`
`In the Inter Partes Review of:
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`Trial Number: To Be Assigned
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`U.S. Patent No. 9,187,405
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`Filed: April 21, 2014
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`Issued: November 17, 2015
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`Inventor(s): Peter C. Hiestand, Christian Schnell
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`Assignee: Novartis A.G.
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`Title: S1P receptor modulators for treating relapsing-
`remitting multiple sclerosis
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`Panel: To Be Assigned
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`Mail Stop Inter Partes Review
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 9,187,405
`UNDER 35 U.S.C. §§ 311-319 and 37 C.F.R. § 42.100
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`Patent No. 9,187,405
`Petition For Inter Partes Review
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`Table of Contents
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`
`I.
`
`INTRODUCTION ........................................................................................... 1
`A.
`Brief Overview of the ’405 Patent ........................................................ 3
`B.
`Brief Overview of the Prosecution History ........................................... 5
`C.
`Brief Overview of the Grounds ............................................................. 6
`D.
`Brief Overview of the Scope and Content of the Prior Art ................... 9
`i.
`International Publication No. WO 2006/058316
`(“Kovarik,” EX1004) ............................................................... 10
`Thomson, FTY720 in multiple sclerosis: the emerging
`evidence of its therapeutic value, CORE EVIDENCE,
`1(3): 157-167 (2006) (“Thomson,” EX1005) .......................... 11
`iii. U.S. Patent No. 6,004,565 to Chiba (“Chiba,” EX1006).......... 13
`iv. Kappos, et al., FTY720 in relapsing MS: results of a
`double-blind placebo-controlled trial with a novel oral
`immunomodulator, JOURNAL OF NEUROLOGY
`252(Suppl 2): 11/41, Abstract O141(2005) (“Kappos
`2005,” EX1007) ........................................................................ 14
`Budde, et al., First human trial of FTY720, a novel
`immunomodulator, in stable renal transplant patients,
`JOURNAL OF THE AMERICAN SOCIETY FOR
`NEPHROLOGY, 13:1073-1083 (2002) (“Budde,”
`EX1008) .................................................................................... 16
`vi. Kappos, et al., A Placebo-Controlled Trial of Oral
`Fingolimod in Relapsing Multiple Sclerosis, NEW
`ENGLAND JOURNAL OF MEDICINE, 362(5):387-
`401 (2010) (“Kappos 2010,” EX1038) .................................... 17
`Brief Overview of the Level of Skill in the Art .................................. 19
`E.
`II. GROUNDS FOR STANDING ...................................................................... 20
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`ii.
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`v.
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`i
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`Patent No. 9,187,405
`Petition For Inter Partes Review
`III. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8 ................................. 20
`IV. STATEMENT OF THE PRECISE RELIEF REQUESTED ........................ 22
`V.
`STATEMENT OF NON-REDUNDANCY .................................................. 23
`VI. CLAIM CONSTRUCTION .......................................................................... 23
`A.
`“a subject in need” ............................................................................... 24
`B.
`“A method for...” ................................................................................. 25
`VII. BACKGROUND KNOWLEDGE IN THE ART PRIOR TO JUNE
`27, 2006 ......................................................................................................... 26
`A. Multiple Sclerosis ................................................................................ 27
`B. Disease Modifying Therapies .............................................................. 28
`C.
`Fingolimod .......................................................................................... 29
`D.
`Loading Dose Regimens ..................................................................... 31
`VIII. DETAILED EXPLANATION OF GROUNDS FOR
`UNPATENTABILITY .................................................................................. 33
`A.
`[Ground 1] Claims 1-6 are Obvious under 35 U.S.C. § 103 over
`Kovarik and Thomson. ........................................................................ 33
`i.
`Claims 1, 3, and 5...................................................................... 33
`ii.
`Claims 2, 4, and 6...................................................................... 48
`[Ground 2] Claims 1-6 are Obvious under 35 U.S.C. § 103 over
`Chiba, Kappos 2005, and Budde. ........................................................ 49
`i.
`Claims 2, 4, and 6...................................................................... 58
`[Ground 3] Claims 1-6 are Anticipated under 35 U.S.C. § 102
`by Kappos 2010 (EX1038) .................................................................. 59
`i.
`Claims 2, 4, and 6...................................................................... 62
`
`B.
