`
`
`
`
`
`
`
`
` Paper No. 13
`
`
` Entered: May 4, 2017
`
`Trials@uspto.gov
`571-272-7822
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`ALKERMES PHARMA IRELAND LTD.
`and ALKERMES, INC.,
`Petitioners,
`
`v.
`
`OTSUKA PHARMACEUTICAL CO., LTD.,
`Patent Owner.
`____________
`
`Case IPR2017-00287
`Patent 9,125,939 B2
`____________
`
`
`
`Before JACQUELINE WRIGHT BONILLA, Vice Chief Administrative
`Patent Judge, SUSAN L. C. MITCHELL and JACQUELINE T. HARLOW,
`Administrative Patent Judges.
`
`HARLOW, Administrative Patent Judge.
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`IPR2017-00287
`Patent 9,125,939 B2
`
`
`
`I.
`INTRODUCTION
`Petitioners, Alkermes Pharma Ireland Ltd. and Alkermes, Inc.
`(collectively, “Alkermes”), filed a Petition requesting an inter partes review
`of claims 2, 6, 7, and 9 of U.S. Patent No. 9,125,939 B2 (Ex. 1001, “the
`’939 patent”). Paper 1 (“Pet.”). Patent Owner, Otsuka Pharmaceutical Co.,
`Ltd. (“Otsuka”), filed a Preliminary Response. Paper 10 (“Prelim. Resp.”).
`We have authority to determine whether to institute an inter partes review
`under 35 U.S.C. § 314, which provides that an inter partes review may not
`be instituted unless the information presented in the petition “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.”
`For the reasons set forth below, we deny the Petition.
`
`A. Related Matters
`
`The parties have not identified any related proceedings in which the
`’939 patent is currently asserted. Pet. 4–5; Paper 9, 1–2.
`
`B. The ’939 Patent
`
`The ’939 patent is titled “Carbostyril derivatives and mood stabilizers
`for treating mood disorders.” Ex. 1001 [54]. The ’939 patent issued from
`U.S. Patent Application No. 10/556,600, filed on May 19, 2004. Id. [21],
`[22]. The ’939 patent claims priority to U.S. Provisional Patent Application
`No. 60/473,378, filed on May 23, 2003. Id. [60].
`The ’939 patent describes compositions and methods for the treatment
`of mood disorders, including bipolar disorder. Id. at 1:15–23. In particular,
`2
`
`
`
`IPR2017-00287
`Patent 9,125,939 B2
`
`
`the ’939 patent teaches the use of the carbostyril derivative aripiprazole, “an
`antipsychotic drug having [a] new mechanism of action which is different
`from that of other atypical antipsychotic drugs” (id. at 8:33–35), in
`combination with a mood stabilizer, such as lithium, to treat bipolar disorder
`in patients partially nonresponsive to mood stabilizer monotherapy. Id. at
`26:53–27:56.
`The ’939 patent explains that rather than acting as a dopamine-D2
`receptor antagonist like other antipsychotic medications—including other
`atypical antipsychotics—aripiprazole is a partial agonist of dopamine-D2 and
`serotonin 5-HT1A receptors, and an antagonist of serotonin 5-HT2A receptors.
`Id. at 8:35–44. The ’939 patent accordingly identifies aripiprazole as “a
`drug belonging to [a] new category defined as a dopamine-serotonin system
`stabilizer (dopamine-serotonin nervous system stabilizer[)].” Id. at 8:44–49.
`
`C. Illustrative Claim
`
`Claim 2, the sole independent claim challenged in the Petition, is
`reproduced below.
`A method of treating bipolar disorder in a patient
`2.
`partially nonresponsive to lithium or valproic acid, divalproex
`sodium or a salt thereof monotherapy comprising:
`administering separately a first amount of aripiprazole,
`and a second amount of lithium, wherein the amount of lithium
`is about 0.01 to 500 parts by weight and the amount of
`aripiprazole is about 1 part by weight,
`wherein the bipolar disorder is chosen from bipolar
`disorder I, polar [sic] disorder II, bipolar disorder with or without
`
`3
`
`
`
`IPR2017-00287
`Patent 9,125,939 B2
`
`
`
`psychotic features, mania, acute mania, bipolar depression, and
`mixed episodes.
`Ex. 1001, 29:15–30:4.
`
`D. Prior Art Relied Upon
`
`Alkermes relies upon the following prior art references (Pet. 14–22):
`American Psychiatric Association, Practice guideline for the treatment of
`patients with bipolar disorder (Revision), 159 AM. J. PSYCHIATRY 1–50
`(2002) (“APA Guidelines”) (Ex. 1009).
