Trials@uspto.gov
`571-272-7822
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` Paper 112
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`Entered: September 24, 2015
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`TORRENT PHARMACEUTICALS LIMITED
`and
`APOTEX, INC. AND MYLAN PHARMACEUTICALS INC.,
`Petitioners,
`
`v.
`
`NOVARTIS AG AND MITSUBISHI PHARMA CORP.,
`Patent Owners.
`____________
`
`Case IPR2014-00784
`Case IPR2015-00518
`Patent 8,324,283 B2
`_______________
`
`
`
`Before LORA M. GREEN, CHRISTOPHER M. KAISER, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`KAISER, Administrative Patent Judge.
`
`
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
`
`
`
`
`
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`
`INTRODUCTION
`Torrent Pharmaceuticals Limited (“Torrent”) filed a Petition to
`institute an inter partes review of claims 1–32 of U.S. Patent No. 8,324,283
`B2 (“the ’283 patent,” Ex. 1001). Paper 2 (“Pet.”).1 On December 1, 2014,
`the Board instituted trial to review patentability of the challenged claims.
`Paper 11 (“Dec. on Inst.”). Apotex, Inc. and Mylan Pharmaceuticals Inc.
`(“Apotex,” or, together with Torrent, “Petitioners”) filed a separate Petition
`also seeking to institute an inter partes review of claims 1–32 of the ’283
`patent. IPR2015-00518, Paper 1 (“IPR-518 Pet.”). This second Petition was
`accompanied by a motion seeking joinder with the trial that had been
`instituted in IPR2014-00784. IPR2015-00518, Paper 2 (“IPR-518 Joinder
`Mot.”). On February 17, 2015, the Board instituted trial in IPR2015-00518
`and joined the proceedings in IPR2014-00784 and IPR2015-00518.
`IPR2015-00518, Paper 8 (“IPR-518 Dec.”).
`Thereafter, Novartis AG and Mitsubishi Pharma Corp. (“Patent
`Owners”) filed a Response (Paper 28 (“PO Resp.”)), and Petitioners filed a
`Reply (Paper 55).2 Patent Owners also filed a motion to amend the
`challenged claims by replacing them with proposed amended claims 33–64
`(Paper 26 (“Mot. to Amend”)), Petitioners filed an opposition to this motion
`(Paper 52 (“Mot. to Amend Opp.”)), and Patent Owners filed a reply (Paper
`
`
`1 This decision refers to papers and exhibits filed in both the joined
`proceedings (IPR2014-00784 and IPR2015-00518). Except where noted
`otherwise, citations are to the papers and exhibits filed in IPR2014-00784.
`2 Redacted versions of the Response and Reply were filed as Paper 30 and
`Paper 54, respectively.
`
`
`
`2
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`62 (“Mot. to Amend Reply”)).3 Both Petitioners and Patent Owners
`requested oral argument, and an oral hearing was held July 31, 2015. A
`transcript of the oral argument is included in the record.4 Paper 111 (“Tr.”).5
`Each side filed a motion to exclude certain evidence submitted by the other
`side. Paper 73; Paper 78. The parties filed oppositions to these motions to
`exclude, Paper 80; Paper 83, as well as replies to the oppositions, Paper 91,
`Paper 94. In addition, there are multiple pending motions to seal various
`pleadings and exhibits.
`We have jurisdiction under 35 U.S.C. § 6(c), and we issue this Final
`Written Decision pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73. We
`conclude Petitioners have established by a preponderance of the evidence
`that claims 1–32 of the ’283 patent are unpatentable. We also conclude that
`Patent Owners have failed to establish by a preponderance of the evidence
`that proposed amended claims 33–64 are patentable. In addition, we deny in
`
`3 Redacted versions of the Motion to Amend, the Opposition to the Motion
`to Amend, and the Reply to the Opposition to the Motion to Amend were
`filed as Paper 27, Paper 53, and Paper 63, respectively.
`4 The parties are directed to file a redacted version of the transcript that will
`be publicly available. The redacted version of the transcript shall be filed no
`later than one week after the entry of the present decision.
`5 Patent Owner filed objections to the demonstrative exhibits used by
`Petitioners at the hearing. Paper 105. In reaching our decision on the
`merits, we have considered arguments and evidence that are presented in the
`demonstrative exhibits only where those arguments and evidence were
`presented previously and are supported by the record. We expunge all the
`demonstrative exhibits themselves from the record, because they constitute
`neither evidence nor, to the extent that they differ from the written briefing,
`argument allowable under our rules.