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`C.
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`ii
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`Patent No. 9,187,405
`Petition For Inter Partes Review
`IX. NO EVIDENCE OF UNEXPECTED RESULTS OR SECONDARY
`CONSIDERATIONS ARE ATTRIBUTABLE TO NOVEL
`ASPECTS OF THE CLAIMS ....................................................................... 63
`PAYMENT OF FEES UNDER 37 C.F.R. §§ 42.15(A) AND 42.103.......... 65
`X.
`XI. CONCLUSION .............................................................................................. 65
`XII. CERTIFICATE OF COMPLIANCE ............................................................ 66
`XIII. APPENDIX – LIST OF EXHIBITS .............................................................. 67
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`
`
`iii
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`Patent No. 9,187,405
`Petition For Inter Partes Review
`I.
`INTRODUCTION
`Pursuant to 35 U.S.C. § 311 and § 6 of the America Invents Act (“AIA”),
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`and 37 C.F.R. Part 42, Actavis Elizabeth LLC and Teva Pharmaceuticals USA,
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`Inc., (“Petitioners”) request review of U.S. Patent No. 9,187,405 to Peter C.
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`Hiestand et al. (“the ’405 patent,” EX1001), issued on November 17, 2015, and
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`assigned to Novartis A.G. (“Patent Owner”). Petitioners are filing, concurrently
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`herewith, a Motion for Joinder under 35 U.S.C. § 315(c), 37 C.F.R. § 42.22 and §
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`42.122(b) to the inter partes review involving the same patent and the same
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`grounds of invalidity in Apotex, Inc. and Apotex Corp. v. Novartis AG, IPR2017-
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`00854 (“Apotex IPR”), which was filed on February 3, 2017. The instant Petition
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`is substantially identical to the Petition filed in the Apotex IPR.
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`The ’405 patent claims a method of administering fingolimod hydrochloride
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`(“FTY720”), a previously known immunosuppressant, for the treatment of a
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`subject with Relapsing-Remitting Multiple Sclerosis (“RR-MS”). The claimed
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`method recites “a daily dosage of 0.5 mg” that was known and reported to be safe
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`and pharmacologically effective in humans more than one year before the earliest
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`effective filing date of the ’405 patent. For example, International Publication No.
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`WO 2006/058316 (“Kovarik,” EX1004), teaches treating multiple sclerosis by
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`administering a 0.5 mg oral daily dose of fingolimod hydrochloride.
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`1
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`Patent No. 9,187,405
`Petition For Inter Partes Review
`The ’405 patent claims also employ a negative limitation regarding the
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`absence of a loading dose regimen. Yet, Kovarik teaches that a maintenance dose
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`is a therapeutically effective dose and teaches 0.5 mg fingolimod hydrochloride as
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`a standard daily (maintenance) dose for treating MS. Indeed, the evidence shows
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`that of the six FDA-approved treatments for RR-MS, none described the use of
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`loading doses as part of an approved regimen.
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`The prior art also teaches 0.5 mg fingolimod hydrochloride was
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`pharmacologically effective in inducing lymphopenia (the mechanism by which
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`fingolimod hydrochloride was understood to treat MS). Moreover, the prior art
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`teaches that fingolimod hydrochloride was effective in treating RR-MS by
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`reducing, preventing or alleviating relapses and slowing the progression of the
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`disease. In view of the prior art, it would have been obvious to administer a 0.5 mg
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`daily dose of fingolimod hydrochloride absent an immediately preceding loading
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`dose regimen to a patient with RR-MS.
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`This petition also establishes that the negative limitation regarding the
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`absence of a loading dose regimen was not supported by the ’405 patent
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`specification, nor in any priority documents. Thus, claims 1-6 of the ’405 patent
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`are anticipated by the 2010 disclosure of the results of a phase III clinical trial
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`administering a 0.5 mg daily dose of fingolimod hydrochloride for the treatment of
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`RR-MS.
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`Patent No. 9,187,405
`Petition For Inter Partes Review
`For the reasons discussed herein, this Petition demonstrates by a
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`preponderance of the evidence that it is more likely than not that claims 1-6 of the
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`’405 patent are unpatentable for failing to distinguish over prior art and should be
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`found unpatentable and canceled.
