`Paper No. ____
`Filed: February 3, 2017
`
`Filed on behalf of: Apotex Inc. & Apotex Corp.
`By: Steven W. Parmelee (sparmelee@wsgr.com)
`
`Michael T. Rosato (mrosato@wsgr.com)
`
`Jad A. Mills (jmills@wsgr.com)
`WILSON SONSINI GOODRICH & ROSATI
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`
`APOTEX INC. AND
`APOTEX CORP.
`Petitioners,
`
`v.
`
`NOVARTIS A.G.,
`Patent Owner.
`
`_____________________________
`
`IPR2017-00854
`Patent No. 9,187,405
`
`_____________________________
`
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 9,187,405
`
`
`
`

`

`TABLE OF CONTENTS
`
`
`
`Page
`
`I.
`
`Introduction .................................................................................................. 1
`
`A.
`
`Brief Overview of the ’405 Patent....................................................... 2
`
`B.
`
`C.
`
`Brief Overview of the Prosecution History ......................................... 4
`
`Brief Overview of the Grounds ........................................................... 5
`
`D.
`
`Brief Overview of the Scope and Content of the Prior Art .................. 9
`
`i.
`
`ii.
`
`International Publication No. WO 2006/058316
`(“Kovarik,” EX1004) ................................................................ 9
`
`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) ......... 12
`
`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
`
`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) .............................. 15
`
`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
`
`E.
`
`Brief Overview of the Level of Skill in the Art ................................. 18
`
`II.
`
`Grounds for Standing .................................................................................. 20
`
`-i-
`
`

`

`
`
`III. Mandatory Notices under 37 C.F.R. § 42.8 ................................................. 20
`
`IV. Statement of the Precise Relief Requested .................................................. 21
`
`V.
`
`Statement of Non-Redundancy ................................................................... 21
`
`VI. Claim Construction ..................................................................................... 22
`
`i.
`
`ii.
`
`“a subject in need” .................................................................. 22
`
`“A method for reducing or preventing or alleviating
`relapses,” “A method for treating,” “A method for
`slowing progression” .............................................................. 24
`
`VII. Background Knowledge in the Art Prior to June 27, 2006 .......................... 25
`
`A. Multiple Sclerosis ............................................................................. 25
`
`B.
`
`C.
`
`Disease Modifying Therapies............................................................ 27
`
`Fingolimod ....................................................................................... 28
`
`D.
`
`Loading Dose Regimens ................................................................... 30
`
`VIII. Detailed Explanation of Grounds for Unpatentability ................................. 32
`
`A.
`
`[Ground 1] Claims 1-6 are Obvious under 35 U.S.C. § 103 over
`Kovarik and Thomson. ...................................................................... 32
`
`i.
`
`ii.
`
`Claims 1, 3, and 5 ................................................................... 32
`
`Claims 2, 4, and 6 ................................................................... 47
`
`B.
`
`[Ground 2] Claims 1-6 are Obvious under 35 U.S.C. § 103 over
`Chiba, Kappos 2005, and Budde. ...................................................... 48
`
`i.
`
`Claims 2, 4, and 6 ................................................................... 56
`
`C.
`
`[Ground 3] Claims 1-6 are Anticipated under 35 U.S.C. § 102
`by Kappos 2010 (EX1038)................................................................ 57
`
`i.
`
`Claims 2, 4, and 6 ................................................................... 61
`
`-ii-
`
`

`

`
`
`
`IX. No Evidence of Unexpected Results or Secondary Considerations are
`Attributable to Novel Aspects of the Claims ............................................... 61
`
`X.
`
`Conclusion .................................................................................................. 63
`
`XI. Certificate of Compliance ........................................................................... 64
`
`XII. Payment of Fees under 37 C.F.R. §§ 42.15(a) and 42.103........................... 65
`
`XIII. Appendix – List of Exhibits ........................................................................ 66
`
`-iii-
`
`