`
`
`
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`part and dismiss in part each side’s motion to exclude evidence, we seal
`certain pleadings and exhibits, and we unseal several exhibits that we
`substantively rely on in reaching our decision.
`
`
`The ’283 Patent
`The ’283 patent relates to a solid pharmaceutical composition suitable
`for oral administration, wherein the composition comprises a sphingosine-1
`phosphate (S1P) receptor agonist and a sugar alcohol. Ex. 1001, 1:11–14,
`1:33–35. “The sugar alcohol may act as a diluent, carrier, filler or bulking
`agent, and may suitably be mannitol.” Id. at 9:53–54. The ’283 patent
`indicates that solid compositions comprising a sugar alcohol are
`“particularly well suited to the oral administration of S1P receptor agonists,”
`“provide a convenient means of systemic administration of S1P receptor
`agonists, do not suffer from the disadvantages of liquid formulations for
`injection or oral use, and have good physicochemical and storage
`properties.” Id. at 1:36–42. According to the ’283 patent, a “particularly
`preferred S1P receptor agonist . . . is FTY720, i.e. 2-amino-[2-(4-
`octylphenyl)ethyl]propane-1,3-diol.” Id. at 8:23–25. FTY720 is also known
`as fingolimod. Ex. 2007 ¶ 13; Tr. 31:13–15. The ’283 patent further
`describes that solid compositions comprising a sugar alcohol “may show a
`high level of uniformity in the distribution of the S1P receptor agonist
`through the composition, as well as high stability” and “may be
`manufactured on high speed automated equipment.” Ex. 1001, 1:42–48.
`S1P receptor agonists are immunomodulating compounds, and solid
`pharmaceutical compositions comprising S1P receptors may be useful for
`
`
`
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`treating and preventing organ/tissue transplant rejection, autoimmune
`disease/inflammatory conditions, or viral myocarditis and viral diseases
`caused by viral mycocarditis. Id. at 1:18–22, 12:19–37.
`Claims 1 and 19 of the ’283 patent are independent claims and are
`illustrative of the claimed subject matter. They are reproduced below.
`1. A solid pharmaceutical composition suitable for oral
`administration, comprising:
`(a) a SIP receptor agonist which is selected from 2-amino-
`2-[4-(3-benzyloxyphenoxy)-2-chlorophenyl]propyl-1,3-
`propane-diol or 2-amino-2-[4-(3-benzyloxyphenylthio)-
`2-chlorophenyl]propyl-1,3-propane-diol, 2-amino-2-[4-
`(3-benzyloxyphenylthio)-2-chlorophenyl]-2-ethyl-1,3-
`propane-diol, and its phosphates or a pharmaceutically
`acceptable salt thereof; and
`(b) a sugar alcohol.
`
`19. A solid pharmaceutical composition suitable for oral
`administration, comprising mannitol and 2-amino-2-[2-(4-
`octylphenyl)ethyl]propane-1,3-diol or a pharmaceutically
`acceptable salt thereof.
`
`Id. at 17:2–11, 18:7–10.
`
`
`Reviewed Ground of Unpatentability
`The Board instituted trial to review the patentability of the challenged
`claims on the following ground:
`Claim(s)
`Challenged
`1–32
`
`References
`Chiba6 and Aulton7
`
`Basis
`§ 103
`
`
`6 Chiba et al., US 6,004,565, issued Dec. 21, 1999 (“Chiba,” Ex. 1006).
`5
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`
`ANALYSIS
`Claim Construction
`In an inter partes review, the Board interprets a claim term in an
`unexpired patent according to its broadest reasonable construction in light of
`the specification of the patent in which it appears. 37 C.F.R. § 42.100(b);
`see In re Cuozzo Speed Techs., LLC, 793 F.3d 1268, 1276–79 (Fed. Cir.
`2015). Under that standard, absent any special definitions, we assign claim
`terms their ordinary and customary meaning, as understood by a person of
`ordinary skill in the art, in the context of the entire patent disclosure. In re
`Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007). Only terms
`which are in controversy need to be construed, and then only to the extent
`necessary to resolve the controversy. Vivid Techs., Inc. v. Am. Sci. & Eng’g,
`Inc., 200 F.3d 795, 803 (Fed. Cir. 1999). For this reason, we do not construe
`several terms for which constructions were proposed in the Petition but
`about which the parties do not disagree.