`
`Citrome et al., Pharmacokinetics and safety of aripiprazole and concomitant
`mood stabilizers, Abstracts of the 2002 Annual Meeting of the American
`Psychiatric Association, NR317 (2002) (“Citrome”) (Ex. 1008).
`
`Keck et al., Aripiprazole versus placebo in acute mania, Abstracts of the
`2002 Annual Meeting of the American Psychiatric Association, NR314
`(2002) (“Keck”) (Ex. 1007).
`
`Sachs et al., The Expert Consensus Guideline Series Medication Treatment
`of Bipolar Disorder 2000, POSTGRAD MED. SPECIAL REPORT (2000) (“Expert
`Consensus”) (Ex. 1026).
`
`Tohen et al., Efficacy of olanzapine in combination with valproate or lithium
`in the treatment of mania in patients partially nonresponsive to valproate or
`lithium monotherapy, 59 ARCH. GEN. PSYCHIATRY 62-69 (2002) (“Tohen”)
`(Ex. 1006).
`
`Data demonstrate aripiprazole significantly improved symptoms of acute
`mania in patients with bipolar disorder; new data presented today at
`American Psychiatric Association Annual Meeting, PR Newswire (2002)
`(“Otsuka Press Release”) (Ex. 1028).
`
`4
`
`
`
`IPR2017-00287
`Patent 9,125,939 B2
`
`
`
`E. Asserted Grounds of Unpatentability
`
`Alkermes asserts the following grounds of unpatentability (Pet. 23–
`
`24):
`
`Claims
`
`2, 6, 7, 9
`2, 6, 7, 9
`2, 6, 7, 9
`
`2, 6, 7, 9
`2, 6, 7, 9
`2, 6, 7, 9
`
`References
`Basis
`§ 103(a) APA Guidelines and Keck or Otsuka Press
`Release
`§ 103(a) Tohen and Keck or Otsuka Press Release
`§ 103(a) Expert Consensus and Keck or Otsuka Press
`Release
`§ 103(a) APA Guidelines, Tohen, and Keck or Otsuka
`Press Release
`§ 103(a) Citrome and APA Guidelines
`§ 103(a) Citrome, Tohen, and/or Keck or Otsuka Press
`Release
`
`II. ANALYSIS
`
`A. Claim Construction
`
`In an inter partes review, claim terms in an unexpired patent are given
`their broadest reasonable interpretation in light of the specification of the
`patent in which they appear. 37 C.F.R. § 42.100(b). Under the broadest
`reasonable interpretation standard, claim terms are given their ordinary and
`customary meaning as would be understood by one of ordinary skill in the
`art in the context of the entire disclosure. In re Translogic Tech., Inc.,
`504 F.3d 1249, 1257 (Fed. Cir. 2007). Only those terms that are in
`controversy need be construed, and 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).
`
`5
`
`
`
`IPR2017-00287
`Patent 9,125,939 B2
`
`
`
`The parties propose constructions for several claim terms. Pet. 9–11;
`Prelim. Resp. 28. For purposes of this Decision, we find it necessary to
`address only whether the following claim 2 preamble limits claim scope:
`“[a] method of treating bipolar disorder in a patient partially nonresponsive
`to lithium or valproic acid, divalproex sodium or a salt thereof monotherapy
`comprising”.
`
`1. “A method of treating bipolar disorder in a patient partially
`nonresponsive to lithium or valproic acid, divalproex
`sodium or a salt thereof monotherapy comprising”
`The preamble of claim 2 recites “[a] method of treating bipolar disorder
`in a patient partially nonresponsive to lithium or valproic acid, divalproex
`sodium or a salt thereof monotherapy comprising[.] . . .” Ex. 1001, 29:15–
`17. Otsuka contends that this preamble limits claim scope. Prelim.
`Resp. 28. Alkermes tacitly admits that the preamble is limiting. See, e.g.,
`Pet. 25–26 (“a person of ordinary skill in the art wanting to treat a patient
`with bipolar disorder who is partially nonresponsive to lithium/divalproex
`monotherapy therapy would have looked to use a combination therapy”);
`Ex. 1002 ¶ 49 (“the patient being treated with the claimed method of use is
`at least partially nonresponsive to lithium, valproic acid, or divalproex
`sodium or a salt thereof monotherapy.”). Indeed, Alkermes affirmatively
`asserts that the preamble language “a patient partially nonresponsive to
`lithium or valproic acid, divalproex sodium or a salt thereof monotherapy”
`should be construed to mean “a patient that has shown an inadequate
`response to lithium, valproic acid, or divalproex sodium or salt thereof, as a
`
`6
`
`
`
`IPR2017-00287
`Patent 9,125,939 B2
`
`
`monotherapy.” Pet. 10; Ex. 1002 ¶ 59.