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`A. Brief Overview of the ’405 Patent
`The ’405 patent is entitled “S1P Receptor Modulators for Treating
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`Relapsing-Remitting Multiple Sclerosis.” In a general sense, the ’405 patent is
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`directed to the use of sphingosine 1-phosphate (S1P) receptor agonists for the
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`treatment of demyelinating diseases such as multiple sclerosis. See, e.g., EX1001,
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`1:5-8; EX1002, ¶13. The specification describes a genus of sphingosine analogs
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`(EX1001. at 1:15-18), including 2-amino-2-[2-(4-octylphenyl)ethyl]propane-l,3-
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`diol hydrochloride, also known as fingolimod hydrochloride or as FTY720. Id. at
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`8:18-30; EX1002, ¶¶8, 12, 16, 56.
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`The ’405 patent asserts that S1P agonists “are known as having
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`immunosuppressive properties or anti-angiogenic properties,” and that “multiple
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`sclerosis (MS) is an immune-mediated disease of the central nervous systems[.]”
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`EX1001, 8:56-67. No data on the efficacy of the claimed method to treat or slow
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`the progression of RR-MS are presented in the ’405 patent. EX1002, ¶¶15-16. The
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`patent also does not present data on the effect of the claimed method on relapse
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`reduction, prevention, or alleviation in patients suffering from RR-MS. Id. Instead,
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`Patent No. 9,187,405
`Petition For Inter Partes Review
`Patent No. 9,187,405 Petition For Inter Partes Review prophetically-written
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`experiments are described to permit an assessment of whether compounds such as
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`fingolimod hydrochloride are able to “completely inhibit[] the relapse phases”
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`using a rat model of relapsing multiple sclerosis. EX1001, 10:67; see also id. at
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`10:32-11:2. A clinical trial is also proposed to assess the claimed methods’
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`“clinical benefit” in RR-MS patients. EX1001, 11:6-38. EX1002, ¶16.
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`Claim 1 of the ’405 patent is representative of the independent claims at
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`issue:
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`A method for reducing or preventing or alleviating relapses in
`Relapsing-Remitting multiple sclerosis in a subject in need thereof,
`comprising orally administering to said subject 2-amino-2-[2-(4-
`octylphenyl)ethyl]propane-1,3-diol, in free form or in a
`pharmaceutically acceptable salt form, at a daily dosage of 0.5 mg,
`absent an immediately preceding loading dose regimen.
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`EX1001, 12:49-55; EX1002, ¶9.
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`Independent claims 3 and 5 are also directed to administering a daily oral 0.5
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`mg dose of fingolimod, in free form or as a salt, to a subject in need, absent an
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`immediately preceding loading dose regimen. EX1001, 12:59-13:6; EX1002, ¶¶10-
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`11. Claim 3 specifies that the subject is in need of a method for treating RR-MS.
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`EX1001, 12:59-13:6. Claim 5 specifies that the subject is in need of a method for
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`slowing progression of RR-MS. Id. Claims 2, 4, and 6 depend, respectively, from
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`4
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`Patent No. 9,187,405
`Petition For Inter Partes Review
`claims 1, 3, and 5, and each specify that fingolimod is administered as fingolimod
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`hydrochloride. Id. at 12:56-13:9; EX1002, ¶12.
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`B.
`Brief Overview of the Prosecution History
`The patent application that matured into the ’405 patent, 14/257,342 (“the
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`’342 application”), was filed on April 21, 2014, as a divisional application of
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`13/149,468 (“the ’468 application”), which itself issued as U.S. Patent No.
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`8,741,963 (“the ’963 patent,” EX1013). EX1002, ¶¶17-19, 22. The ʼ468
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`application was filed as a continuation of 12/303,765 (“the ’765 application,”
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`EX1009), which was the U.S. entry of PCT/EP2007/005597 that was filed on June
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`25, 2007. Id. PCT/EP2007/005597 claims priority to foreign application
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`GB0612721.1 (EX1012), which was filed on June 27, 2006. EX1001 at cover.