`

`
`
`I.
`
`INTRODUCTION
`
`Pursuant to 35 U.S.C. § 311 and § 6 of the America Invents Act (“AIA”),
`
`and 37 C.F.R. Part 42, Apotex, Inc. and Apotex Corp., (“Petitioners”) request
`
`review of U.S. Patent No. 9,187,405 to Peter C. Hiestand et al. (“the ’405 patent,”
`
`EX1001) that issued on November 17, 2015, and is assigned to Novartis A.G.
`
`(“Patent Owner”).
`
`The ’405 patent claims a method of administering fingolimod hydrochloride
`
`(“FTY720”), a previously known immunosuppressant, for the treatment of a
`
`subject with Relapsing-Remitting Multiple Sclerosis (“RR-MS”). The claimed
`
`method recites “a daily dosage of 0.5 mg” that was known and reported to be safe
`
`and pharmacologically effective in humans more than one year before the earliest
`
`effective filing date of the ’405 patent. For example, International Publication No.
`
`WO 2006/058316 (“Kovarik,” EX1004), teaches treating multiple sclerosis by
`
`administering a 0.5 mg oral daily dose of fingolimod hydrochloride.
`
`The ’405 patent claims also employ a negative limitation regarding the
`
`absence of a loading dose regimen. Yet, Kovarik teaches that a maintenance dose
`
`is a therapeutically effective dose and teaches 0.5 mg fingolimod hydrochloride as
`
`a standard daily (maintenance) dose for treating MS. Indeed, the evidence shows
`
`that of the six FDA-approved treatments for RR-MS, none described the use of
`
`loading doses as part of an approved regimen.
`
`1
`
`

`

`
`
`
`The prior art also teaches 0.5 mg fingolimod hydrochloride was
`
`pharmacologically effective in inducing lymphopenia (the mechanism by which
`
`fingolimod hydrochloride was understood to treat MS). Moreover, the prior art
`
`teaches that fingolimod hydrochloride was effective in treating RR-MS by
`
`reducing, preventing or alleviating relapses and slowing the progression of the
`
`disease. In view of the prior art, it would have been obvious to administer a 0.5 mg
`
`daily dose of fingolimod hydrochloride absent an immediately preceding loading
`
`dose regimen to a patient with RR-MS.
`
`This petition also establishes that the negative limitation regarding the
`
`absence of a loading dose regimen was not supported by the ’405 patent
`
`specification, nor in any priority documents. Thus, claims 1-6 of the ’405 patent
`
`are anticipated by the 2010 disclosure of the results of a phase III clinical trial
`
`administering a 0.5 mg daily dose of fingolimod hydrochloride for the treatment of
`
`RR-MS.
`
`For the reasons discussed herein, this Petition demonstrates by a
`
`preponderance of the evidence that it is more likely than not that claims 1-6 of the
`
`’405 patent are unpatentable for failing to distinguish over prior art and should be
`
`found unpatentable and canceled.
`
`A. Brief Overview of the ’405 Patent
`
`The ’405 patent is entitled “S1P Receptor Modulators for Treating
`
`-2-
`
`

`

`
`
`
`Relapsing-Remitting Multiple Sclerosis.” In a general sense, the ’405 patent is
`
`directed to the use of sphingosine 1-phosphate (S1P) receptor agonists for the
`
`treatment of demyelinating diseases such as multiple sclerosis. See, e.g., EX1001,
`
`1:5-8; EX1002, ¶13. The specification describes a genus of sphingosine analogs
`
`(id. at 1:15-18), including 2-amino-2-[2-(4-octylphenyl)ethyl]propane-l,3-diol
`
`hydrochloride, also known as fingolimod hydrochloride or as FTY720. Id. at 8:18-
`
`30; EX1002, ¶¶8, 12, 16, 56.
`
`The ’405 patent asserts that S1P agonists “are known as having
`
`immunosuppressive properties or anti-angiogenic properties,” and that “multiple
`
`sclerosis (MS) is an immune-mediated disease of the central nervous systems[.]”
`
`EX1001, 8:56-67. No data on the efficacy of the claimed method to treat or slow
`
`the progression of RR-MS are presented in the ’405 patent. EX1002, ¶¶15-16. The
`
`patent also does not present data on the effect of the claimed method on relapse
`
`reduction, prevention, or alleviation in patients suffering from RR-MS. Id. Instead,
`
`prophetically-written experiments are described to permit an assessment of
`
`whether compounds such as fingolimod hydrochloride are able to “completely
`
`inhibit[] the relapse phases” using a rat model of relapsing multiple sclerosis.
`
`EX1001, 10:67; see also id. at 10:32-11:2. A clinical trial is also proposed to assess
`
`the claimed methods’ “clinical benefit” in RR-MS patients. EX1001, 11:6-38.
`
`EX1002, ¶16.
`
`-3-
`
`