`We agree with Otsuka that the preamble of claim 2 is limiting.
`“Whether a preamble stating the purpose and context of the invention
`constitutes a limitation of the claimed process is determined on the facts of
`each case in light of the overall form of the claim, and the invention as
`described in the specification and illuminated in the prosecution history.”
`Applied Materials, Inc. v. Advanced Semiconductor Materials Am., Inc.,
`98 F.3d 1563, 1572–1573 (Fed. Cir. 1996). The preamble recitation that the
`claimed method is directed towards treating a particular patient population,
`namely, patients partially nonresponsive to certain mood stabilizer
`monotherapies “is necessary to give life, meaning, and vitality to the claim.”
`Catalina Mktg. Int’l, Inc. v. Coolsavings.com, Inc., 289 F.3d 801, 808 (Fed.
`Cir. 2002) (internal quotation omitted). In addition, the claim 2 preamble
`provides antecedent basis for the claim phrase “wherein the bipolar disorder
`is chosen from. . .” (Ex. 1001, 30:1). See Bell Communications Research,
`Inc. v. Vitalink Communications Corp., 55 F.3d 615, 620 (Fed. Cir. 1995)
`(“[W]hen the claim drafter chooses to use both the preamble and the body to
`define the subject matter of the claimed invention, the invention so defined,
`and not some other, is the one the patent protects.”).
`Moreover, during prosecution, Patent Owner added and relied upon
`the preamble language specifying that the method claimed is directed
`towards treatment of the patient population “partially nonresponsive to
`lithium or valproic acid, divalproex sodium or a salt thereof monotherapy”
`(Ex. 1076, 1052–1055) to distinguish the claimed invention from the prior
`
`7
`
`
`
`IPR2017-00287
`Patent 9,125,939 B2
`
`
`art (id. at 1062–1064). That action by Patent Owner during prosecution
`reasonably “transforms the preamble into a claim limitation because such
`reliance indicates use of the preamble to define, in part, the claimed
`invention.” Catalina Mktg. Int’l, 289 F.3d at 808. Consistently, the
`description in the specification of the ’939 patent of treating patients
`partially nonresponsive to mood stabilizer monotherapy with a combination
`of aripiprazole and lithium or valproate (Ex. 1001, 26:51–27:56) lends
`further support to the conclusion that the preamble of claim 2 is limiting.
`See Corning Glass Works v. Sumitomo Electric U.S.A., Inc., 868 F.2d 1251,
`1257 (Fed. Cir. 1989) (limiting claim scope to “optical waveguides” rather
`than all optical fibers in light of specification).
`Accordingly, on the record before us, and for purposes of this decision,
`we determine that the claim 2 preamble, “[a] method of treating bipolar
`disorder in a patient partially nonresponsive to lithium or valproic acid,
`divalproex sodium or a salt thereof monotherapy comprising[,]” limits the
`scope of that claim, as well as the scope of claims 6, 7, and 9, which each
`depend from claim 2. We additionally determine that, for purposes of this
`decision, the claim 2 preamble does not require express construction, and
`should be given its plain and ordinary meaning.
`
`B. Principles of Law
`
`A patent claim is unpatentable under 35 U.S.C. § 103(a) if the
`differences between the claimed subject matter and the prior art are such that
`the subject matter, as a whole, would have been obvious at the time the
`
`8
`
`
`
`IPR2017-00287
`Patent 9,125,939 B2
`
`
`invention was made to a person having ordinary skill in the art to which said
`subject matter pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
`(2007). The question of obviousness is resolved on the basis of underlying
`factual determinations including: (1) the scope and content of the prior art;
`(2) any differences between the claimed subject matter and the prior art;
`(3) the level of ordinary skill in the art; and (4) objective evidence of
`nonobviousness. Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966).
`We are mindful that the level of ordinary skill in the art is reflected by
`the prior art of record.1 See Okajima v. Bourdeau, 261 F.3d 1350, 1355
`(Fed. Cir. 2001); In re GPAC Inc., 57 F.3d 1573, 1579 (Fed. Cir. 1995); In
`re Oelrich, 579 F.2d 86, 91 (CCPA 1978).
