
`multiple sclerosis. Ann Neurol. 2006 Jul;60(1):12-21.
`Teshima et al. FTY720, A Novel Immunosuppressant, Possessing
`Unique Mechanisms. Abstract 5127. 9th International Congress of
`Immunology, July 23-29, 1995.
`Xie JH, et al. Sphingosine-1-phosphate receptor agonism impairs
`the efficiency of the local immune response by altering trafficking
`of naive and antigen-activated CD4+ T cells. J Immunol. 2003
`Apr 1;170(7):3662-70.
`
`_________________
`*Exhibits marked with an asterisk have been served on Petitioner but not filed with the Board as
`of the date of the Certificate of Service herewith.
`
`
`
`
`

`

`
`
`Exhibit
`2054
`
`2055
`
`2056
`
`2057
`
`2058
`
`2059
`
`2060
`
`2061
`
`2062
`
`2063
`
`2064
`
`2065
`
`
`
`
`
`Reference
`Lymphocytopenia - Hematology and Oncology - Merck Manuals
`Professional Edition, accessed on November 7, 2017 at
`www.merckmanuals.com/professional/hematology-and-
`oncology/leukopenias/lymphocytopenia
`Meno-Tetang GM, et al. Physiologically based pharmacokinetic
`modeling of FTY720 (2-amino-2[2-(-4-
`octylphenyl)ethyl]propane-1,3-diol hydrochloride) in rats after
`oral and intravenous doses. Drug Metab Dispos. 2006
`Sep;34(9):1480-7. Epub 2006 Jun 2.
`Derfuss et al. The ACROSS study: long-term efficacy of
`fingolimod in patients with RRMS (Follow-up at 10 years)
`ECTRIMS Online Library. Sep 16, 2016; 145896.
`Hiestand et al. "Effects of FTY720 on experimental autoimmune
`encephalomyelitis-induced angiogenesis (acute and relapsing)."
`Novartis report, May 12, 2009.
`Mager DE and Jusko WJ. Development of translational
`pharmacokinetic-pharmacodynamic models. Clin Pharmacol
`Ther. 2008 Jun;83(6):909-12.
`Chow FS et al. Modeling interactions between adrenal
`suppression and T-helper lymphocyte trafficking during multiple
`dosing of methylprednisolone. J Pharmacokinet Biopharm. 1999
`Dec;27(6):559-75.
`DeVane CL and Jusko WJ. Dosage regimen design. Pharmacol
`Ther. 1982;17(2):143-63.
`Chiba K, Adachi K. FTY720, immunosuppressant. Drugs of the
`Future. 1997;22:18-22.
`Functional Systems Scores (FSS) and Expanded Disability Status
`Scale (EDSS), National MS Society, accessed on November 10,
`2017 at www.nationalmssociety.org
`Redacted Email from Sylvia Burns with cc to Fred Lublin dated
`June 22, 2007 regarding Novartis 2302 IRB Deferral
`Novartis Letter to Dr. Katz dated March 3, 2008 re DSMB's
`benefit/risk analysis of 0.5 mg dose
`Email from Tom Watson to Colleen Farrell dated June 5, 2007
`regarding “letter for you IRB”
`
`_________________
`*Exhibits marked with an asterisk have been served on Petitioner but not filed with the Board as
`of the date of the Certificate of Service herewith.
`
`
`
`
`

`

`
`
`Exhibit
`2066
`
`2067
`
`2068
`
`2069
`
`2070
`
`2071
`
`2072
`
`2073
`
`2074
`2075
`2076*
`2077*
`2078
`2079*
`
`2080*
`
`
`
`
`
`Reference
`Novartis Letter to Dr. Miller dated June 5, 2007 regarding
`Protocol CFTY720D2302
`Tanaka M et al. Reduced fingolimod dosage treatment for patients
`with multiple sclerosis and lymphopenia or neutropenia. Mult
`Scler. 2013 Aug;19(9):1244-5.
`Yamout BI et al. Safety and efficacy of reduced fingolimod
`dosage treatment. J Neuroimmunol. 2015 Aug 15;285:13-5.
`Zecca C et al. Half-dose fingolimod for treating relapsing-
`remitting multiple sclerosis: Observational study. Mult Scler.
`2017 Feb 1:1352458517694089.
`Novartis, “Effects of FTY720 on experimental autoimmune
`encephalomyelitis-induced angiogenesis (acute and relapsing)”
`signature sheet
`INTEGRATION OF PHARMACOKINETICS,
`PHARMACODYNAMICS, AND TOXICOKINETICS IN
`RATIONAL DRUG DEVELOPMENT. Yacobi et al., eds.
`Plenum Press, New York, New York 10013. 1993.
`Novartis Media Release, “Phase II data for FTY720 shows
`sustained efficacy and good tolerability over 18 months in patients
`with relapsing multiple sclerosis (MS)” Basel, April 6, 2006.
`Interferon beta-1b is effective in relapsing-remitting multiple
`sclerosis. I. Clinical results of a multicenter, randomized, double-
`blind, placebo-controlled trial. The IFNB Multiple Sclerosis Study
`Group. Neurology. 1993 Apr;43(4):655-61.
`Stipulated Standard Protective Order
`Stipulated Standard Protective Order (Redline)
`Third Declaration of William J. Jusko, Ph.D.
`Second Declaration of Lawrence Steinman, M.D.
`Declaration of Peter J. Waibel, Esq.
`Karopka T et al. The Autoimmune Disease Database: a
`dynamically compiled literature-derived database. BMC
`Bioinformatics. 2006 Jun 27;7:325.
`Kurtzke JF. Rating neurologic impairment in multiple sclerosis:
`an expanded disability status scale (EDSS). Neurology. 1983
`Nov;33(11):1444-52.
`
`_________________
`*Exhibits marked with an asterisk have been served on Petitioner but not filed with the Board as
`of the date of the Certificate of Service herewith.
`
`
`
`
`