`
`Solid Pharmaceutical Composition Suitable for Oral Administration
`In our decision instituting trial, we construed “solid pharmaceutical
`composition suitable for oral administration” as “solid composition capable
`of delivering a pharmaceutical effect when administered orally.” Dec. on
`Inst. 5. In the post-institution briefing, neither party challenged this
`construction, and we have not identified any reason to change it.
`
`
`7 PHARMACEUTICS: THE SCIENCE OF DOSAGE FORM DESIGN, 223–321
`(Michael E. Aulton ed., 1988) (“Aulton,” Ex. 1021).
`6
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`Accordingly, we maintain our previous construction of “solid
`pharmaceutical composition suitable for oral administration” as “solid
`composition capable of delivering a pharmaceutical effect when
`administered orally.”
`
`
`Is Stable
`Patent Owners propose constructions for three terms used in the
`proposed amended claims. First, they argue that “is stable,” with respect to
`a pharmaceutical composition, means “meets stability requirements of a test
`required by FDA for approval.” Mot. to Amend Reply 26–27. Petitioners
`disagree with this proposed construction but do not offer an alternative
`construction, arguing instead merely that the ’283 patent itself would not
`lead a person of ordinary skill in the art to any understanding of the meaning
`of “is stable” at all. Mot. to Amend Opp. 19–21. We are not persuaded by
`this argument. Claim terms are to be construed in the context of the entire
`patent disclosure, but they are also to be construed from the perspective of
`the understanding of a person of ordinary skill in the art. Here, there is
`evidence that a person of ordinary skill in the art would understand the
`requirement for stability “in the context of requirements for FDA approval.”
`Ex. 2042 ¶¶ 73–75.8 We have not been directed to any contrary evidence.
`Accordingly, we construe “is stable” to mean “meets stability requirements
`of a test required by FDA for approval.”
`
`
`
`8 A public version is available at Ex. 2263 ¶¶ 73–75.
`7
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`
`Has Substantially Uniform Distribution . . . Throughout the Composition
`Patent Owners propose that a pharmaceutical composition that “has
`substantially uniform distribution . . . throughout the composition” is one
`that “meets content uniformity requirements for active ingredients in solid
`oral unit dosage forms as defined by the [United States Pharmacopeia].”
`Mot. to Amend 27–28. Petitioners argue that this is incorrect, pointing out
`first that the content uniformity requirements in the United States
`Pharmacopeia are designed to ensure a consistent dose of an active
`ingredient from one oral dosage unit (e.g., a tablet or capsule) to the next,
`and noting next that “uniform distribution . . . throughout the composition”
`would instead be interpreted by a person of ordinary skill in the art to refer
`to a uniform distribution of the active ingredient throughout a single oral
`dose unit. Mot. to Amend Opp. 17–19. Petitioners are correct that the
`United States Pharmacopeia is directed at ensuring a minimum of variation
`from one oral dosage unit to the next. Ex. 2072, 3–5.9 But there is evidence
`of record that “[a] person skilled in formulation in 2003 would have also
`used [the United States Pharmacopeia] analysis to infer that the drug was
`homogeneously distributed within each tablet,” Ex. 2280 ¶ 49,10 and this
`evidence is unrebutted. Accordingly, we construe a pharmaceutical
`composition that “has substantially uniform distribution . . . throughout the
`composition” as one that “meets content uniformity requirements for active
`
`9 Unless stated otherwise, our citations are the page numbers of the exhibit
`itself rather than to the page numbers of the original document from which
`the exhibit is extracted.
`10 A public version is available at Ex. 2285 ¶ 49.
`8
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`ingredients in solid oral unit dosage forms as defined by the [United States
`Pharmacopeia].”
`
`
`Rough Particle Surface
`Patent Owners argue that “rough particle surface” means “with higher
`surface area than a sphere.” Mot. to Amend 28. Petitioners dispute this
`construction but do not provide an alternative, arguing instead only that a
`person of ordinary skill in the art would be unable to determine the meaning
`of this term at all. Mot. to Amend Opp. 21–22. Patent Owners’ evidence
`shows that “rough particle surface,” with respect to sugar alcohol particles,
`includes sugar alcohol particles “having a higher surface area than a routine
`sugar alcohol particle obtained from a spray-dry method.” Mot. to Amend
`28 (citing Ex. 1001, 9:60–10:1; Ex. 2042 ¶¶ 76–81). But “rough particle
`surface” should not be limited to this narrow embodiment. See Phillips v.