`We analyze the asserted grounds of unpatentability in accordance with
`the above-stated principles.
`
`
`1 Alkermes states that an ordinarily skilled artisan at the time of the
`invention would have been an “M.D. psychiatrist with significant experience
`in treating patients with psychiatric disorders, including familiarity and
`personal experience in treating bipolar disorder and mania.” Pet. 11 (citing
`Ex. 1002 ¶ 57). Otsuka does not offer an explicit definition for a relevant
`skilled artisan. See generally Prelim. Resp. We apply Alkermes’ stated
`level of ordinary skill in the art, which is supported by Dr. Frances’
`testimony, because of the type of problems encountered in the art, the
`sophistication of the technology, and the educational level of those who
`work in this area. See In re GPAC, 57 F.3d 1573, 1579 (Fed. Cir. 1995).
`9
`
`
`
`IPR2017-00287
`Patent 9,125,939 B2
`
`
`
`C. Obviousness Ground of Unpatentability
`Based on APA Guidelines and Keck or Otsuka Press Release
`
`Alkermes asserts that claim 2, and its dependent claims 6, 7, and 9,
`are unpatentable under 35 U.S.C. § 103(a) as obvious in view of the APA
`Guidelines and Keck or the Otsuka Press Release. Pet. 24–30, 41–49.
`Alkermes relies upon the Declaration of Allen Frances, M.D. (“Frances
`Declaration”) (Ex. 1002) and the Declaration of Jessie Au, Pharm. D., Ph.D.
`(“Au Declaration”) (Ex. 1004) to support its positions.
`Otsuka responds that Alkermes has not established that either Keck or
`the Otsuka Press Release qualifies as a publicly accessible printed
`publication, and these references, therefore, are not available as prior art.
`Prelim. Resp. 3–16. Otsuka additionally asserts that an ordinarily skilled
`artisan would not have had reason to combine, or a reasonable expectation of
`success in combining, the cited references to arrive at the claimed invention.
`Id. at 16–33. Otsuka also contends that the Petition should be denied under
`35 U.S.C. § 325(d) (id. at 33–59), and that the asserted ground of
`unpatentability over the APA Guidelines and Keck or Otsuka Press Release
`is both horizontally and vertically redundant of other grounds set forth in the
`Petition (id. at 59–62).
`
`1. Overview of APA Guidelines
`The APA Guidelines disclose that, for the treatment of acute mania,
`“[t]he combination of an antipsychotic with either lithium or valproate may
`be more effective than any of these agents alone.” Ex. 1009, 15. The APA
`Guidelines note, however, that “caution should be exercised when
`10
`
`
`
`IPR2017-00287
`Patent 9,125,939 B2
`
`
`combining medications, since side effects may be additive and metabolism
`of other agents may be affected.” Id.
`With regard to the use of combination therapy in treating patients
`exhibiting an “incomplete response to monotherapy,” the APA Guidelines
`describe studies relating exclusively to the efficacy of two atypical
`antipsychotics—olanzapine and risperidone—in cotherapy with mood
`stabilizers. Id. at 31. The APA Guidelines do not discuss aripiprazole.
`
`2. Overview of Keck
`Keck describes a study comparing “the efficacy and safety of
`aripiprazole, the first next-generation atypical antipsychotic with a unique
`mechanism of action (dopamine-serotonin system stabilizer) to placebo in
`patients with acute bipolar mania.” Ex. 1007, 2. Keck reports that treatment
`for three weeks with 30 mg of aripiprazole (reduced to 15 mg if poorly
`tolerated) produced statistically significant improvement in Young Mania
`Rating Scale (“Y-MRS”) scores versus placebo. Id. Keck additionally
`reports that “[d]iscontinuations due to adverse events did not differ between
`the aripiprazole and placebo groups, and there were no significant changes
`in weight versus placebo.” Id. Keck states that “[a]ripiprazole was effective
`and well tolerated in the treatment of acute mania in patients with bipolar
`disorder.” Id.
`
`3. Overview of Otsuka Press Release
`The Otsuka Press Release describes the study performed by Keck, and
`provides further information concerning aripiprazole. Ex. 1028, 1. For
`
`11
`
`
`
`IPR2017-00287
`Patent 9,125,939 B2
`
`
`example, in addition to reporting that “40 percent of patients treated with
`aripiprazole responded to treatment, compared to 19 percent of patients
`treated with placebo” (id.) as reported by Keck (Ex. 1007, 2), the Otsuka
`Press Release notes that in a second placebo-controlled study, “aripiprazole
`did not show statistical separation from placebo.” Ex. 1028, 1.