`

`
`
`Exhibit
`2081*
`
`2082*
`
`2083*
`
`2084*
`
`2085
`
`2086
`
`2087
`
`
`
`
`
`Reference
`MCALPINE’S MULTIPLE SCLEROSIS, 4th Edition, Compston,
`ed (Elsevier, Inc., December 2005), chapters 7, 14, and 19.
`Lymphocytopenia - Hematology and Oncology - Merck Manuals
`Seventeenth Edition, Centennial Edition, 1999.
`Park et al. "Peripheral Blood FTY720
`Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling in Renal
`Transplanted Recipients," Abstract #707, Kidney:
`Pharmacogenetics, Kinetics and New Drug, p. 333-334.
`Levy, G. “The Case for Preclinical Pharmacodynamics,”
`INTEGRATION OF PHARMACOKINETICS,
`PHARMACODYNAMICS, AND TOXICOKINETICS IN
`RATIONAL DRUG DEVELOPMENT, Yacobi, A. et al. (eds.)
`Plenum Press, New York 1993, 7-13.
`Email from Jane M. Love, Ph.D. to Althea Wilburn, et al.
`regarding “RE: Conference Call – IPR2017-00854 – January 10
`@ 11amET” sent January 5, 2018, with “IPR2017 00854 Email
`chain of Dec 11 2017.pdf” attached.
`Email from Jad Mills to Jane M. Love, Ph.D., et al. regarding
`“RE: IPR2017-00854” sent December 11, 2017.
`Transcript of January 24, 2018 Proceeding
`
`
`
`_________________
`*Exhibits marked with an asterisk have been served on Petitioner but not filed with the Board as
`of the date of the Certificate of Service herewith.
`
`
`
`
`

`

`CERTIFICATE OF SERVICE
`Pursuant to 37 C.F.R. § 42.6(e), I hereby certify that on January 25, 2018, a
`
`true and accurate copy of PATENT OWNER’S UPDATED EXHIBIT LIST was
`
`served via electronic mail on the following counsel of record for Petitioners:
`
`For Apotex:
`
`For Argentum:
`
`
`For Sun:
`
`
`
`Steven W. Parmelee: sparmelee@wsgr.com
`Michael T. Rosato: mrosato@wsgr.com
`Jad A. Mills: jmills@wsgr.com
`
`Wilson Sonsini Goodrich & Rosati
`701 Fifth Avenue, Suite 5100
`Seattle, WA 98104
`Telephone: 206-883-2542
`
`
`Teresa Stanek Rea: trea@crowell.com
`Deborah H. Yellin: dyellin@crowell.com
`Shannon M. Lentz: slentz@crowell.com
`Tyler C. Liu: TLiu@agpharm.com
`
`Crowell & Moring LLP
`Intellectual Property Group
`1001 Pennsylvania Ave, NW
`Washington, DC 20004-2595
`(202) 624-2620
`
`Samuel Park: SPark@winston.com
`Charles B. Klein: CKlein@winston.com
`Sharick Naqi: SNaqi@winston.com
`
`Winston & Strawn LLP
`35 W. Wacker Drive
`Chicago, IL 60601
`
`
`
`

`

`
`
`
`
`
`For Teva:
`
`
`
`Dated: January 25, 2018
`
`Telephone: (312) 558-7931
`
`Amanda Hollis: amanda.hollis@kirkland.com
`Eugene Goryunov: egoryunov@kirkland.com
`Gregory Springsted: gregory.springsted@kirkland.com
`
`Kirkland & Ellis LLP
`300 North LaSalle
`Chicago, IL 60654
`Telephone: (312) 862-2000
`(202) 624-2620
`
`/Jane M. Love, Ph.D./
`Jane M. Love, Ph.D.
`Reg. No. 42,812
`Lead Counsel for Patent Owners
`Gibson, Dunn & Crutcher LLP
`200 Park Avenue
`New York, New York 10166-0193
`jlove@gibsondunn.com
`Tel: 212-351-3922
`
`
`
`
`
`
`
`
`
`