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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`_____________________________
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`
`
`APOTEX INC. AND
`APOTEX CORP.,
`Petitioners,
`
`v.
`
`NOVARTIS A.G.,
`Patent Owner.
`
`_____________________________
`
`Patent No. 9,187,405
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`_____________________________
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`
`
`DECLARATION OF BARBARA S. GIESSER
`
`
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`APOTEX - EXHIBIT 1002
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`
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`TABLE OF CONTENTS
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`
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`
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`I.
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`QUALIFICATIONS ........................................................................................... 1
`
`II.
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`SCOPE OF WORK ............................................................................................ 2
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`III. OVERVIEW OF THE 9,187,405 PATENT ............................................................ 3
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`IV. RELATED PROSECUTION ................................................................................. 6
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`V.
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`LEGAL STANDARDS ..................................................................................... 13
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`VI. LEVEL OF ORDINARY SKILL AND RELEVANT TIME ........................................ 16
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`VII. CLAIM CONSTRUCTION ................................................................................ 17
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`VIII. STATE OF THE ART ....................................................................................... 20
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`IX. PRIOR ART REFERENCES DISCLOSE THE CLAIMED FEATURES OF THE
`’405 PATENT ............................................................................................... 33
`
`X.
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`THE PRIOR ART TEACHES EVERY ELEMENT OF CLAIMS 1-6 OF THE ’405
`PATENT ....................................................................................................... 45
`
`XI. NO EVIDENCE OF UNEXPECTED RESULTS OR SECONDARY
`CONSIDERATIONS ARE ATTRIBUTABLE TO NOVEL ASPECTS OF THE
`CLAIMS ....................................................................................................... 70
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`XII. CONCLUDING STATEMENTS .......................................................................... 72
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`XIII. APPENDIX – LIST OF EXHIBITS ..................................................................... 73
`
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`-i-
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`
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`I, Barbara S. Giesser, declare as follows:
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`I.
`
`QUALIFICATIONS
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`1.
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`I am currently a Professor of Clinical Neurology at the David Geffen
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`School of Medicine at UCLA and have held faculty appointments there since 2002.
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`Prior to my appointments at UCLA, I was an Associate Professor of Clinical
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`Neurology at the Arizona Health Sciences Center at the University of Arizona,
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`from 1992-2002. Prior to joining the University of Arizona, I was an Assistant
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`Professor of Neurology at Albert Einstein College of Medicine in Bronx, New
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`York from 1983-1991.
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`2.
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`I received a Master’s Degree in Virology from the University of
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`Texas Graduate School of Biomedical Sciences in 1974 and an M.D. from the
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`University of Texas Medical School at San Antonio in 1978. I completed a medical
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`fellowship in Neurology at the Albert Einstein College of Medicine in 1983 after
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`first completing my medical residency in Neurology at the Bronx Municipal
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`Hospital Center.
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`3.
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`I became board certified by the American Board of Psychiatry and
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`Neurology in 1985 and by the American Society of Neurorehabilitation in 1992. I
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`became a Fellow of the American Academy of Neurology in 1993 and of the
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`American Neurological Association in 2012. I continue to hold active medical
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`licenses in New York and in California.
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`1
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`
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`4.
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`I have more than thirty years of experience in the treatment of patients
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`with, and research regarding, multiple sclerosis (“MS”), including relapsing-
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`remitting MS. I have received numerous research grants, including several research
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`grants from the National Multiple Sclerosis Society. I have also participated in
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`numerous clinical trials for MS, including trials involving patients with relapsing-
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`remitting MS. I have given dozens of invited lectures and presentations and have
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`been an author or co-author of dozens of books, book chapters, reviews, or peer-
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`reviewed research papers. I have served on numerous professional committees,
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`received many awards, and provided editorial services for multiple journals. For a
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`more detailed listing of my credentials and publications, please see my curriculum
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`vitae, attached as EX1003.
`
`II.
`
`SCOPE OF WORK
`
`5.