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`The claims of the ’342 application were initially rejected as obvious over
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`Virley, Developing Therapeutics for the Treatment of Multiple Sclerosis,
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`NEURORX, 2:638-649 (2005) (“Virely,” EX1016) and International Publication
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`No. WO 2006/058316 (published June 1, 2006) (“Kovarik,” EX1004). EX1011 at
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`0052-56; EX1002, ¶¶23-24. Patent Owner offered only attorney argument in
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`response to the non-final rejection. EX1011 at 0033-34; EX1002, ¶25. A notice of
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`allowance ensued. EX1011 at 0007; EX1002, ¶26.
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`Patent No. 9,187,405
`Petition For Inter Partes Review
`C. Brief Overview of the Grounds
`Ground 1 provides new evidence and argument regarding the obviousness of
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`the challenged claims in view of Kovarik (EX1004) and Thomson (EX1005), with
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`only the former reference having been discussed substantively during prosecution.
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`For example, this petition is accompanied by the supporting declaration of Dr.
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`Barbara S. Giesser, Professor of Clinical Neurology at UCLA with over 30 years
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`of experience in the treatment of patients with, and research regarding, multiple
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`sclerosis. EX1002, ¶¶1-4. Dr. Giesser states that, in her opinion, several of the
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`assertions made by the Applicants’ attorneys during prosecution to overcome the
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`rejection are incorrect. EX1002, ¶27.
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`For one, Dr. Giesser notes that the Applicants’ attorneys argued that the
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`maintenance dose is “dependent on the immediately preceding loading dose,”
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`thereby incorrectly implying that the maintenance dose disclosed for the treatment
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`of MS in Kovarik would be inapplicable absent an immediately preceding loading
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`dose. EX1011 at 0033; EX1002, ¶28. As explained by Dr. Giesser, however,
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`therapeutic efficacy of a maintenance dose depends on the desired steady-state
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`plasma concentration and the clearance rate of the drug, neither of which are
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`dependent on a loading dose regimen. EX1002, ¶¶29-30, citing EX1021 at 91, 93
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`(which teaches that a “maintenance dose...is equal to the product of clearance...
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`and [the] desired steady state plasma concentration....”). A loading dose regimen
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`Patent No. 9,187,405
`Petition For Inter Partes Review
`merely increases the speed at which this steady-state plasma concentration is
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`achieved. Id.; EX1002, ¶¶19-20, 57. Thus, Applicants’ attorney argument that
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`daily dosage depends on a given loading dose regimen is contradicted by the
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`teachings of Kovarik and the expert testimony of Dr. Giesser.
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`Applicants’ attorneys further argued that a skilled artisan “would attach no
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`significance to the suitability of any daily dosage mentioned therein [Kovarik]
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`outside the context of an immediately preceding loading dose regimen.” EX1011 at
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`0034; EX1002, ¶¶29-30. Dr. Giesser notes this unsupported assertion is
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`contradicted by Kovarik itself, which teaches:
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`Preferred medications comprise medication for . . . patients suffering
`from autoimmune diseases, e.g., multiple sclerosis. . . . In view of the
`normally prolonged taking of the medication, the standard daily
`dosage (also called maintenance dose) refers to the dosage of an S1P
`receptor modulator or agonist necessary for a steady-state trough
`blood level of the medication or its active metabolite(s) providing
`effective treatment.
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`EX1004 at 14 (emphasis added). Thus, Kovarik confirms that the 0.5 mg
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`maintenance dose is effective for the treatment of multiple sclerosis regardless of
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`whether it was immediately preceded by a loading dose regimen. EX1002, ¶¶2930;
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`see also EX1010 at 0109 (“standard daily dosage” is “the dosage necessary for a
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`steady-state trough blood level of the drug providing effective treatment.”).
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`Patent No. 9,187,405
`Petition For Inter Partes Review
`The Applicants’ attorneys also argued that the “daily dosage administered
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`after the initial period can vary substantially relative to the standard daily dosage.”
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`EX1011 at 0033. However, as Dr. Giesser notes, Kovarik teaches administering
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`fingolimod hydrochloride in the narrow range of 0.1 mg - 0.5 mg per day in the
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`treatment of autoimmune diseases, including multiple sclerosis. EX1004 at 17;
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`EX1002, ¶27. She also notes that Kovarik teaches a dosing regimen that involves
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`maintenance therapy with a 0.5 mg daily dose. EX1004 at 15; EX1002, ¶76. Thus,
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`Kovarik not only teaches a narrow range of maintenance doses for MS treatment
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`that encompasses the Applicants’ claimed daily dose, but also specifically
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`describes the claimed 0.5 mg daily dosage as part of a preferred embodiment.
