Trials@uspto.gov
`571-272-7822
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`Paper 11
`Entered: July 18, 2017
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
`APOTEX INC. and APOTEX CORP.,
`Petitioner,
`v.
`NOVARTIS AG,
`Patent Owner.
`_______________
`
`Case IPR2017-00854
`Patent US 9,187,405 B2
`_______________
`
`Before LORA M. GREEN, CHRISTOPHER M. KAISER, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge.
`
`
`DECISION
`Instituting Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
`
`571-272-7822
`
`
`
`
`
`Paper 11
`Entered: July 18, 2017
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
`APOTEX INC. and APOTEX CORP.,
`Petitioner,
`v.
`NOVARTIS AG,
`Patent Owner.
`_______________
`
`Case IPR2017-00854
`Patent US 9,187,405 B2
`_______________
`
`Before LORA M. GREEN, CHRISTOPHER M. KAISER, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge.
`
`
`DECISION
`Instituting Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
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`I.
`INTRODUCTION
`Apotex Inc. and Apotex Corp. (“Apotex” or “Petitioner”) filed a
`Petition requesting an inter partes review of claims 1–6 of U.S. Patent
`No. US 9,187,405 B2 (Ex. 1001, “the ’405 patent”). Paper 2 (“Pet.”).
`Novartis AG, (“Novartis” or “Patent Owner”) filed a Preliminary Response
`to the Petition. Paper 8 (“Prelim. Resp.”).
`Institution of an inter partes review is authorized by statute when “the
`information presented in the petition . . . and any response . . . shows that
`there is a reasonable likelihood that the petitioner would prevail with respect
`to at least 1 of the claims challenged in the petition.” 35 U.S.C. § 314; see
`37 C.F.R. §§ 42.4, 42.108. Upon considering the Petition, we determine that
`Petitioner has shown a reasonable likelihood that it would prevail in showing
`the unpatentability of at least one challenged claim. Accordingly, we
`institute an inter partes review of claims 1–6 of the ’405 patent.
`
`A.
`
`Related Proceedings
`According to Patent Owner, there are no other judicial or
`administrative matters that would affect, or be affected by, a decision in this
`proceeding. Paper 4, 2. Petitioner, however, notes that in IPR2014-00784,
`the Board issued a Final Written Decision relating to U.S. Patent No.
`8,324,283 B2, and that “[a]lthough not from the same patent family as the
`’405 patent, the ’283 patent included claims to pharmaceutical compositions
`of fingolimod, or a pharmaceutically acceptable salt thereof, that is suitable
`for oral administration, as well as claims directed to the treatment of
`multiple sclerosis using S1P receptor agonists.” Pet. 20.
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`B.
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`The ‘405 Patent and Relevant Background
`The ’405 Patent, entitled “S1P Receptor Modulators for Treating
`Relapsing-Remitting Multiple Sclerosis,” issued to Peter C. Hiestand and
`Christian Schnell from U.S. Application No. 14/257,342 (“the ’342
`application”), filed April 21, 2014. Ex. 1001, at [21], [60], [71], [72]. The
`’342 application is a divisional of Application No. 13/149,468 (“the ’468
`application”) (now U.S. Pat. No. 8,741,963). Id. at [60]. The ’468
`application, in turn, is a continuation of Application No. 12/303,765 (“the
`’765 application.”), which is the U.S. entry of PCT/EP2007/005597, filed
`June 25, 2007. Id.; Ex. 1009, 21, 40. PCT/EP2007/005597 claims priority
`to foreign application GB0612721.1 (Ex. 1012), filed on June 27, 2006.
`Ex. 1001, at [30]; see Ex. 1009, 57–58.
`The instant “invention relates to the use of an S1P1 receptor modulator
`in the treatment or prevention of neo-angiogenesis associated with a
`demyelinating disease, e.g. multiple sclerosis.” Ex. 1001, 1:5-8.