`AWH Corp., 415 F.3d 1303, 1323 (Fed. Cir. 2005) (en banc) (“[A]lthough
`the specification often describes very specific embodiments of the invention,
`we have repeatedly warned against confining the claims to those
`embodiments.”). That said, to construe “rough particle surface” to mean
`merely “with higher surface area than a sphere,” as Patent Owners suggest,
`would be to interpret the term as essentially unbounded. Any particle, even
`a perfect sphere, could be said to have a surface area higher than that of an
`unspecified sphere, which could be arbitrarily small. In order to avoid this
`problem, we construe a particle with a “rough particle surface” to be a
`particle “with higher surface area than a sphere of a diameter equal to the
`average diameter of the particle in question.”
`
`
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`
`
`
`Prior Art Disclosures
`Chiba
`Chiba teaches immunosuppressive compounds with fingolimod as the
`preferred species. Ex. 1006, 4:64–5:5. 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. Id. at
`6:26–49. Chiba teaches oral administration of fingolimod, including
`“admix[ing] with [a] carrier, excipient, diluent, and so on and formulat[ion]
`into . . . capsules [or] tablets . . . for administering to patients.” Id. at 8:19–
`26. In discussing the preparation of these capsules and tablets for oral
`administration of fingolimod, Chiba teaches that
`[o]ne skilled in the art is familiar with numerous methods and
`tests for determining the effectiveness of a selected route of
`administration.
`
`Furthermore,
`pharmaceutically
`or
`physiologically acceptable carriers or excipients for use with
`the . . . compounds noted herein are known in the art or can be
`readily found by methods and tests known in the art.
`Id. at 11:22–28.
`
`
`Aulton
`Aulton teaches the use of tablets and capsules to administer drugs
`orally. Ex. 1021, 5. It also teaches that “[t]he successful formulation of a
`stable and effective solid dosage form depends on the careful selection of
`excipients which are added to facilitate administration, promote the
`consistent release and bioavailability of the drug and protect it from
`10
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`degradation.” Id. at 30–31. Aulton recommends a short list of “[p]rimary
`excipients . . . for initial screening for table[t] and capsule formulations,” id.
`at 31, Table 13.16, although no sugar alcohol appears on the list. Despite
`this, Aulton lists mannitol as a common diluent used in “[t]ableting by the
`wet granulation process,” which Aulton describes as “the most widely used
`method for pharmaceutical materials.” Id. at 39–41, Table 18.1; see also id.
`at 38 (identifying mannitol among the “[m]aterials currently available as
`direct compression diluents”). Aulton teaches that mannitol is “expensive,”
`but still “commonly used.” Id. at 41. In addition to these teachings
`regarding mannitol, Aulton teaches that magnesium stearate “is the most
`popular lubricant used” in tableting. Id. at 42.
`
`
`Obviousness of Challenged Claims over Chiba and Aulton
`Petitioners argue that claims 1–32 would have been obvious over
`Chiba and Aulton. Pet. 20–43. Petitioners rely on the Declaration of John
`S. Kent, Ph.D., to support the Petition. Ex. 1004. Patent Owners dispute the
`unpatentability of claims 1–32, supported by the Declarations of Supriya
`Rane, M.S. (Ex. 2007); Madhusudhan Pudipeddi, Ph.D. (Ex. 2041); Stephen
`Byrn, Ph.D. (Ex. 2042); Tomoyuki Oomura, M.S. (Ex. 2043); Fred D.
`Lublin, M.D. (Ex. 2044); and David Blackburn, Ph.D. (Ex. 2045). In
`addition, Petitioners’ Reply relies on the Reply Declaration of John S. Kent,
`Ph.D. (Ex. 1031) and the Declaration of Joel W. Hay, Ph.D. (Ex. 1041).