`
`I understand that a petition is being filed with the United States Patent
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`and Trademark Office for Inter Partes Review of U.S. Patent No. 9,187,405
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`(“the ’405 patent,” EX1001). I have been retained by the Petitioner to provide
`
`analysis and opinions regarding the ’405 patent. I have reviewed the ’405 patent
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`(EX1001) and relevant sections of its prosecution history in the United States
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`Patent and Trademark Office. EX1011. I have also reviewed certain publications in
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`arriving at my opinions, and cite them in this declaration. For convenience,
`
`documents cited in this declaration are listed in the Appendix in Section XIII.
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`-2-
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`6.
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`I am compensated at the rate of $350/hour for my work except that I
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`will be paid $500 per hour for time spent testifying in deposition or at trial. My
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`compensation does not depend on the outcome of this matter.
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`III. OVERVIEW OF THE 9,187,405 PATENT
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`7.
`
`The ’405 patent is entitled “S1P Receptor Modulators For Treating
`
`Relapsing-Remitting Multiple Sclerosis.” The first page of the patent claims
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`priority to a foreign application, 0612721.1 (GB), filed on June 27, 2006 via U.S.
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`Patent Application No. 13/149,468 filed on May 31, 2011, now Patent No.
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`8,741,963, and via U.S. Patent Application No. 12/303,765 filed as application
`
`number PCT/EP2007/005597 on June 25, 2007. EX1001. For the purposes of my
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`analysis, I have assumed that the applicable invention date of the ’405 patent is
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`June 27, 2006. However, the results of my analysis would not change if the
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`applicable invention date were June 25, 2007, May 31, 2011, or April 21, 2014.
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`8.
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`The ’405 patent is generally directed to a dosing regimen for the prior
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`art MS drug identified as 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol. For
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`convenience, I will refer to this compound as fingolimod.
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`9.
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`Claim 1 of the ’405 patent is an independent claim and recites the
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`following:
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`A method for reducing or preventing or alleviating relapses in
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`Relapsing-Remitting multiple sclerosis in a subject in need thereof,
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`comprising orally administering to said subject 2-amino-2-[2-(4-
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`-3-
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`
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`octylphenyl)ethyl]propane-1,3-diol, in free form or in a
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`pharmaceutically acceptable salt form, at a daily dosage of 0.5 mg,
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`absent an immediately preceding loading dose regimen.
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`10. Claim 3 of the ’405 patent is an independent claim and recites the
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`following:
`
`A method for treating Relapsing-Remitting multiple sclerosis in a
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`subject in need thereof, comprising orally administering to said
`
`subject 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, in free
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`form or in a pharmaceutically acceptable salt form, at a daily dosage
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`of 0.5 mg, absent an immediately preceding loading dose regimen.
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`11. Claim 5 of the ’405 patent is an independent claim and recites the
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`following:
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`A method for slowing progression of Relapsing-Remitting multiple
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`sclerosis in a subject in need thereof, comprising orally administering
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`to said subject 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, in
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`free form or in a pharmaceutically acceptable salt form, at a daily
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`dosage of 0.5 mg, absent an immediately preceding loading dose
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`regimen.
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`12. Claims 2, 4, and 6 depend from claims 1, 3, and 5, respectively, and
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`further recite administration of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-
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`diol hydrochloride, referred to herein as fingolimod hydrochloride or FTY720.
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`13. The ’405 patent describes the invention as “the use of an S1P receptor
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`modulator in the treatment or prevention of neo-angiogenesis associated with a
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`-4-
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`
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`demyelinating disease, e.g. multiple sclerosis.” EX1001, col. 1, ll. 5-8. It states that
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`“[p]referred S1P receptor modulators… have accelerating lymphocyte homing
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`properties, e.g. compounds which elicit a lymphopenia resulting from a re-
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`distribution, preferably reversible, of lymphocytes from circulation to secondary
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`lymphatic tissue, without evoking a generalized immunosuppression.” EX1001, col.
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`2, ll. 16-22.