`“Characteristic pathological features of demyelinating diseases include
`inflammation, demyelination and axonal and oligodendrocyte loss. In
`addition[,] lesions can also have a significant vascular component. A firm
`link has recently been established between chronic inflammation and
`angiogenesis and neovascularization seems to have a significant role in the
`progression of disease.” Id. at 9:6–12. According to the inventors, “[i]t has
`now been found that S1P receptor modulators have an inhibitory effect on
`neo-angiogenesis associated with demyelinating diseases, e.g. [multiple
`sclerosis].” Id. at 9:13–15.
`
`
`1 S1P refers to sphingosine-1 phosphate, a natural serum lipid. Ex. 1001,
`1:13–14.
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`3
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`“Multiple sclerosis (MS) is an immune-mediated disease of the central
`nervous system with chronic inflammatory demyelination leading to
`progressive decline of motor and sensory functions and permanent
`disability.” Ex. 1001, 8:61–64. The inventors state that S1P receptor
`agonists or modulators may be useful in the treatment of MS, including the
`Relapsing-Remitting MS (RR-MS) form, which accounts for 85% of
`patients’ initial experience with the disease and is the precursor to the more
`debilitating Secondary-Progressive form (SPMS). Id. at 9:64–10:21; see
`also id. at 10:3–5 (noting that within 10 years of onset about half of RR-MS
`patients will develop SPMS); Ex. 1005,2 159–60, Fig. 1 (discussing the
`pathophysiology, classification, and clinical course of MS).
`“S1P receptor agonists or modulators are known as having
`immunosuppressive properties or anti-angiogenic properties in the treatment
`of tumors. . . .” Ex. 1001, 8:56–60. Preferred compounds stimulate
`lymphocyte homing, thereby “elicit[ing] a lymphopenia resulting from a re-
`distribution, preferably reversible, of lymphocytes from circulation to
`secondary lymphatic tissue, without evoking a generalized
`immunosuppression.” Id. at 2:17–23. “A particularly preferred S1P
`receptor agonist . . . is FTY720, i.e., 2-amino-2-[2-(4-octyphenyl)ethyl]
`propane-1,3-diol. . . .” Id. at 8:17–30. This compound, also known as
`fingolimod, is the active ingredient in Novartis’s Gilenya product
`(fingolimod hydrochloride) approved for the treatment of RR-MS. See id. at
`9:64– 10:16; Pet. 62; Prelim. Resp. 1.
`
`
`2 Thomson, “FTY720 in Multiple Sclerosis: The Emerging Evidence of
`its Therapeutic Value,” 1(3) CORE EVIDENCE 157-167 (2006). Ex. 1005.
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`C.
`
`Challenged Claims
`Illustrative claim 3 recites (paragraphing added):
`
`3. A method for treating 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.
`
`The remaining independent claims differ only in the language of the
`preamble, such that the “treating” language of claim 3 is replaced with
`“reducing or preventing or alleviating relapses” (claim 1) or “slowing
`progression” of RR-MS (claim 5).
`Depending from claims 1, 3, and 5, respectively, claims 2, 4, and 6
`specify that the 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol is the
`hydrochloride salt form—i.e., fingolimod hydrochloride.
`
`D.
`
`The Asserted Prior art and Grounds of Unpatentability
`Petitioner asserts the following grounds of unpatentability (Pet. 21):
`
`Ground Claims
`1
`1–6
`
`References
`Kovarik3 and Thomson
`
`Basis
`§ 103
`
`
`3 Kovarik and Appel-Dingemanse, WO 2006/058316, published June 1,
`2006. Ex. 1004.
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`5
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`Ground Claims
`2
`1–6
`3
`1–6
`
`
`References
`Chiba,4 Kappos 2005,5 and Budde6
`Kappos 20107
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`Basis
`§ 103
`§ 102
`
`Petitioner further relies on the testimony of Barbara S. Giesser, M.D.
`(Ex. 1002). Patent Owner relies on the testimony of Fred D. Lublin, M.D.
`(Ex. 2003) and William J. Jusko, Ph.D. (Ex. 2005).