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`EX1004 at 15 (“[T]reatment is continued with the maintenance therapy, e.g. a daily
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`dosage of 0.5 mg.”).
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`For the reasons discussed above, the Board should not defer to the Patent
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`Owner’s unsupported attorney arguments during prosecution.
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`Ground 2 presents new arguments and evidence regarding the obviousness
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`of the challenged claims in view of Chiba (EX1006), Kappos 2005 (EX1007), and
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`Budde (EX1008). Chiba was not of record during prosecution of the ’405 patent.
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`Kappos 2005 and Budde were not substantively discussed during prosecution.
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`Ground 3 presents new arguments and evidence regarding the
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`unpatentability of the challenged claims in view of Kappos 2010 (EX1038), which
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`8
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`Patent No. 9,187,405
`Petition For Inter Partes Review
`was not of record during prosecution of the ’405 patent. Ground 3 presents an
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`argument not previously considered by the Patent Office that the claims of the ’405
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`patent are not entitled to the benefit of a filing date earlier than April 21, 2014.
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`For the reasons discussed above, the Board should consider the evidence and
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`arguments in this petition without substantial deference to the decision by the
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`Office to allow the ’342 application.
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`D. Brief Overview of the Scope and Content of the Prior Art
`The priority document for the ’405 patent is a foreign patent application (GB
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`0612721.1, EX1012), which was filed June 27, 2006. For the purposes of pre-AIA
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`35 U.S.C. § 102(b), the relevant date is that of first United States filing. See 35
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`U.S.C. § 119(a) (pre-AIA) (“[B]ut no patent shall be granted on any application for
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`patent for an invention which had been patented or described in a printed
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`publication in any country more than one year before the date of the actual filing
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`of the application in this country, or which had been in public use or on sale in
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`this country more than one year prior to such filing.”); see also MPEP § 706.02
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`(“In examining applications subject to pre-AIA 35 U.S.C. 102, the effective filing
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`date is the filing date of the U.S. application... not the filing date of the foreign
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`priority document.”). In this case, “the actual filing of the application in this
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`country” is no earlier than June 25, 2007, the filing date of PCT/EP2007/005597.
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`9
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`Patent No. 9,187,405
`Petition For Inter Partes Review
`Therefore, at least publications that pre-date June 25, 2006, are prior art to the
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`claims of the ’405 patent under 35 U.S.C. § 102(b).
`
`i.
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`International Publication No. WO 2006/058316 (“Kovarik,”
`EX1004)
`Kovarik is a PCT application that published in English on June 1, 2006, and
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`was filed as PCT/US2005/043044 by Novartis Pharma GmbH on November 28,
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`2005. Kovarik claims priority to U.S. Provisional Application No. 60/631,483
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`(filed November 29, 2004) (EX1015). EX1002, ¶74.
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`Kovarik discloses a genus of agonists for the S1P receptor that are “useful
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`for the treatment of inflammatory and autoimmune diseases” due to their
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`“immune-modulating potency.” EX1004 at 1; EX1002, ¶75. Kovarik teaches that
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`“preferred” species are those “which in addition to their S1P binding properties
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`also have accelerating lymphocyte homing properties, e.g. compounds which elicit
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`a lymphopenia[.]” EX1004 at 2. Kovarik teaches “[a] particularly preferred S1P
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`receptor agonist ... is FTY720, i.e. 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-
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`diol in free form or in a pharmaceutically acceptable salt form . . . e.g. the
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`hydrochloride, as shown:
`
`.”
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`Id. at 13; EX1002, ¶75.
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`10
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`Patent No. 9,187,405
`Petition For Inter Partes Review
`Kovarik teaches daily oral dosage regimens of fingolimod hydrochloride
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`(FTY720) for the treatment of “autoimmune diseases, e.g. multiple sclerosis,” and
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`for preventing organ rejection. EX1004 at 14, 18. Kovarik teaches “[a] method for
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`treating an autoimmune disease in a subject in need thereof, comprising
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`administering to the subject, after a loading regimen, a daily dosage of FTY720 of
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`about 0.1 to 0.5 mg.” Id. at 17; EX1002, ¶¶76-77. Kovarik further teaches that the
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`standard daily (maintenance) dosage of 0.5 mg FTY720 may be administered for
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`the treatment of multiple sclerosis and that the loading dose regimen allows for a
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`steady-state concentration of FTY720 to be achieved in less than one week.