`After reviewing the complete record, we conclude Petitioners have
`shown that Chiba and Aulton teach or suggest each limitation of claims 1–32
`
`
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`of the ’283 patent, that a person of ordinary skill in the art11 would have had
`a reason to combine the teachings of Chiba and Aulton, and that a person of
`ordinary skill in the art would have had a reasonable expectation of success
`in combining the teachings of Chiba and Aulton. Even when considering the
`record evidence of objective indicia of nonobviousness, we conclude that
`Petitioners have shown, by a preponderance of the evidence, that each of the
`challenged claims would have been obvious over the combination of Chiba
`and Aulton.
`
`
`Claim 19
`Independent claim 19 recites “[a] solid pharmaceutical composition
`suitable for oral administration, comprising mannitol and [fingolimod] or a
`pharmaceutically acceptable salt thereof.” Ex. 1001, 18:7–10.
`There is no dispute that Chiba and Aulton together teach all the
`limitations of claim 19. Chiba teaches the claimed “solid pharmaceutical
`composition suitable for oral administration, comprising” fingolimod, and
`Aulton teaches the claimed mannitol excipient. Ex. 1006, 3:25–43, 4:64–
`5:5, 8:19–28, 11:20–34; Ex. 1021, 40–41; Ex. 1004 ¶¶ 93–94, 170. The
`remaining questions regarding whether claim 19 would have been obvious
`over the combination of Chiba and Aulton are whether a person of ordinary
`
`
`11 The parties do not dispute the level of skill in the art. We also note that
`“[a] specific finding on the level of skill in the art is not . . . required where
`the prior art itself reflects an appropriate level and a need for testimony is
`not shown.” Litton Indus. Prods., Inc. v. Solid State Sys. Corp., 755 F.2d
`158, 163–64 (Fed. Cir. 1985).
`
`
`
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`skill in the art would have had a reason to combine the teachings of the
`references and whether that person would have had a reasonable expectation
`of success in doing so. In addition, Patent Owners argue that several
`objective indicia show that claim 19 would not have been obvious.
`
`
`1. Reason to Combine Chiba’s Fingolimod Teaching and
`Aulton’s Mannitol Teaching
`
`In arguing against the unpatentability of claim 19, Patent Owners
`argue first that the inventors of the ’283 patent discovered the reason to
`combine mannitol and fingolimod and that Petitioners have failed to prove
`adequately that a person of ordinary skill in the art at the time of the
`invention would have had any reason to combine them. PO Resp. 34–48.
`As an initial matter, we agree with Patent Owners that Petitioners bear
`the burden of persuasion with respect to a reason for the person of ordinary
`skill in the art to combine the teachings of Chiba and Aulton. Petitioners
`“bear the burden of proving a proposition of unpatentability by a
`preponderance of the evidence,” 35 U.S.C. § 316(e), and, to the extent that
`Petitioners seek to prove the unpatentability of claim 19 by establishing that
`it would have been obvious over the combined teachings of Chiba and
`Aulton, they must establish as part of their “proposition of unpatentability”
`that a person of ordinary skill in the art would have had a reason to combine
`those teachings.
`We disagree, however, with Patent Owners’ argument that the
`inventors’ mere discovery of a new reason to combine fingolimod and
`mannitol renders nonobvious an invention that was known in the prior art.
`
`
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`Where the prior art teaches the claimed invention, a claim is not rendered
`patentable by virtue of being motivated in the inventors’ minds by a newly-
`discovered advantage of the prior-art combination; allowing such a claim to
`stand “would remove from the public that which is in the public domain.” In
`re Wiseman, 596 F.2d 1019, 1022 (CCPA 1979); see also Cross Med.
`Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323 (Fed.
`Cir. 2005) (“One of ordinary skill in the art need not see the identical
`problem addressed in a prior art reference to be motivated to apply its
`teachings.”). Here, Patent Owners argue that the newly discovered low-dose
`instability of fingolimod when mixed with common excipients motivated the
`inventors’ choice of the allegedly less common mannitol as an excipient.
`PO Resp. 12–15 (citing Ex. 2043 ¶¶ 14–19, 22, 24–36). As explained
`above, though, it does not matter that the prior art failed to recognize this
`advantage of a fingolimod-mannitol combination. “[T]he motivation in the
`prior art to combine the references does not have to be identical to that of the
`[patentee] to establish obviousness.” In re Kemps, 97 F.3d 1427, 1430 (Fed.
`Cir. 1996).