`
`II.
`ANALYSIS
`To anticipate a claim under 35 U.S.C. § 102, “a single prior art
`reference must expressly or inherently disclose each claim limitation.”
`Finisar Corp. v. DirecTV Group, Inc., 523 F.3d 1323, 1334 (Fed. Cir. 2008).
`That “single reference must describe the claimed invention with sufficient
`precision and detail to establish that the subject matter existed in the
`prior art.” Verve, LLC v. Crane Cams, Inc., 311 F.3d 1116, 1120 (Fed. Cir.
`2002).
`A claim is unpatentable under 35 U.S.C. § 103(a) if the differences
`between the subject matter sought to be patented and the 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 that
`
`
`4 Chiba et al., US 6,004,565, issued Dec. 21, 1999. Ex. 1006.
`5 Kappos et al., “FTY720 in Relapsing MS: Results of a Double-Blind
`Placebo-Controlled Trial with a Novel Oral Immunomodulator,” 252 (Suppl
`2) J. NEUROLOGY Abstract O141 (2005). Ex. 1007.
`6 Budde, et al., “First Human Trial of FTY720, a Novel Immunomodulator,
`in Stable Renal Transplant Patients,” 13 J. AM. SOC. NEPHROLOGY 1073-
`1083 (2002). Ex. 1008.
`7 Kappos et al., “A Placebo-Controlled Trial of Oral Fingolimod
`in Relapsing Multiple Sclerosis,” 362(5) N. Engl. J. Med. 387–401.
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`subject matter pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
`(2007). In analyzing the obviousness of a combination of prior art elements,
`it can be important to identify a reason that would have prompted one of
`skill in the art to combine the elements in the way the claimed invention
`does. Id.
`A precise teaching directed to the specific subject matter of a
`challenged claim is not necessary to establish obviousness. Id. Rather, “any
`need or problem known in the field of endeavor at the time of invention and
`addressed by the patent can provide a reason for combining the elements in
`the manner claimed.” Id. at 420. Accordingly, a party that petitions the
`Board for a determination of unpatentability based on obviousness must
`show that “a skilled artisan would have been motivated to combine the
`teachings of the prior art references to achieve the claimed invention, and
`that the skilled artisan would have had a reasonable expectation of success in
`doing so.” Warsaw Orthopedic, Inc., 832 F.3d 1327, 1333 (Fed. Cir. 2016)
`(“As part of the obviousness inquiry, we consider ‘whether a [PHOSITA]
`would have been motivated to combine the prior art to achieve the claimed
`invention and whether there would have been a reasonable expectation of
`success in doing so.’” (quoting DyStar Textilfarben GmbH & Co.
`Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360 (Fed. Cir. 2006)).
`
`A.
`
`Person of Ordinary Skill in the Art.
`Petitioner contends that a person of ordinary skill in the art as of the
`date of the invention
`would typically include a person with a medical degree (M.D.)
`and several years of experience treating multiple sclerosis
`patients. . . . would be familiar with administering therapeutic
`agents for the treatment of multiple sclerosis, including RR-MS,
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`and dosing regimens of the various therapeutic agents available
`for treating RR-MS. . . . [and] would be knowledgeable about the
`multiple sclerosis medical literature available at the relevant
`time.
`Pet. 18–19 (citations to Ex. 1002 ¶¶ 39–40 omitted). This is consistent with
`the definition offered during prosecution that, “[t]he relative skill of those in
`the art is high, generally that of an M.D. or Ph.D. with expertise in the area
`of neurology.” Ex. 1009, 13. Further, in focusing on the MS disease state
`and the conduct of a prophetic clinical trial of fingolimod (“Compound A”)
`in treating RR-MS, the Specification suggests that one of ordinary skill in
`the art would possess a medical or related doctoral degree and have
`experience in the field of MS treatment and clinical research. See, e.g.,
`Ex. 1001, 8:61–9:12, 9:64–10:16, 11:4–12:13.