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`14. The ’405 patent states that “[c]linicians usually categorize patients
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`having MS into four types of disease patterns” which are relapsing-remitting (“RR-
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`MS”), secondary-progressive (“SP-MS”), primary-progressive (“PP-MS”), and
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`progressive-relapsing (“PR-MS”). EX1001, col. 9, ll. 64-col. 10, ll. 15. RR-MS
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`accounts for about 85% of multiple sclerosis patients. Id.
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`15. No data are presented or discussed in the ’405 patent regarding the
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`efficacy of the claimed dosing regimens in humans. More specifically, no data are
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`presented to support efficacy of the 0.5 mg daily dose. No data are presented or
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`discussed in the ’405 patent relating fingolimod blood concentration to therapeutic
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`effect on RR-MS symptoms in humans. Other than in the issued claims, there is no
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`discussion in the ’405 patent or in any of the priority documents of whether a
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`loading dose regimen should or should not be employed in the treatment of
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`multiple sclerosis. EX1011 at 0111-27; EX1012 at 0001-21.
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`-5-
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`
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`16. The ’405 patent states that the “[u]tility of the S1P receptor
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`modulators, e.g. the S1P receptor modulators comprising a group of formula X, in
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`preventing or treating neo-angiogenesis associated with a demyelinating
`
`disease…may be demonstrated in animal test methods as well as in clinic[.]”
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`EX1001, col. 10, ll. 25-29. Formula X encompasses fingolimod. EX1001, col. 1, ll.
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`13-45. The ’405 patent presents two examples, both proposed studies, for assessing
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`the utility of S1P receptor modulators. EX1001, col. 10, l. 35- col. 11, l. 67. No
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`data are presented in support of selecting 0.5 mg fingolimod or 0.5 mg FTY720 per
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`day as a dosing regimen.
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`IV. RELATED PROSECUTION
`
`17. As discussed above, the ’405 patent claims priority to U.S. Pat. Appl.
`
`12/303,765 which represents the U.S. entry of PCT/EP2007/005597 filed on June
`
`25, 2007. EX1001. In addition to the ’405 patent, U.S. Pat. No. 8,741,963
`
`(the ’963 patent) claims priority to U.S. Pat. Appl. 12/303,765 (“the ’765
`
`application”). EX1013 at cover. Both the ’963 and the ’405 patents claim methods
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`for treating multiple sclerosis with FTY720. EX1001, col. 12, l. 49- col. 13, l. 9;
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`EX1013, col. 12, ll. 27-61.
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`18. The patent examiner in the ’765 application asked the applicants to
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`choose a particular demyelinating disease and a particular S1P receptor modulators.
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`EX1009 at 0036-37. The applicant elected multiple sclerosis as the demyelinating
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`-6-
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`
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`disease and fingolimod, in free form or as the FTY720 hydrochloride salt, as the
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`S1P receptor modulator. EX1009 at 0028. The patent examiner issued a non-final
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`office action rejecting the pending claims under 35 U.S.C. §§ 103 and 112.
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`EX1009 at 0008-18. The ’765 application was abandoned after the applicants
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`failed to respond to the non-final office action. EX1009 at 0002.
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`19. U.S. Pat. Appl. 13/149,468 (“the ’468 application”) is a continuation
`
`of the ’765 application. EX1001 at cover. The original claims in the ’468
`
`application were directed to methods for inhibiting neo-angiogenesis associated
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`with multiple sclerosis and methods for reducing or alleviating relapses in MS
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`patients by administration of fingolimod, in free form or as a pharmaceutically
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`acceptable salt. EX1010 at 0491-92. All claims were rejected in the first office
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`action as obvious over Virley, “Developing Therapeutics for the Treatment of
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`Multiple Sclerosis,” NeuroRx, 2:638-649 (2005) (“Virely,” EX1016), LaMontagne,
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`et al., “Antagonism of Sphingosine-1-Phosphate Receptors by FTY720 Inhibits
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`Angiogenesis,” Cancer Res., 66:221-231 (Jan. 2006) (“LaMontagne,” EX1039),
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`and International Publication No. WO 2006/058316 (published June 1, 2006)
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`(“Kovarik,” EX1004).