`We are not persuaded otherwise by Leo Pharmaceutical Products,
`Ltd. v. Rea, discussed by Patent Owners at pages 35–36 of the Response. In
`that case, although the inventors argued that they discovered a stability
`problem with a combination of ingredients known in the prior art, in fact
`there was evidence that the prior art taught away from combining those
`ingredients. Leo Pharm. Prods., Ltd. v. Rea, 726 F.3d 1346, 1353–54 (Fed.
`Cir. 2013). Patent Owners have not alleged, and the record does not support,
`that the prior art here taught away from combining mannitol and fingolimod.
`
`
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`
`Thus, the fact that the inventors of the ’283 patent may have
`discovered a new advantage of a combination of prior-art ingredients is not
`sufficient to render the claims of the ’283 patent patentable, as long as there
`was some reason to combine the prior-art teachings that those ingredients
`should be used. Patent Owners argue that Petitioners have failed to prove
`such a reason to combine, PO Resp. 41–49, but the record establishes
`otherwise. First, Chiba teaches that a person of ordinary skill in the art
`would have been able to identify or easily determine excipients that would
`have been compatible with fingolimod. Ex. 1006, 11:24–28
`(“pharmaceutically or physiologically acceptable carriers or excipients for
`use with the . . . compounds noted herein are known in the art or can be
`readily found by methods and tests known in the art”). Second, Aulton
`teaches that mannitol is not only a known diluent for direct compression
`manufacturing, but also commonly used in wet granulation, which Aulton
`teaches is “the most widely used method for pharmaceutical materials.”12
`Ex. 1021, 39–41, Table 18.1. This combination of teachings already
`strongly suggests that mannitol likely would have been a target of
`investigation for a person of ordinary skill in the art interested in finding an
`excipient compatible with fingolimod, but there is additional evidence of the
`reason to combine fingolimod and mannitol.
`
`
`12 There is additional evidence that wet granulation is “[o]ne of the most
`common steps in the manufacture of capsules and tablets.” Ex. 1031 ¶ 43.
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`
`One prior-art reference, Sakai,13 directly instructs that the two
`ingredients should be combined. Ex. 1005, 10:31–48. Patent Owners argue
`that Sakai’s teaching of the combination of fingolimod and mannitol is
`irrelevant because Sakai is limited to liquid-phase pharmaceutical
`compositions, as opposed to the claimed solid oral dosage forms. PO Resp.
`41 (citing Ex. 2042 ¶ 3014 (“The excipients used in liquid formulations are
`not relevant for solid formulations.”)). But Patent Owners’ own declarant
`(as the author of Ex. 2042), Dr. Stephen Byrn, wrote an article stating
`otherwise: “Most, but not all, drug degradations in the solid state take place
`via chemical mechanisms that are identical to those that occur in solution.
`Hence, a mechanistic understanding gained from solution studies can be
`very helpful.” Ex. 1030, 5. Although Patent Owners note that Exhibit 1030
`goes on to discuss specific exceptions to this rule, Tr. 42:13–16, we have not
`been directed to any evidence of record that suggests that any of those
`exceptions applies here. The fact is that, according to Patent Owners’ own
`declarant, a suggestion to combine ingredients in the liquid phase would
`have been relevant to the determination of a person of ordinary skill in the
`art to combine the same ingredients in the solid phase.15
`
`
`13 Sakai et al., US 6,277,888 B1, issued Aug. 21, 2001 (“Sakai,” Ex. 1005).
`14 A public version is available at Ex. 2263 ¶ 30.
`15 Our conclusion in our institution decision that Sakai’s teaching of a
`combination of mannitol and fingolimod in the liquid phase was not
`sufficient on its own to “teach that mannitol is a conventional excipient for
`use in solid pharmaceutical compositions,” Dec. on Inst. 12, does not require
`us to ignore the record evidence that Sakai’s teaching would have been
`relevant to the decision of which excipient to use in formulating a solid oral
`16
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`In addition to the direct teaching in Sakai that mannitol and
`fingolimod should be combined, several documents that would have been
`known to a person of ordinary skill in the art teach that mannitol provides
`advantages when used as a diluent in tableting. Remington’s Pharmaceutical
`Sciences, described as “[a] textbook and reference work for pharmacists,
`physicians and other practitioners of the pharmaceutical and medical
`sciences,” lists mannitol as one of nine diluents used “to make tableting
`possible.” Ex. 2050, 5, 86. It also states that mannitol is one of nine
`“common diluents” that are useful as “[d]irect-compression vehicles or
`carriers” because they “have good flow and compressible characteristics.”