`In the Preliminary Response, however, Patent Owner contends that
`Apotex’s proposed definition “is plainly incorrect” because “a person of
`skill in other dosing patent cases almost always includes a pharmacologist,”
`the ’405 Patent and relevant references include pharmacologists as “essential
`contributing authors,” and “[p]harmacologists would have to interpret that
`data before reaching any conclusions about the obviousness of a 0.5 mg
`daily dose.” Prelim. Resp. 39–43.
`In the context of the ’405 patent and prior art, we agree with Patent
`Owner that expertise in pharmacology may be useful in determining
`obviousness, particularly in light of the prior art proffered in the
`Preliminarily Response. See id. at 41–43; see also Okajima v. Bourdeau,
`261 F.3d 1350, 1355 (Fed. Cir. 2001) (the level of ordinary skill in the art
`may be evident from the prior art). This is not to say that a person of
`ordinary skill in the art would lack an M.D. degree, other related doctoral
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`degree, or expertise in the treatment of multiple sclerosis. Accordingly, we
`do not consider this a binary choice. To the contrary, courts and tribunals
`have frequently identified the hypothetical person of ordinary skill as a
`composite or team of individuals with complementary backgrounds and
`skills. See, e.g., AstraZeneca Pharm. LP v. Anchen Pharm., Inc., No. 10-
`CV-1835 JAP TJB, 2012 WL 1065458, at *19, *22 (D.N.J. Mar. 29, 2012),
`aff'd, 498 F. App’x 999 (Fed. Cir. 2013) (collecting cases); Merial, Inc. v.
`Fidopharm Inc., IPR2016-01182, Paper 11 at 9 (PTAB Nov. 7, 2016).
`Indeed, Patent Owner relies on one such case in which “a person of skill
`would be a ‘multi-member drug development team’ including in the
`‘pertinent art[s]’ of ‘pharmaceutical science,’ ‘clinical medicine,’ and
`formulation pharmaceuticals.’” Prelim. Resp. 51 (citing Helsinn Healthcare
`S.A. v. Dr. Reddy’s Labs. Ltd., No. CV 11-3962 (MLC), 2016 WL 832089,
`at *72 (D.N.J. Mar. 3, 2016) (reversed on other grounds by Helsinn
`Healthcare S.A. v. Teva Pharm. USA, Inc., No. 2016-1284, 2017 WL
`1541518 (Fed. Cir. May 1, 2017)).
`On the record before us, we find that one of ordinary skill in the art
`may be part of a multi-disciplinary research team including 1) a Ph.D. with
`expertise in the area of neurology and/or an M.D. having several years of
`clinical experience treating multiple sclerosis patients, and who would be
`knowledgeable about the multiple sclerosis medical literature, and 2) a
`pharmacologist with experience in drug development.
`Patent Owner addresses the definition of one of ordinary skill in the
`art, at least in part, by asserting that Petitioner’s expert, Dr. Giesser, is “a
`physician without the necessary expertise to opine on what a person of skill
`would have inferred from the prior art as fingolimod’s dosing.” Prelim.
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`Resp. 36. Although Dr. Giesser appears to lack a formal degree in
`pharmacology, she does have extensive experience in the field of medicine,
`particularly with respect to MS treatment and clinical research. See
`generally Ex. 1002 ¶¶ 1–4; Ex. 1003. In light of Dr. Giesser’s background
`and experience in these areas, which would necessitate at least some
`familiarity with pharmacological principles, we decline to dismiss her
`opinions on the ’405 Patent and relevant literature. See SEB S.A. v.
`Montgomery Ward & Co., 594 F.3d 1360, 1373 (Fed. Cir. 2010), aff’d sub
`nom. Glob.-Tech Appliances, Inc. v. SEB S.A., 563 U.S. 754 (2011) (expert
`testimony admissible where testimony established an “adequate
`relationship” between witness’s experience and the claimed invention). In
`determining the evidentiary weight to be accorded to Dr. Giesser’s
`testimony, we are cognizant of the fact that she lacks a formal degree in
`pharmacology.