`

`
`
`
`Claim 1 of the ’405 patent is representative of the independent claims at
`
`issue:
`
`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.
`
`EX1001, 12:49-55; EX1002, ¶9. Independent claims 3 and 5 are also directed to
`
`administering a daily oral 0.5 mg dose of fingolimod, in free form or as a salt, to a
`
`subject in need, absent an immediately preceding loading dose regimen. EX1001,
`
`12:59-13:6; EX1002, ¶¶10-11. Claim 3 specifies that the subject is in need of a
`
`method for treating RR-MS. EX1001, 12:59-13:6. Claim 5 specifies that the
`
`subject is in need of a method for slowing progression of RR-MS. Id. Claims 2, 4,
`
`and 6 depend, respectively, from claims 1, 3, and 5, and each specify that
`
`fingolimod is administered as fingolimod hydrochloride. Id. at 12:56-13:9;
`
`EX1002, ¶12.
`
`B.
`
`Brief Overview of the Prosecution History
`
`The patent application that matured into the ’405 patent, 14/257,342 (“the
`
`’342 application”), was filed on April 21, 2014, as a divisional application of
`
`13/149,468 (“the ’468 application”), which itself issued as U.S. Patent No.
`
`-4-
`
`

`

`
`
`
`8,741,963 (“the ’963 patent,” EX1013). EX1002, ¶¶17-19, 22. The ʼ468
`
`application was filed as a continuation of 12/303,765 (“the ’765 application,”
`
`EX1009), which was the U.S. entry of PCT/EP2007/005597 that was filed on June
`
`25, 2007. Id. PCT/EP2007/005597 claims priority to foreign application
`
`GB0612721.1 (EX1012), which was filed on June 27, 2006. EX1001 at cover.
`
`
`
`The claims of the ’342 application were initially rejected as obvious over
`
`Virley, Developing Therapeutics for the Treatment of Multiple Sclerosis,
`
`NEURORX, 2:638-649 (2005) (“Virely,” EX1016) and International Publication No.
`
`WO 2006/058316 (published June 1, 2006) (“Kovarik,” EX1004). EX1011 at
`
`0052-56; EX1002, ¶¶23-24. Patent Owner offered only attorney argument in
`
`response to the non-final rejection. EX1011 at 0033-34; EX1002, ¶25. A notice of
`
`allowance ensued. EX1011 at 0007; EX1002, ¶26.
`
`C. Brief Overview of the Grounds
`
`Ground 1 provides new evidence and argument regarding the obviousness of
`
`the challenged claims in view of Kovarik (EX1004) and Thomson (EX1005), with
`
`only the former reference having been discussed substantively during prosecution.
`
`For example, this petition is accompanied by the supporting declaration of Dr.
`
`Barbara S. Giesser, Professor of Clinical Neurology at UCLA with over 30 years
`
`of experience in the treatment of patients with, and research regarding, multiple
`
`sclerosis. EX1002, ¶¶1-4. Dr. Giesser states that, in her opinion, several of the
`
`-5-
`
`