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`20. Regarding Kovarik, the examiner stated:
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`Kovarik teaches dosage regimens involving S1P receptor agonists, of
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`which FTY720 is clearly encompassed. Maintenance dosages are
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`disclosed on page 15, line 9, as required by all of the present claims.
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`-7-
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`
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`Specifically, on line 16, page 17, a daily dose of 0.5 mg is taught for
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`the treatment of autoimmune diseases, of which MS is recited as an
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`example, on lines 7-8 on page 14.
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`EX1010 at 0267 (citing Kovarik, EX1004).
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`21. The applicants responded to the non-final rejection by arguing, among
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`other things, that a fingolimod dosing regimen for prevention of organ rejection
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`was not relevant for treating multiple sclerosis:
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`The skilled person would not expect the optimal dosage or dosing
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`regimen for treating transplant patients to be indicative of the optimal
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`dosage or dosing regimen for treating an immune disorder such as
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`multiple sclerosis. When treating a transplant patient, it is important
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`to deliver a very high dose very early in treatment to counter
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`rejection of the transplanted tissue, a consideration that does not
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`apply to chronic immune disorders such as multiple sclerosis, where
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`the goal is to degrade the disease over the period of the patient’s
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`natural life.
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`EX1010 at 0110 (emphasis added).
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`22. The ’963 patent ultimately issued from the ’468 application after the
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`applicants amended the claims to exclude dosing regimens employing a loading
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`dose regimen. EX1010 at 0085-88, 0038-39.
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`-8-
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`
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`23.
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` U.S. Pat. Appl. 14/257,342 (“the ’342 application,” EX1011) is a
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`divisional of the ’468 application. The ’342 application was also directed to using
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`fingolimod, in free form or as a pharmaceutically acceptable salt, to treat MS.
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`24. The patent examiner in the first office action rejected all claims as
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`obvious over Virley (EX1016) and Kovarik (EX1004). The examiner stated:
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`[Virley] teaches the administration of the active agent [, FTY720,] at
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`the point of relapse significantly suppressed further progression of
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`clinical signs and providing compelling evidence for this agent as a
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`potential therapeutic agent for MS. Data from a phase II clinical trial
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`with FTY720, confirmed a relapse reduction rate of more than 50% in
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`281 relapsing-remitting MS patients for 6 months of treatment.
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`EX1011 at 0055 (citing Virley, EX1016 at 638, 640).
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`The examiner also stated that Virley does not teach dosing regimens, but that this
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`limitation is supplied by Kovarik:
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`Kovarik et al., teaches dosage regimens involving S1P receptor
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`agonists, of which FTY720 is clearly encompassed.… [A] daily dose
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`of 0.5 mg is disclosed for the treatment [of] autoimmune diseases, of
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`which MS is recited as an example[.]
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`EX1011 at 0055 (citing Kovarik, EX1004 at 14, 17).
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`25. The applicants argued in response:
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`. . . Kovarik’s mention of a dosage of 0.5 mg is limited to the context
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`of a dosage that follows, immediately, the loading dose regimen
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`-9-
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`
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`described therein. Indeed, the very passage cited by the Examiner. P.