`
`B.
`
`Claim Construction
`In an inter partes review, claim terms in an unexpired patent are
`interpreted according to their broadest reasonable construction in light of the
`specification of the patent in which they appear. 37 C.F.R. § 42.100(b);
`Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2144–46 (2016)
`(upholding the use of the broadest reasonable interpretation standard).
`Under that standard, we presume that a claim term carries its “ordinary and
`customary meaning,” which “is the meaning the term would have to a person
`of ordinary skill in the art in question” at the time of the invention. In re
`Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007).
`The preambles of the independent claims recite methods for “reducing
`or preventing or alleviating relapses in” (claim 1), “treating” (claim 3), and
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`“slowing progression of” (claim 5) RR-MS “in a subject in need thereof.”
`This “subject in need thereof” is then reflected in the body of each claim as
`it recites the step of orally administering fingolimod “to said subject.”
`Petitioner argues that the preambles of the independent claims should
`be accorded no patentable weight as they “at most merely describe[] the
`intended purpose of the method and that the subject receiving fingolimod is
`a subject with RR-MS.” Pet. 24–25; Ex. 1002 ¶¶ 43–45. As we understand
`the argument, Petitioner proposes that “said subject” is any subject with
`RR-MS, as such persons inherently are, or will be, “in need of a treatment
`that reduces, prevents or alleviates relapses and slows the progression of
`RR-MS.” Id. at 22–23; Ex. 1002 ¶¶ 43–45. Petitioner’s argument, however,
`conflates the etiology and progression of multiple sclerosis with the plain
`language of the claims. Thus, for example, Petitioner may be correct that
`because patients accrue neurologic disability with each relapse episode “an
`RR-MS patient is in need of a treatment that reduces, prevents or alleviates
`relapses and slows the progression of RR-MS.” See Pet. 23. But Petitioner
`does not present evidence that “reduc[ing], prevent[ing] or alleviat[ing]
`relapses,” as set forth in claim 1, is necessarily the same as the arguably
`broader language, “treating,” recited in claim 3. See CAE Screen Plates, Inc.
`v. Heinrich Fiedler GMBH & Co. KG, 224 F.3d 1308, 1317 (Fed. Cir. 2000)
`(“In the absence of any evidence to the contrary, we must presume that the
`use of these different terms in the claims connotes different meanings.”).
`In contrast to Petitioner’s position, Patent Owner contends that the
`preambles of independent claims 1, 3, and 5, limit the scope the challenged
`claims. Prelim Resp. 29–35. Relying on the testimony of its expert,
`Dr. Lublin, Patent Owner presents evidence that “a person of skill would not
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`understand reducing relapses, treating the disease, and slowing its
`progression to mean the same thing.” Id. at. 32–33 (relying on Ex. 2003 ¶¶
`5–7, 43–55). As noted above, we do not ascertain where Petitioner or
`Petitioner’s expert, Dr. Giesser, argues that these terms are synonymous.
`Patent Owner also points out that failing to accord meaning to the
`differences in the preambles “would eliminate any differences among claims
`1–2, 3–4, and 5–6.” Id. at 30–31. On balance, we agree with Patent Owner
`that the presumption against claim redundancy weighs against Petitioner’s
`proposed construction.
`We also find persuasive Patent Owner’s argument that the words in
`the preambles inform the scope of “said subject” in the body of each claim.
`Prelim. Resp. 29–35. In particular, the preambles of claims 1, 3 and 5:
`provide[] an antecedent basis for terms used in the body of each
`claim, specifying the needs of the “subject” alluded to later. This
`is a classic example of the preamble defining a term—the
`“subject in need” of certain effects—which then is subsequently
`used in the body of the claim—“to said subject.”
`Id. at 34.