`

`
`
`
`assertions made by the Applicants’ attorneys during prosecution to overcome the
`
`rejection are incorrect. EX1002, ¶27.
`
`For one, Dr. Giesser notes that the Applicants’ attorneys argued that the
`
`maintenance dose is “dependent on the immediately preceding loading dose,”
`
`thereby incorrectly implying that the maintenance dose disclosed for the treatment
`
`of MS in Kovarik would be inapplicable absent an immediately preceding loading
`
`dose. EX1011 at 0033; EX1002, ¶28. As explained by Dr. Giesser, however,
`
`therapeutic efficacy of a maintenance dose depends on the desired steady-state
`
`plasma concentration and the clearance rate of the drug, neither of which are
`
`dependent on a loading dose regimen. EX1002, ¶¶29-30, citing EX1021 at 91, 93
`
`(which teaches that a “maintenance dose…is equal to the product of
`
`clearance…and [the] desired steady state plasma concentration.…”). A loading
`
`dose regimen merely increases the speed at which this steady-state plasma
`
`concentration is achieved. Id.; EX1002, ¶¶19-20, 57. Thus, Applicants’ attorney
`
`argument that daily dosage depends on a given loading dose regimen is
`
`contradicted by the teachings of Kovarik and the expert testimony of Dr. Giesser.
`
`Applicants’ attorneys further argued that a skilled artisan “would attach no
`
`significance to the suitability of any daily dosage mentioned therein [Kovarik]
`
`outside the context of an immediately preceding loading dose regimen.” EX1011 at
`
`-6-
`
`

`

`
`
`
`0034; EX1002, ¶¶29-30. Dr. Giesser notes this unsupported assertion is
`
`contradicted by Kovarik itself, which teaches:
`
`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.
`
`EX1004 at 14 (emphasis added). Thus, Kovarik confirms that the 0.5 mg
`
`maintenance dose is effective for the treatment of multiple sclerosis regardless of
`
`whether it was immediately preceded by a loading dose regimen. EX1002, ¶¶29-
`
`30; see also EX1010 at 0109 (“standard daily dosage” is “the dosage necessary for
`
`a steady-state trough blood level of the drug providing effective treatment.”).
`
`The Applicants’ attorneys also argued that the “daily dosage administered
`
`after the initial period can vary substantially relative to the standard daily dosage.”
`
`EX1011 at 0033. However, as Dr. Giesser notes, Kovarik teaches administering
`
`fingolimod hydrochloride in the narrow range of 0.1 mg - 0.5 mg per day in the
`
`treatment of autoimmune diseases, including multiple sclerosis. EX1004 at 17;
`
`EX1002, ¶27. She also notes that Kovarik teaches a dosing regimen that involves
`
`maintenance therapy with a 0.5 mg daily dose. EX1004 at 15; EX1002, ¶76. Thus,
`
`-7-
`
`

`

`
`
`
`Kovarik not only teaches a narrow range of maintenance doses for MS treatment
`
`that encompasses the Applicants’ claimed daily dose, but also specifically
`
`describes the claimed 0.5 mg daily dosage as part of a preferred embodiment.
`
`EX1004 at 15 (“[T]reatment is continued with the maintenance therapy, e.g. a daily
`
`dosage of 0,5 mg.”).
`
`For the reasons discussed above, the Board should not defer to the Patent
`
`Owner’s unsupported attorney arguments during prosecution.
`
`Ground 2 presents new arguments and evidence regarding the obviousness
`
`of the challenged claims in view of Chiba (EX1006), Kappos 2005 (EX1007), and
`
`Budde (EX1008). Chiba was not of record during prosecution of the ’405 patent.
`
`Kappos 2005 and Budde were not substantively discussed during prosecution.
`
`Ground 3 presents new arguments and evidence regarding the
`
`unpatentability of the challenged claims in view of Kappos 2010 (EX1038), which
`
`was not of record during prosecution of the ’405 patent. Ground 3 presents an
`
`argument not previously considered by the Patent Office that the claims of the ’405
`
`patent are not entitled to the benefit of a filing date earlier than April 21, 2014.
`
`For the reasons discussed above, the Board should consider the evidence and
`
`arguments in this petition without substantial deference to the decision by the
`
`Office to allow the ’342 application.
`
`-8-
`
`