`Id. at 96. The Theory and Practice of Industrial Pharmacy, described as “a
`comprehensive reference source on modern industrial pharmacy” that is
`“useful to practitioners in the pharmaceutical and allied health sciences . . .
`and others seeking information concerning the design, manufacture, and
`control of pharmaceutical dosage forms,” lists mannitol as one of fourteen
`diluents in a table of “[c]ommon [t]ablet [e]xcipients.” Ex. 2049, 3, 39. The
`Handbook of Pharmaceutical Excipients describes mannitol as “widely
`used . . . as a diluent . . . in tablet formulations, where it is of particular value
`since it is not hygroscopic.” Ex. 1014, 5. In addition, “[g]ranulations
`containing mannitol have the advantage of being dried easily,” and
`“[m]annitol does not undergo Maillard reactions.” Id. at 5, 8. These known
`
`
`dosage form of fingolimod. Furthermore, “the knowledge of [a person of
`ordinary skill in the art] is part of the store of public knowledge that must be
`consulted when considering whether a claimed invention would have been
`obvious.” Randall Mfg. v. Rea, 733 F.3d 1355, 1362 (Fed. Cir. 2013).
`17
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`advantages of mannitol as a tableting excipient16 provide a strong reason to
`combine Chiba’s teaching of a solid oral dosage form of fingolimod and
`Aulton’s teaching of mannitol as an excipient for making solid oral dosage
`forms. Dystar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick,
`Co., 464 F.3d 1356, 1368 (Fed. Cir. 2006) (“[A]n implicit motivation to
`combine exists . . . when . . . the combination of references results in a
`product or process that is more desirable. . . . [T]here exists in these
`situations a motivation to combine prior art references even absent any hint
`of suggestion in the references themselves.”).
`Given (1) the knowledge in the art that mannitol provided advantages
`in formulating tablets generally, (2) Chiba’s teaching that a person of
`ordinary skill in the art would have been able to identify or easily determine
`excipients that would have been compatible with fingolimod, (3) Aulton’s
`teaching that mannitol was a diluent commonly used in the most common
`form of pharmaceutical manufacture, (4) Sakai’s teaching that mannitol and
`fingolimod should be combined in the liquid phase, and (5) Dr. Byrn’s
`
`
`16 Mannitol has other advantages, such as a sweet taste and a negative heat
`of solution, that are more relevant to chewable tablets than to other solid oral
`dosage forms. Ex. 1021, 41. Although the claims of the ’283 patent are not
`limited to non-chewable tablets, there is evidence of record that suggests that
`fingolimod would be unlikely to be administered in a chewable tablet,
`making these advantages less relevant to the reason-to-combine analysis.
`Ex. 2263 ¶ 53; Ex. 2043 ¶ 38. Still, the evidence of record does not support
`Patent Owners’ contention that mannitol was used only in chewable tablets.
`See Ex. 1031 ¶ 27 (citing Ex. 1032; Ex. 1033; Ex. 1034; Ex. 1042; Ex. 1043;
`Ex. 1044; Ex. 1045; Ex. 1046; Ex. 1047) (listing non-chewable tablets and
`capsules containing mannitol that were marketed before 2003).
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`statement that liquid-phase compatibility was relevant to the prediction of
`solid-phase compatibility, we conclude that Petitioners have shown a reason
`to combine the teachings of Chiba and Aulton.17 It is irrelevant that
`Petitioners have failed to establish that the inventors’ actual subjective
`reason for combining mannitol and fingolimod was known in the prior art.
`
`
`2. Reasonable Expectation of Success in Combining
`Fingolimod and Mannitol
`
`Patent Owners argue next that Petitioners have failed to establish that
`Chiba and Aulton provided a reasonable expectation of success in
`combining mannitol and fingolimod. PO Resp. 49–51. According to Patent
`Owners, because Chiba does not discuss mannitol specifically, and because
`Aulton does not discuss fingolimod specifically, the combination of Chiba
`and Aulton would not “have provided a reasonable expectation that
`fingolimod and mannitol would be stable.” Id. at 50. Thus, argue Patent
`Owners, a person