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`EX1004 at 14-15, 17; EX1002, ¶¶77-78, 105.
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`Kovarik published on June 1, 2006, and is prior art to the claims of the ’405
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`patent at least under 35 U.S.C. §§ 102(a), (b), (e).
`
`ii.
`
`Thomson, FTY720 in multiple sclerosis: the emerging evidence
`of its therapeutic value, CORE EVIDENCE, 1(3): 157-167
`(2006) (“Thomson,” EX1005)
`Thomson reviews medical literature describing the use of FTY720 in the
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`treatment of multiple sclerosis. EX1005 at 157, EX1002, ¶81. Thomson teaches
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`that FTY720 reduces inflammatory disease activity, thereby reducing relapse rates,
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`increasing the time to first relapse, and increasing intervals between relapses:
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`FTY720 (administered orally once a day for up to 12 months)
`improved the patient-oriented outcomes of relapse rate and the
`likelihood of remaining relapse-free. In addition, there is moderate
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`11
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`Patent No. 9,187,405
`Petition For Inter Partes Review
`evidence that disease-oriented outcomes were also improved by
`FTY720 in that inflammatory disease activity (both new and existing)
`was reduced as determined by MRI.
`
`EX1005 at 166-67; EX1002, ¶¶83, 85-86. Thomson concludes, “FTY720 has the
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`potential to be an effective disease-modifying agent for the treatment of RRMS.”
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`EX1005 at 167; EX1002, ¶82.
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`Thomson additionally provides data from clinical trials focused on the use of
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`fingolimod hydrochloride in preventing organ rejection following transplantation.
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`EX1005 at 157; EX1002, ¶84. Thomson explains that “[p]harmacokinetic and
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`pharmacodynamic outcomes . . . are not affected by disease status and may be
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`extrapolated to include those patients with multiple sclerosis.” EX1005 at 162;
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`EX1002, ¶84. Thomson additionally explains that induction of a reversible
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`lymphopenia provides for “good evidence that FTY720 achieves
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`immunomodulation” and thus “has the potential to be an effective disease
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`modifying agent for the treatment of multiple sclerosis.” EX1005 at 157; see also
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`EX1002, ¶¶58, 60-61, 64, 84, citing EX1022 at 309, EX1018 at 237-39, Park, et
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`al., Pharmacokinetic/Pharmacodynamic Relationships of FTY720 in Kidney
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`Transplant Patients, BRAZILIAN JOURNAL OF MEDICAL AND
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`BIOLOGICAL RESEARCH, 38: 683-694 (2005) (“Park,” EX1019) at 684,
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`EX1031 at 1081, EX1028 at 440. Thomson teaches that single oral doses in the
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`12
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`Patent No. 9,187,405
`Petition For Inter Partes Review
`range of 0.25 to 3.5 mg are sufficient to induce lymphopenia and that there is “[n]o
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`clear dose response” over this dose range. EX1005 at 163; EX1002, ¶85.
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`Thomson published on March 31, 2006 (see also EX1040) and is prior art to
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`the claims of the ’405 patent at least under 35 U.S.C. §§ 102 (a) and (b).
`
`iii. U.S. Patent No. 6,004,565 to Chiba (“Chiba,” EX1006)
`Chiba teaches compounds that promote accelerated lymphocyte homing
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`(“ALH”), “show superior immunosuppressive effects and are useful themselves, or
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`in methods, for the prevention or treatment of . . . autoimmune diseases such as . . .
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`multiple sclerosis[.]” EX1006, 2:55-58; id. at 6:26-49; EX1002, ¶¶90-91. Chiba
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`notes a preferred ALH-immunosuppressive compound called “FTY720, 2-amino-
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`2[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride, shown below.
`
`.”
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`EX1006, 4:64-5:7; EX1002, ¶90.
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`Thus, Chiba teaches that FTY720, fingolimod hydrochloride, suppresses the
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`immune response of mammals through accelerated lymphocyte homing and is
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`useful for the treatment of MS. EX1006, 4:64-67; EX1002, ¶90. Chiba teaches oral
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`administration of FTY720 in a 0.01-10 mg daily oral dose. EX1006, 6:26-31, 6:41-
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`43, 8:19-34, 11:20-21; EX1002, ¶¶91-92.