`
`In accord with the above, at least for the purpose of deciding whether
`to institute review, we find the preambles of claims 1, 3, and 5 limiting, and
`accord the ordinary and customary meaning to the claim language “reducing
`or preventing or alleviating relapses in,” “treating,” and “slowing
`progression of” RR-MS “in a subject in need thereof.” We further construe
`the terms “reducing or preventing or alleviating relapses” and “slowing
`progression” as subsumed within the genus of “treating” RR-MS. No other
`claim term requires express construction for purposes of this Decision.
`Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir.
`1999).
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`C. Ground I: Obviousness of Claims 1–6 Over Kovarik and Thomson
`1.
`35 U.S.C. § 325(d)
`Petitioner challenges claims 1–6 under 35 U.S.C. § 103 as obvious in
`view of Kovarik and Thomson. Pet. 21, 32–48. Patent Owner opposes on
`the merits and further requests that we reject this challenge under § 325(d).
`Prelim. Resp. 2–3, 21–36. With respect to the latter, Patent Owner argues
`that the Board should not “rehash” prosecution in this IPR because
`Applicants overcame a rejection based on Kovarik and Virley (a reference
`allegedly interchangeable with Thomson). See id. at 21–23.
`Anticipating the § 325(d) argument, Petitioner admits that Kovarik
`was substantively discussed during prosecution but argues that, “Ground 1
`provides new evidence and argument regarding the obviousness of the
`challenged claims,” including Dr. Giesser’s testimony that “several
`assertions made by Applicants’ attorneys during prosecution to overcome
`the rejection are incorrect.” Pet. 5–6; see Ex. 1002 ¶¶ 27–30. Dr. Giesser
`testifies, for example, that
`applicants state that the maintenance dose is “dependent on the
`immediately preceding loading dose.” EX1011 at 0034.
`However, this is incorrect. As discussed more fully below in
`Section VIII.E, maintenance doses are not dependent on loading
`dose regimens. Rather maintenance doses are dependent on the
`desired steady state plasma concentration and the clearance rate
`of the drug.
`Ex. 1002 ¶ 28 (citations omitted).
`Patent Owner attempts to provide context to those statements, stating,
`for example, that Applicant’s attorney, Dr. Holmes, “summarized Kovarik as
`teaching ‘that the daily dosage administered after the initial period can vary
`substantially relative to the standard daily dosage and is dependent on the
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`immediately preceding loading dose administered during the initial phase.’”
`See, e.g., Prelim Resp. 25–26 (quoting Ex. 1001 ¶ 33). Nevertheless, on the
`present record, we find Petitioner’s argument persuasive. Accordingly, we
`decline to exercise our discretion to deny institution under § 325(d).
`
`Overview of Kovarik
`2.
`Kovarik relates to an improved dosage regimen of S1P receptor
`modulators or agonists for the treatment of transplant patients suffering from
`autoimmune diseases or disorders, including multiple sclerosis. Ex. 1004, 1,
`14. Preferred S1P receptor modulators or agonists “elicit a lymphopenia
`resulting from a re-distribution, preferably reversible, of lymphocytes from
`circulation to secondary lymphatic tissue, without evoking a generalized
`immunosuppression.” Id. at 2. In a particularly preferred embodiment, the
`S1P receptor agonist is FTY720 (i.e., fingolimod). Id. at 13.
`Kovarik teaches that S1P receptor modulators or agonists are used in
`combination with cyclosporine A and everolimus in transplantation
`experiments and “[d]ue to their immune-modulating potency . . . are also
`useful for the treatment of inflammatory and autoimmune diseases.” Id. at 1.
`According to Kovarik, “[i]t has now surprisingly been found that a specific
`dosage regimen, e.g. a loading dose, will provide further unexpected
`benefits.” Id. In particular, an “S1P receptor modulator or agonist . . . is
`administered in such a way that during the initial 3 to 6 days . . . of treatment
`the dosage of said S1P receptor modulator or agonist is raised so that in total
`the R-fold (R being the accumulation factor) standard daily dosage of said
`S1P receptor modulator or agonist is administered and thereafter the
`treatment is continued with the standard or a lower daily dosage. . . .” Id. at
`13–14. “[T]he standard daily dosage (also called maintenance dose) refers
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`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.” Id. at 14.