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`17, line 16, specifies that a daily dosage of 0.1 to 0.5 mg follows a
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`loading regimen.… Kovarik also states that the daily dosage
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`employed following a loading dose regimen can be 0.1 - 0.5 mg or
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`can be much larger, e.g., 2.5 or 5.0 mg. Thus, Kovarik teaches that the
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`daily dosage administered after the initial period can vary
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`substantially relative to the standard daily dosage and is dependent on
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`the immediately preceding loading dose administered during the
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`initial phase. In addition to being only one of a wide range of dosages
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`that can be employed following a loading dose regimen of an S1P
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`receptor modulator or agonist, the 0.5 mg daily dosage referenced in
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`Kovarik is mentioned only in the context of a dosage employed
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`following the conclusion of a loading dose regimen. In view of the
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`above, Applicants submit that the skilled person reading Kovarik
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`would attach no significance to the suitability of any daily dosage
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`mentioned therein outside the context of an immediately preceding
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`loading dose regimen. Put another way, Kovarik teaches such a broad
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`daily dosage range that one skilled in the art would not arrive at the
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`specific, claimed daily dose (0.5 mg), even if the skilled artisan
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`followed Kovarik's loading dose regimen as taught. Therefore,
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`Applicants respectfully contend that in the absence of a prior loading
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`dose regimen, there is no way, without extensive and undue
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`experimentation, that a skilled artisan would be able to arrive at the
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`claimed daily dose with any expectation of success.
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`EX1011 at 0033-34 (formatting removed).
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`-10-
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`26. On August 21, 2015, a Notice of Allowance issued without stating
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`any reasons for the allowance. EX1011 at 0007. The ’405 patent issued on
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`November 17, 2015.
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`27.
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`I disagree with the applicant’s characterization of Kovarik in the
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`response to the non-final office action on several points. First, the applicants allege
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`that the daily dosage can “vary substantially” over a range of 0.1 - 0.5 mg or larger,
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`e.g., 2.5 or 5.0 mg. Although a broader range is disclosed, Kovarik explicitly
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`teaches that FTY720 dosages in the narrow range of 0.1 – 0.5 mg are used for
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`treating autoimmune diseases. EX1004 at 17.
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`28. Second, the applicants state that the maintenance dose is “dependent
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`on the immediately preceding loading dose.” EX1011 at 0034. However, this is
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`incorrect. As discussed more fully below in Section VIII.E, maintenance doses are
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`not dependent on loading dose regimens. Rather maintenance doses are dependent
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`on the desired steady state plasma concentration and the clearance rate of the drug.
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`“Clinical Pharmacology in the Critically Ill Child,” in CRITICAL CARE PEDIATRICS,
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`Zimmerman and Gildea eds (Saunders Company 1985) (“Critical Care,” EX1021)
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`at 93 (“[M]aintenance dose…is equal to the product of clearance…and [the]
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`desired steady state plasma concentration.…”). Clearance, in turn, is related to the
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`half-life of the drug and the volume of distribution. EX1021 at 91. These
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`-11-
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`parameters are not dependent on the loading dose regimen. The desired steady-
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`state plasma concentration is that which is safe and effective.
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`29. Further, the applicants argued that the skilled artisan thus “would
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`attach no significance to the suitability of any daily dosage mentioned therein
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`outside the context of an immediately preceding loading dose regimen.” EX1011 at
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`0034. I disagree with this statement, and it is also contradicted by the teachings of
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`Kovarik. For example, Kovarik states:
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`In view of the normally prolonged taking of the medication, the
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`standard daily dosage (also called maintenance dose) refers to the
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`dosage of an S1P receptor modulator or agonist necessary for a
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`steady-state trough blood level of the medication or its active
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`metabolite(s) providing effective treatment. Said dosage is dependent
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`on the accumulation factor (R). By blood level is meant the
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`concentration of a drug in blood at any time. Trough blood level
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`corresponds to a pre-dose blood level. Steady-state means whether the
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`trough or blood level is stable over time. Steady-state trough blood
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`levels may be assessed, for example, by obtaining a pre-dose blood
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`sample any time after month 3. The accumulation factor (R) is
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`calculated on the ratio of the steady-state trough to the trough just
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`before the second dose.
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`EX1004 at 14.
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`30.