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`13
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`Patent No. 9,187,405
`Petition For Inter Partes Review
`The Board has previously considered Chiba as part of IPR2014-00784—an
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`inter partes review of U.S. Patent No. 8,324,283 (“the ’283 patent,” EX1037). The
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`’283 patent, assigned to Novartis AG and Mitsubishi Pharma Corporation
`
`according to PTO assignment records, claims pharmaceutical compositions of
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`fingolimod. The Board outlined the teachings of Chiba in the Final Written
`
`Decision finding the claims of the ’283 patent unpatentable:
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`Chiba teaches immunosuppressive compounds with fingolimod as the
`preferred species. Chiba also teaches that the immunosuppressive
`compounds it teaches are useful for treating “transplantation rejection
`of organs or tissues” and “autoimmune diseases such as ... multiple
`sclerosis,” among other diseases and conditions. Chiba teaches oral
`administration of fingolimod[.]
`
`IPR2014-00784, Paper 112, Final Written Decision (“the ’784 decision,” EX1032)
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`at 10 (citations removed). On the record in that IPR, the panel stated, “Chiba itself
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`suggested treating multiple sclerosis using a solid oral form of fingolimod.” Id. at
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`25.
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`Chiba issued in 1999 and is prior art to the claims of the ’405 patent at least
`
`under 35 U.S.C. §§ 102(a) and 102(b).
`
`iv. Kappos, et al., FTY720 in relapsing MS: results of a double-
`blind placebo-controlled trial with a novel oral
`immunomodulator, JOURNAL OF NEUROLOGY 252(Suppl
`2): 11/41, Abstract O141(2005) (“Kappos 2005,” EX1007)
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`Kappos 2005 teaches that FTY720, fingolimod hydrochloride, “reversibly
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`sequesters tissue damaging T and B cells away from blood and the central nervous
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`system to peripheral lymph nodes.” EX1007 at 41, abstract O141; EX1002, ¶94.
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`Kappos 2005 teaches that “FTY720 has demonstrated both preventative and
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`therapeutic efficacy” in several animal models of MS. EX1007 at 41, abstract
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`O141; EX1002, ¶94.
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`Kappos 2005 discloses the results of a Phase II randomized, double-blind,
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`placebo-controlled study sponsored by Novartis Pharma AG Basel. Id. The trial
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`evaluated the efficacy of daily oral doses of FTY720 for the treatment of relapsing
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`multiple sclerosis patients. Id. Kappos 2005 reports “demonstrated efficacy of
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`FTY720 on MRI and relapse-related endpoints,” including the total number and
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`volume of lesions as evaluated in monthly post baseline MRI scans. EX1007 at 41,
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`abstract O141; EX1002, ¶95. Kappos 2005 also reported that FTY720 provided a
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`higher “proportion of relapse-free patients,” as well as a lower “annualized relapse
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`rate” and longer “time to first relapse” as compared to placebo. EX1007 at 41,
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`abstract O141. Additionally, Kappos 2005 teaches that there were “no compelling
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`dose-related difference in efficacy on MRI or clinical endpoints.” Id. Kappos 2005
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`states that these results “strongly suggest that FTY720 has the potential to be an
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`efficacious disease modifying treatment for relapsing forms of MS with the
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`additional benefit of once daily oral administration.” Id.; EX1002, ¶95.
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`Patent No. 9,187,405
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`Kappos 2005 published in 20051 and is prior art to the claims of the ’405
`
`patent at least under 35 U.S.C. §§ 102(a) and 102(b).
`
`v.
`
`Budde, et al., First human trial of FTY720, a novel
`immunomodulator, in stable renal transplant patients,
`JOURNAL OF THE AMERICAN SOCIETY FOR
`NEPHROLOGY, 13:1073-1083 (2002) (“Budde,” EX1008)
`Budde describes a clinical study of FTY720 in renal transplant patients.