`In one embodiment of the invention, a loading dose of, e.g., 0.5 mg,
`1 mg, 1.5 mg, or 2 mg fingolimod per day is administered “during the initial
`period of four days. Thereafter the treatment is continued with the
`maintenance therapy, e.g. a daily dosage of 0[.]5 mg.” Id. at 15.
`
`Overview of Thomson
`3.
`Thomson teaches that “[fingolimod] elicits lymphocyte sequestration
`by facilitating a reversible redistribution of lymphocytes from the circulation
`to secondary lymphoid tissues. This is a unique immunomodulation
`mechanism whereby T lymphocytes are effectively directed away from
`inflammatory sites toward the lymphatic system.” Ex. 1005, 162; see also
`id. at Abstract (“There is good evidence that FTY720 achieves
`immunomodulation as shown by a reversible redistribution of peripheral
`blood lymphocytes after oral administration.”). According to Thomson:
`FTY720 has shown promising results in preclinical models of
`EAE, which in part has led to its clinical evaluation in multiple
`sclerosis. There is moderate evidence from two meeting
`abstracts of a phase II study that FTY720 (administered orally
`once daily 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.
`Id. at 166–167.
`In reviewing the emerging clinical evidence for fingolimod as a
`treatment for multiple sclerosis, Thomson reports that “[t]wo meeting
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`abstracts have been published showing results obtained with FTY720 in a
`12-month phase II clinical trial in patients with active relapsing multiple
`sclerosis.” Ex. 1005, Abstract. These publications disclosed the benefits of
`fingolimod as compared to placebo at doses of 1.25 and 5 mg per day.8 See
`id. at 164–65, Table 4.
`Thomson also reviews a number of shorter-term clinical trials relating
`to pharmacodynamic and pharmacokinetic outcomes of fingolimod
`administration. Id. at 162–164, Table 3. In one multi-dose study, Thomson
`notes that “[p]eripheral blood lymphocyte counts decreased from baseline to
`nadir (range 3–7 d after first dose) by 80 and 88% in subjects receiving
`FTY720 1.25 and 5 mg, respectively.” Id. at Table 3.
`With respect to another study involving single doses of 0.25, 0.5,
`0.75, 1, 2, or 3.5 milligrams of FTY720, Thomson states that “All FTY720
`groups showed a temporal pattern of relative lymphocyte sequestration, seen
`at the latest 6 h postdose. No clear dose response, but the highest doses
`showed a more pronounced reduction in lymphocyte numbers.” Id.
`(referencing, in part, Budde 2002 (Ex. 1008)); see also id. at 163 (“Although
`the higher doses of FTY720 produced a more rapid and sustained
`lymphocyte sequestration, the actual degree of this property was similar
`across the range of doses used in the study and no clear dose–response
`relationship was detected.”).
`With respect to yet another study involving renal transplant patients
`co-administered cyclosporine and 0.25, 0.5, 1, or 2.5 mg doses of fingolimod
`for twelve weeks, Thomson reports that “lymphocyte sequestration was seen
`
`
`8 We note that one of the referenced studies is Kappos 2005 (Ex. 1007).
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`as early as w 1, nadir was reached at w 4 and was fully reversed 4-8 w after
`cessation of treatment. The pharmacodynamics were not dose-linear over
`the 10-fold dose range.” Id. at Table 3; see id. at 164.
`
`Analysis of Ground I
`4.
`In arguing that the challenged claims would have been obvious over
`Kovarik and Thomson, Petitioner states that “Kovarik discloses that the oral
`administration of a 0.5 mg daily dose of FTY720 provides effective
`treatment of multiple sclerosis. . . .” Pet. 36; see Ex. 1002 ¶¶ 119, 126.
`According to Petitioner:
`A person of skill in that art would have read Kovarik’s teachings
`as readily applicable to a patient with the RR-MS form of the
`disease because RR-MS is by far the most common form of the
`disease at onset and accounts for approximately 85% of cases.