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`In other words, the daily dosage is dependent on the pharmacokinetic
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`properties of the medication and the desired concentration level of the medication
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`-12-
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`
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`(EX1021 at 93), and not on whether a loading dose regimen is used. More
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`specifically, loading dose regimens impact the speed at which the medication
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`reaches the equilibrium in a patient. Patients given only the maintenance dose will
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`reach the same equilibrium concentration level attained by patients given a loading
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`dose regimen followed by the maintenance dose. EX1021 at 94 (“Administration
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`of an appropriate loading dose eliminates the delay (4t1/2) in achieving equilibrium
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`concentration[.]”). Therefore, a skilled artisan would consider the daily dosages
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`taught by Kovarik as relevant to dosing regimens for MS and RR-MS regardless of
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`whether a loading dose regimen is used.
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`V. LEGAL STANDARDS
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`31.
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`I have been informed that a claimed invention is not patentable under
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`35 U.S.C. §103, for obviousness, if the differences between the invention and the
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`prior art are such that the subject matter as a whole would have been obvious at the
`
`time the invention was made to a person having ordinary skill in the art to which
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`the subject matter pertains.
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`32.
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`I have been instructed that, a determination of obviousness requires
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`inquiries into (i) the scope and content of the art when the invention was made; (ii)
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`the differences between the art and the claims at issue; (iii) the level of ordinary
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`skill in the pertinent art when the invention was made; and, to the extent they exist,
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`any secondary considerations.
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`33.
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`I understand that a claim can be found to be obvious if all the claimed
`
`elements were known in the prior art and one skilled in the art could have
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`combined the elements as claimed by known methods with no change in their
`
`respective functions, and the combination would have yielded nothing more than
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`predictable and expected results to one of ordinary skill in the art. Further, it is my
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`understanding that a claim can be found to be obvious when a claimed amount lies
`
`within a range disclosed in the prior art.
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`34.
`
`I understand that hindsight must not be used when comparing the
`
`prior art to the invention for obviousness. Thus, a conclusion of obviousness must
`
`be firmly based on the knowledge and skill of a person of ordinary skill in the art at
`
`the time the invention was made, without the use of post-filing knowledge.
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`35.
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`I understand that in order for a claimed invention to be considered
`
`obvious, there must be some supporting rationale for combining cited references as
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`proposed.
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`36.
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`I have been informed that obviousness may also be shown by
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`demonstrating that it would have been obvious to modify what is taught in a single
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`piece of prior art to create the patented invention. Obviousness may be
`
`demonstrated by showing that it would have been obvious to combine the
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`teachings of more than one item of prior art. In determining whether a piece of
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`prior art could have been combined with other prior art or with other information
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`-14-
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`within the knowledge of one of ordinary skill in the art, the following are examples
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`of approaches and rationales that may be considered: combining prior art elements
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`according to known methods to yield predictable results; simple substitution of one
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`known element for another to obtain predictable results; use of a known technique
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`to improve similar methods or products in the same way; applying a known
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`technique to a known method or product ready for improvement to yield
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`predictable results; applying a technique or approach that would have been
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`“obvious to try” (choosing from a finite number of identified, predictable solutions,
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`with a reasonable expectation of success); known work in one field of endeavor
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`may prompt variations of it for use in either the same field or a different one based
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`on design incentives or other market forces if the variations would have been
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`predictable to one of ordinary skill in the art; or some teaching, suggestion, or
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`motivation in the prior art that would have led one of ordinary skill to modify the
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`prior art reference or to combine prior art reference teachings to arrive at the
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`claimed invention.
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`37.
`
`I also understand that “secondary considerations” may be considered
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`when in evidence to rebut a conclusion of prima facie obviousness where
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`appropriate.
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`38.
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`I understand that such secondary considerations include: (i)
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`commercial success of a product due to the merits of the claimed invention; (ii) a
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`long-felt, but unsatisfied need for the invention; (iii) failure of others to find the
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`solution provided by the claimed invention; (iv) deliberate copying of the invention
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`by others; (v) unexpected results achieved by the invention; (vi) praise of the
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`invention by others skilled in the art; (vii) lack of independent simultaneous
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`invention within a comparatively short space of time; and (viii) teaching away
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`from the invention in the prior art. Secondary considerations are relevant where
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`there is a connection, or relationship, between the evidence and the claimed
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`invention.