`
`EX1008 at 1073; EX1002, ¶97. Budde teaches that oral doses of 0.25, 0.5, 0.75, 1,
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`2, and 3.5 mg are each effective for induction of lymphopenia within 4.7-8 hours
`
`of administration. EX1008 at 1078; EX1002, ¶97. Budde expressly teaches the
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`safety and lymphopenia-inducing efficacy of administering a dose of 0.5 mg
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`FTY720. EX1008 at 1075-76; EX1002, ¶98. Budde also teaches that at “doses
`
`ranging from 0.5 mg to 3.5 mg, no clear dose response relationship was
`
`detected[.]” Id. at 1079; EX1002, ¶98. However, Budde teaches that doses ≥0.75
`
`mg are associated with bradycardia (slowing of the heart rate). EX1008 at 1075-76;
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`EX1002, ¶98.
`
`
`1 Kappos 2005 is an abstract for an oral presentation presented between June 18-
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`22, 2005 in Vienna, Austria, and was published in the second 2005
`
`supplemental issue of the 252nd volume of the Journal of Neurology. Kappos
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`2005 is also cited in Thomson. EX1005 at 167.
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`Budde was previously considered by a panel of the Board in IPR2014-
`
`00784. In ruling on the admissibility of expert testimony relying on Budde, the
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`Board concluded:
`
`[T]he evidence of record shows that Budde describes a clinical effect
`of a low dose of fingolimod and that a formulator would attempt to
`use the proper effective dose when studying compatibility with
`excipients. (“Single oral doses of FTY720 ranging from 0.25 to 3.5
`mg ... caused a reversible selective lymphopenia.”)[.]
`
`EX1032 at 52.
`
`Budde was published in 2002 and is prior art to the claims of the ’405 patent
`
`at least under 35 U.S.C. §§ 102 (a) and 102 (b).
`
`vi. Kappos, et al., A Placebo-Controlled Trial of Oral Fingolimod
`in Relapsing Multiple Sclerosis, NEW ENGLAND JOURNAL
`OF MEDICINE, 362(5):387-401 (2010) (“Kappos 2010,”
`EX1038)
`Kappos 2010 is prior art to the claims of the ’405 patent at least under 35
`
`U.S.C. §§ 102 (a) and 102 (b) because the claims of the ’405 are not entitled to the
`
`benefit of any pre-2010 filing date. As issued, the claims recite that 0.5 mg
`
`fingolimod is administered “absent an immediately preceding loading dose
`
`regimen.” EX1001, 12:49-13:9. This negative claim limitation first appeared in the
`
`’342 application in a preliminary amendment submitted August 18, 2014. EX1011
`
`at 0079-81. The originally filed ’342 application, the resulting ’405 patent, and
`
`each of the priority documents on which the ’342 relies, are otherwise silent on
`
`
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`Patent No. 9,187,405
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`whether or not to use a loading dose regimen. EX1002, ¶¶15, 144; EX1011 at
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`0111-27; EX1012 (GB0612721.1); EX1009 (Appl. No. 12/303,765); EX1010
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`(Appl. No. 13/149,468). Although the negative limitation was also added to the
`
`claims in the related ’468 application (EX1010 at 0085-86), this occurred after its
`
`2011 filing date.
`
`Because none of its priority documents provide any reason prior to at least
`
`2011 to exclude a loading dose regimen, or even mention the presence or absence
`
`of a loading dose regimen, the ’405 patent is therefore entitled to a priority date no
`
`earlier than the filing date of the ’342 application, April 21, 2014, or the date of the
`
`preliminary amendment, August 18, 2014. Santarus, Inc. v. Par Pharm., Inc., 694
`
`F.3d 1344, 1351 (Fed. Cir. 2012) (“Negative claim limitations are adequately
`
`supported when the specification describes a reason to exclude the relevant
`
`limitation.”); In re Bimeda Research & Dev. Ltd., 724 F.3d 1320, 1323 (Fed. Cir.
`
`2013) (Affirming lack of written description support for a negative claim limitation
`
`because the disclosure did not “describe[] a formulation excluding a specific
`
`species.”). Thus, documents published at least before April 21, 2013, including
`
`Kappos 2010, are prior art to and may be applied against the claims of the ’405
`
`patent under 35 U.S.C. § 102(b).
`
`Kappos 2010 discloses the results of a Phase III randomized, double-blind,
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`placebo-controlled study sponsored by Novartis Pharma. EX1038 at 387; EX1002,
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