`

`
`
`
`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
`
`0612721.1, EX1012), which was filed June 27, 2006. For the purposes of pre-AIA
`
`35 U.S.C. § 102(b), the relevant date is that of first United States filing. See 35
`
`U.S.C. § 119(a) (pre-AIA) (“[B]ut no patent shall be granted on any application for
`
`patent for an invention which had been patented or described in a printed
`
`publication in any country more than one year before the date of the actual filing
`
`of the application in this country, or which had been in public use or on sale in
`
`this country more than one year prior to such filing.”); see also MPEP § 706.02
`
`(“In examining applications subject to pre-AIA 35 U.S.C. 102, the effective filing
`
`date is the filing date of the U.S. application… not the filing date of the foreign
`
`priority document.”). In this case, “the actual filing of the application in this
`
`country” is no earlier than June 25, 2007, the filing date of PCT/EP2007/005597.
`
`Therefore, at least publications that pre-date June 25, 2006, are prior art to the
`
`claims of the ’405 patent under 35 U.S.C. § 102(b).
`
`i.
`
`International Publication No. WO 2006/058316 (“Kovarik,”
`EX1004)
`
`Kovarik is a PCT application that published in English on June 1, 2006, and
`
`was filed as PCT/US2005/043044 by Novartis Pharma GmbH on November 28,
`
`2005. Kovarik claims priority to U.S. Provisional Application No. 60/631,483
`
`(filed November 29, 2004) (EX1015). EX1002, ¶74.
`
`-9-
`
`

`

`
`
`
`Kovarik discloses a genus of agonists for the S1P receptor that are “useful
`
`for the treatment of inflammatory and autoimmune diseases” due to their
`
`“immune-modulating potency.” EX1004 at 1; EX1002, ¶75. Kovarik teaches that
`
`“preferred” species are those “which in addition to their S1P binding properties
`
`also have accelerating lymphocyte homing properties, e.g. compounds which elicit
`
`a lymphopenia[.]” EX1004 at 2. Kovarik teaches “[a] particularly preferred S1P
`
`receptor agonist … is FTY720, i.e. 2-amino-2-[2-(4-octylphenyl)ethyl]propane-
`
`1,3-diol in free form or in a pharmaceutically acceptable salt form . . . e.g. the
`
`hydrochloride, as shown:
`
`.” Id. at 13; EX1002, ¶75.
`
`Kovarik teaches daily oral dosage regimens of fingolimod hydrochloride
`
`(FTY720) for the treatment of “autoimmune diseases, e.g. multiple sclerosis,” and
`
`for preventing organ rejection. EX1004 at 14, 18. Kovarik teaches “[a] method for
`
`treating an autoimmune disease in a subject in need thereof, comprising
`
`administering to the subject, after a loading regimen, a daily dosage of FTY720 of
`
`about 0.1 to 0.5mg.” Id. at 17; EX1002, ¶¶76-77. Kovarik further teaches that the
`
`standard daily (maintenance) dosage of 0.5 mg FTY720 may be administered for
`
`the treatment of multiple sclerosis and that the loading dose regimen allows for a
`
`-10-
`
`

`

`
`
`
`steady-state concentration of FTY720 to be achieved in less than one week.
`
`EX1004 at 14-15, 17; EX1002, ¶¶77-78, 105.
`
`Kovarik published on June 1, 2006, and is prior art to the claims of the ’405
`
`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
`
`treatment of multiple sclerosis. EX1005 at 157, EX1002, ¶81. Thomson teaches
`
`that FTY720 reduces inflammatory disease activity, thereby reducing relapse rates,
`
`increasing the time to first relapse, and increasing intervals between relapses:
`
`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
`
`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
`
`potential to be an effective disease-modifying agent for the treatment of RRMS.”
`
`EX1005 at 167; EX1002, ¶82.
`
`Thomson additionally provides data from clinical trials focused on the use of
`
`fingolimod hydrochloride in preventing organ rejection following transplantation.
`
`-11-
`
`