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`VI. LEVEL OF ORDINARY SKILL AND RELEVANT TIME
`
`39.
`
`I have been advised that “a person of ordinary skill in the art” is a
`
`hypothetical person who is presumed to have known the relevant art at the time of
`
`the invention. A person of ordinary skill in the art is also a person of ordinary
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`creativity. As discussed above, I have assumed that the relevant timeframe for
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`assessing the patentability of claims 1-6 of the ’405 patent is the time prior to June
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`27, 2006.
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`40. By virtue of my education, experience, and training, I am familiar
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`with the level of skill in the art of the ’405 patent prior to June 27, 2006. In my
`
`opinion, a person of ordinary skill in the relevant field prior to June 27, 2006
`
`would include a person with several years of experience as a medical professional,
`
`with experience in treating multiple sclerosis patients and administering to those
`
`-16-
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`
`
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`patients therapeutic agents for the treatment of multiple sclerosis. Such a person
`
`would be familiar with dosing regimens of the various therapeutic agents available
`
`for treating multiple sclerosis. Further, a person of ordinary skill in the art would
`
`be familiar with and able to understand the medical literature on multiple sclerosis
`
`that was available as of the priority date of the patent.
`
`VII. CLAIM CONSTRUCTION
`
`41.
`
`I have been advised that, in the present proceeding, the ’405 patent
`
`claims are to be given their broadest reasonable interpretation (BRI) in view of the
`
`specification. I also understand that, absent some reason to the contrary, claim
`
`terms are typically given their ordinary and customary meaning, as they would
`
`have been understood by one of ordinary skill in the art. I have followed these
`
`principles in my analysis described throughout this declaration.
`
`42. The ’405 patent provides definitions for certain claim terms. In my
`
`opinion, these definitions are conventional. Certain claim terms are not defined in
`
`the ’405 patent. I discuss a few terms below and what I understand as constructions
`
`of these terms.
`
`i. “a subject in need”
`
`43. Claims 1, 3, and 5 each contain a preamble identifying “a subject in
`
`need” of a method. In claim 1, the subject is in need of “[a] method for reducing or
`
`preventing or alleviating relapses in Relapsing-Remitting multiple sclerosis.” In
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`-17-
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`
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`claim 3, the subject is in need of “[a] method for treating Relapsing-Remitting
`
`multiple sclerosis.” In claim 5, the subject is in need of “[a] method for slowing
`
`progression of Relapsing-Remitting multiple sclerosis.” The method of claims 1, 3,
`
`and 5 is performed by (1) orally administering fingolimod at a daily dosage of 0.5
`
`mg to a subject in need; and (2) the daily dosage of 0.5 mg is not immediately
`
`preceded by a loading dose regimen.
`
`44.
`
`It is my opinion that a person of ordinary skill in the art would
`
`understand the preambles of claims 1, 3, and 5 to express, at most, the purpose of
`
`the method. There is no language in claims 1, 3, and 5 that a person of ordinary
`
`skill would understand as requiring a particular outcome to result from performing
`
`the method. Thus, under the broadest reasonable interpretation of the claims of
`
`the ’405 patent, any subject that has RR-MS is a subject in need of a method for
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`“reducing or preventing or alleviating relapses in RR-MS,” “[a] method for
`
`slowing progression of Relapsing-Remitting multiple sclerosis,” and a method for
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`“treating” RR-MS.