`Also, a skilled artisan would have known that inflammation is
`the driver of relapses
`in RR-MS and
`that fingolimod
`hydrochloride was taught to treat MS by reducing inflammation
`through the accelerated lymphocyte homing mechanism taught
`by Kovarik.
`Pet. 41–42 (internal citations omitted). Petitioner further argues that,
`“Thomson provides additional motivation to administer 0.5 mg FTY720 to a
`patient with RR-MS . . . [by] present[ing] an array of evidence supporting
`the efficacy of FTY720 in treating RR-MS by reducing relapse rates and
`slowing progression of RR-MS associated with inflammation.” Pet. 42
`(citing Ex. 1002, ¶ 109). According to Petitioner,
`[t]he skilled artisan would have had a reasonable expectation that
`the daily oral dose of 0.5 mg FTY720 taught by Kovarik would
`be therapeutically effective for patients suffering from RR-MS
`because Thomson describes clinical trials of FTY720 that tested
`doses in the range of 0.25 mg to 3.5 mg, in which it was found
`that “the actual degree of this property [lymphopenia] was
`similar across the range of doses used.”
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`Pet. 43 (citing Ex. 1005, 162–63; Ex. 1002 ¶¶ 112–13).
`In response, Patent Owner contends that Kovarik “indisputably
`mandates a loading dose, without exception,” and therefore teaches away
`from a method that excludes a loading dose as required by the challenged
`claims. See Prelim. Resp. 23–28. However, as noted above, Kovarik
`teaches one embodiment in which 0.5 mg of fingolimod, nominally
`administered as a “loading dose” for four days, is followed by “maintenance
`therapy” at the same daily dose. Ex. 1004, 15. Further, based on the
`evidence of record, we accept the testimony of Petitioner’s expert that “a
`person of ordinary skill would recognize that the loading dose regimen
`taught by Kovarik is not necessary to obtain therapeutic efficacy,” but is
`merely a means to achieve rapid, steady-state drug concentrations, which
`may be beneficial in organ transplantation, but was not standard practice in
`the treatment of MS. See Ex. 1002 ¶¶ 67, 72, 119, 121–22. We further note
`that Kovarik teaches that, whereas, a standard daily dose (i.e., “maintenance
`dose”) provides a steady-state trough blood level of the drug or its active
`metabolites for “effective treatment,” the addition of a loading dose provides
`“further unexpected benefits.” See Ex. 1004, 1, 14 (italics added). Kovarik,
`thus, teaches the addition of a loading dose as an improvement to fingolimod
`dosage regimes known in the art. It, therefore, stands to reason that one of
`ordinary skill in the art would understand that a standard daily dose (e.g., the
`0.5 mg daily dose recited at page 15 of Kovarik) will provide therapeutic
`benefits absent a loading dose. See Ex. 1002 ¶ 120.
`Patent Owner further argues that Ground I should fail because
`Kovarik and Thomson do not provide “any reason to believe that 0.5 mg
`daily doses of fingolimod would actually be of use to a subject in need of
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`“reducing or preventing or alleviating relapses in” RR-MS (claims 1 and 2);
`“treating” RR-MS (claims 3 and 4); or “slowing progression” of RR-MS
`(claims 5 and 6).” Prelim. Resp. 29; see id. at 35–36.
`As an initial matter, in section II(B), above, we construe “reducing or
`preventing or alleviating relapses” and “slowing progression” as subsumed
`within the genus of “treating” RRMS. See Ex. 1002 ¶ 47 (testifying that the
`goals of treating RRMS “include (1) the reduction of, alleviation of, or relief
`from the relapses that characterize RR-MS; and (2) providing some delay,
`even if short, in disease progression”). Patent Owner provides no reasonable
`explanation or evidence as to why one of ordinary skill in the art would have
`believed that “treating” RRMS with fingolimod would not be expected to
`reduce, prevent, or alleviate relapses, or slow the progression of the disease.
`Second, as discussed in sections II(C
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