`

`
`
`
`EX1005 at 157; EX1002, ¶84. Thomson explains that “[p]harmacokinetic and
`
`pharmacodynamic outcomes . . . are not affected by disease status and may be
`
`extrapolated to include those patients with multiple sclerosis.” EX1005 at 162;
`
`EX1002, ¶84. Thomson additionally explains that induction of a reversible
`
`lymphopenia provides for “good evidence that FTY720 achieves
`
`immunomodulation” and thus “has the potential to be an effective disease
`
`modifying agent for the treatment of multiple sclerosis.” EX1005 at 157; see also
`
`EX1002, ¶¶58, 60-61, 64, 84, citing EX1022 at 309, EX1018 at 237-39, Park, et
`
`al., Pharmacokinetic/Pharmacodynamic Relationships of FTY720 in Kidney
`
`Transplant Patients, BRAZILIAN JOURNAL OF MEDICAL AND BIOLOGICAL
`
`RESEARCH, 38: 683-694 (2005) (“Park,” EX1019) at 684, EX1031 at 1081,
`
`EX1028 at 440. Thomson teaches that single oral doses in the range of 0.25 to 3.5
`
`mg are sufficient to induce lymphopenia and that there is “[n]o clear dose
`
`response” over this dose range. EX1005 at 163; EX1002, ¶85.
`
`Thomson published on March 31, 2006 (see also EX1040) and is prior art to
`
`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
`
`(“ALH”), “show superior immunosuppressive effects and are useful themselves, or
`
`in methods, for the prevention or treatment of . . . autoimmune diseases such as . . .
`
`-12-
`
`

`

`multiple sclerosis[.]” EX1006, 2:55-58; id. at 6:26-49; EX1002, ¶¶90-91. Chiba
`
`notes a preferred ALH-immunosuppressive compound called “FTY720, 2-amino-
`
`2[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride, shown below.
`
`
`
`
`.” EX1006, 4:64-5:7;
`
`EX1002, ¶90. Thus, Chiba teaches that FTY720, fingolimod hydrochloride,
`
`suppresses the immune response of mammals through accelerated lymphocyte
`
`homing and is useful for the treatment of MS. EX1006, 4:64-67; EX1002, ¶90.
`
`Chiba teaches oral administration of FTY720 in a 0.01-10 mg daily oral dose.
`
`EX1006, 6:26-31, 6:41-43, 8:19-34, 11:20-21; EX1002, ¶¶91-92.
`
`The Board has previously considered Chiba as part of IPR2014-00784 – an
`
`inter partes review of U.S. Patent No. 8,324,283 (“the ’283 patent,” EX1037). The
`
`’283 patent, assigned to Novartis AG and Mitsubishi Pharma Corporation, claims
`
`pharmaceutical compositions of fingolimod. The Board outlined the teachings of
`
`Chiba in the Final Written Decision finding the claims of the ’283 patent
`
`unpatentable:
`
` 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
`
`-13-
`
`