`
`ii. “A method for reducing or preventing or alleviating relapses,”
`“A method for treating,” “A method for slowing progression”
`
`45. As noted above, the phrase “A method for…” appears in the
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`preambles of each of claims 1, 3, and 5. The ’405 patent explains that 85% of
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`multiple sclerosis patients initially experience the RR-MS form of multiple
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`sclerosis, which involves relapses described in the ’405 patent as “[d]iscrete motor,
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`-18-
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`
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`sensory, cerebellar or visual attacks that occur over 1-2 weeks and often resolve
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`over 1-2 months.” Id. at col. 9, l. 66- col. 10, l. 1 (emphases added). The ’405
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`patent explains that “[s]ome patients accrue disability with each episode, yet
`
`remain clinically stable between relapses.” Id. at col. 10, ll. 1-3 (emphases added);
`
`see also MCALPINE’S MULTIPLE SCLEROSIS, 4th Edition, Compston, ed (Elsevier,
`
`Inc., December 2005) (“McAlpine,” EX1023) at 193 (RR-MS patients accrue
`
`neurologic disability over time because of incomplete recovery from relapses).
`
`The ’405 patent also explains that within 10 years of diagnosis with RR-MS, half
`
`of patients who “initially experience the RR form of MS… will develop the
`
`secondary progressive form.” EX1001, col. 9, l. 64- col. 10, l. 5 (emphases added);
`
`see also EX1023 at 195 (many RR-MS patients will eventually convert to the SP-
`
`MS form).
`
`46. The ’405 patent acknowledges that MS therapy “is only partially
`
`effective, and in most cases only offers a short delay in disease progression despite
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`anti-inflammatory and immunosuppressant treatment.” EX1001, col. 8, ll. 64-67.
`
`The ’405 patent states:
`
`Accordingly, there is a need for agents which are effective in the
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`inhibition or treatment of demyelinating disease, e.g. multiple
`
`sclerosis or Guillain-Barré syndrome, including reduction of,
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`alleviation of, stabilization of, or relief from the symptoms which
`
`affect the organism. Characteristic pathological features of
`
`-19-
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`
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`demyelinating diseases include inflammation, demyelination and
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`axonal and oligodendrocyte loss.
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`Id. at col. 8, l. 67- col. 9, l. 8 (emphases added).
`
`47. These statements are consistent with the teachings of the prior art that
`
`the treatments given to multiple sclerosis patients are termed “disease-modifying
`
`therapies” because these therapies are given with the hope of reducing the
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`frequency or severity of relapses and delaying disease progression. EX1023 at 729-
`
`731. A person of ordinary skill in the art would understand that a method for
`
`treating RR-MS by administering an immunomodulator, such as fingolimod, would
`
`at most be a disease modifying therapy, not a cure. As such, the skilled artisan
`
`would recognize that two of the goals of anti-inflammatory, immunosuppressant or
`
`immunomodulatory treatment of RR-MS patients would include (1) the reduction
`
`of, alleviation of, or relief from the relapses that characterize RR-MS; and (2)
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`providing some delay, even if short, in disease progression. The ’405 patent itself
`
`confirms that alleviating or reducing relapses and delaying disease progression
`
`were goals of anti-inflammatory, immunosuppressant or immunomodulatory
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`treatment of RR-MS patients. See EX1001, col. 8, l. 64- col. 9, ll. 8.
`
`VIII. STATE OF THE ART
`
`48. Below I describe some of the relevant aspects of what was generally
`
`known in the art as of June 27, 2006.
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`-20-
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`
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`A. Multiple Sclerosis
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`49. There are four types of multiple sclerosis, relapsing-remitting (RR-
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`MS), secondary progressive (SP-MS), primary progressive (PP-MS), and
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`progressive relapsing (PR-MS). EX1023 at 194-195. Patients with RR-MS often
`
`convert to the SP-MS form. Id. at 195. Those with SP-MS may or may not
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`experience relapses. Id. Patients with PP-MS do not initially experience relapses
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`but rather experience a continuous progression of symptoms from onset. Id. RR-
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`MS is by far the most common form of MS, with RR-MS constituting
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`approximately 85% of MS patients at disease onset. Id. at 201.
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`50. Clinical evidence from patients suffering the various forms of MS
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`points to inflammation as the underlying cause of the symptoms associated with
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`relapses and to neurodegeneration as the underlying cause of progression. See, e.g.,
`
`Id. at 228-29. In other words:
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`Effector mechanisms
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