`

`
`
`
`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)
`
`at 10 (citations removed). On the record in that IPR, the panel stated, “Chiba itself
`
`suggested treating multiple sclerosis using a solid oral form of fingolimod.” Id. at
`
`25.
`
`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)
`
`Kappos 2005 teaches that FTY720, fingolimod hydrochloride, “reversibly
`
`sequesters tissue damaging T and B cells away from blood and the central nervous
`
`system to peripheral lymph nodes.” EX1007 at 41, abstract O141; EX1002, ¶94.
`
`Kappos 2005 teaches that “FTY720 has demonstrated both preventative and
`
`therapeutic efficacy” in several animal models of MS. EX1007 at 41, abstract
`
`O141; EX1002, ¶94.
`
`Kappos 2005 discloses the results of a Phase II randomized, double-blind,
`
`placebo-controlled study sponsored by Novartis Pharma AG Basel. Id.; EX1002,
`
`¶94. The trial evaluated the efficacy of daily oral doses of FTY720 for the
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`treatment of relapsing multiple sclerosis patients. EX1007 at 41, abstract O141;
`
`EX1002, ¶94. Kappos 2005 reports “demonstrated efficacy of FTY720 on MRI
`
`and relapse-related endpoints,” including the total number and volume of lesions as
`
`evaluated in monthly post baseline MRI scans. EX1007 at 41, abstract O141;
`
`EX1002, ¶95. Kappos 2005 also reported that FTY720 provided a higher
`
`“proportion of relapse-free patients,” as well as a lower “annualized relapse rate”
`
`and longer “time to first relapse” as compared to placebo. EX1007 at 41, abstract
`
`O141. Additionally, Kappos 2005 teaches that there were “no compelling dose-
`
`related difference in efficacy on MRI or clinical endpoints.” Id. Kappos 2005 states
`
`that these results “strongly suggest that FTY720 has the potential to be an
`
`efficacious disease modifying treatment for relapsing forms of MS with the
`
`additional benefit of once daily oral administration.” Id.; EX1002, ¶95.
`
`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
`
`
`1 Kappos 2005 is an abstract for an oral presentation presented between June
`
`18-22, 2005 in Vienna, Austria, and was published in the second 2005
`
`supplemental issue of the 252nd volume of the Journal of Neurology. Kappos 2005
`
`is also cited in Thomson. EX1005 at 167.
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`
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`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,
`
`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
`
`safety and lymphopenia-inducing efficacy of administering a dose of 0.5 mg
`
`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;
`
`EX1002, ¶98.
`
`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
`
`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).
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`
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`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
`
`whether or not to use a loading dose regimen. EX1002, ¶¶15, 144; EX1011 at
`
`0111-27; EX1012 (GB0612721.1); EX1009 (Appl. No. 12/303,765); EX1010
`
`(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
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`

`
`
`
`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,
`
`placebo-controlled study sponsored by Novartis Pharma. EX1038 at 387; EX1002,
`
`¶100. Daily oral doses of 0.5 mg FTY720, also known as fingolimod
`
`hydrochloride, were studied in RR-MS patients over a period of 24 months.
`
`EX1038 at 387; EX1002, ¶100. Kappos 2010 teaches that, as compared to
`
`placebo, daily oral doses of 0.5 mg FTY720 significantly reduced “[r]ates of
`
`relapse, progression of clinical disability, and MRI evidence of inflammatory
`
`lesion activity and tissue destruction[.]” EX1038 at 400; EX1002, ¶100.
`
`E.
`
`Brief Overview of the Level of Skill in the Art
`
`A person of ordinary skill in the art in the relevant field as of June 27, 2006
`
`or April 21, 2014 would typically include a person with a medical degree (M.D.)
`
`and several years of experience treating multiple sclerosis patients. EX1002, ¶¶39-
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`
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`40. Such a person would be familiar with administering therapeutic agents for the
`
`treatment of multiple sclerosis, including RR-MS, and dosing regimens of the
`
`various therapeutic agents available for treating RR-MS. Id. Further, such a person
`
`would be knowledgeable about the multiple sclerosis medical literature available at
`
`the relevant time. EX1002, ¶¶39-40.
`
`As discussed above, this Petition is supported by the expert testimony of
`
`Barbara Giesser, M.D., an expert in the field of RR-MS treatment with more than
`
`30 years of experience. EX1002, ¶¶1-4; EX1003 at 1. She has authored or co-
`
`authored numerous peer-reviewed journal articles, book chapters, abstracts and
`
`literature reviews. Id.; EX1003 at 8-14. She has been principal or co-investigator
`
`on gra