`The Otsuka Press Release explains that “[a]ripiprazole is believed to
`have a mechanism of action that is fundamentally different from available
`antipsychotics. Aripiprazole exhibits potent partial agonism of D2
`dopamine receptors, and is also associated with partial agonism of 5HT(1A)
`serotonin receptors and antagonism of 5HT(2A) serotonin receptors.” Id.
`at 2.
`
`4. Discussion
`Even assuming that Keck and the Otsuka Press Release qualify as
`printed publications, we nevertheless conclude that Alkermes has not
`demonstrated a reasonable likelihood that it would prevail in establishing
`that the combination of the APA Guidelines with Keck or the Otsuka Press
`Release would have rendered the subject matter of the challenged claims
`obvious. Specifically, as discussed in more detail below, Alkermes has not
`shown adequately that an ordinarily skilled artisan would have had a
`reasonable expectation of success in combining the cited references to arrive
`at the claimed invention.2
`
`
`2 Because we determine that Alkermes has not established a reasonable
`likelihood of prevailing on its assertion that an ordinarily skilled artisan
`12
`
`
`
`IPR2017-00287
`Patent 9,125,939 B2
`
`
`
`The obviousness analysis requires, inter alia, consideration of two
`factors:
`(1) whether the prior art would have suggested to those of
`ordinary skill in the art that they should make the claimed
`composition or device, or carry out the claimed process; and
`(2) whether the prior art would also have revealed that in so
`making or carrying out, those of ordinary skill would have a
`reasonable expectation of success.
`Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1164 (Fed. Cir. 2006)
`(quoting Velander v. Garner, 348 F.3d 1359, 1363 (Fed.Cir.2003)). “Both
`the suggestion and the expectation of success must be founded in the prior
`art, not in the applicant’s disclosure.” In re Dow Chemical Co., 837 F.2d
`469, 473 (Fed. Cir. 1988).
`Alkermes contends that the APA Guidelines’ disclosures concerning
`the treatment of refractory bipolar disorder, i.e., bipolar disorder
`inadequately responsive to mood stabilizer monotherapy, using combination
`therapy employing atypical antipsychotics in general, and olanzapine and
`risperidone in particular, taken together with teachings by Keck or the
`Otsuka Press Release regarding the efficacy and beneficial side effect profile
`of aripiprazole monotherapy, would have created a reasonable expectation of
`success in treating bipolar disorder. Pet. 24–27.
`
`
`would have had a reasonable expectation of success in combining the APA
`Guidelines with Keck or the Otsuka Press Release to arrive at the claimed
`invention, we do not need to address whether Alkermes sufficiently
`established that either Keck or the Otsuka Press Release qualifies as a
`printed publication.
`
`13
`
`
`
`IPR2017-00287
`Patent 9,125,939 B2
`
`
`
`As an initial matter, we observe that neither Alkermes nor Dr. Frances
`expressly asserts that an ordinarily skilled artisan in possession of the cited
`references would have had a reasonable expectation of success in treating
`bipolar disorder in a patient partially nonresponsive to mood stabilizer
`monotherapy with a combination of aripiprazole and lithium. Rather,
`Alkermes and Dr. Frances contend that a relevant skilled artisan “would
`have had a reasonable expectation that the combination of aripiprazole with
`lithium would be effective to treat the patient suffering from bipolar
`disorder.” Pet. 27; Ex. 1002 ¶ 64. Such contention is insufficient to support
`a finding that an ordinarily skilled artisan would have had a reasonable
`expectation of success in “treating bipolar disorder in a patient partially
`nonresponsive to lithium or valproic acid, divalproex sodium or a salt
`thereof monotherapy” (Ex. 1001, 29:15–17 (emphasis added)), as required
`by the challenged claims. See Intelligent Bio-Sys., Inc. v. Illumina
`Cambridge Ltd., 821 F.3d 1359, 1367 (Fed. Cir. 2016) (“It is of the utmost
`importance that petitioners in the IPR proceedings adhere to the requirement
`that the initial petition identify ‘with particularity’ the ‘evidence that
`supports the grounds for the challenge to each claim.’”) (quoting 35 U.S.C.
`§ 312(a).
`Furthermore, Alkermes does not adequately explain why, in view of
`the explicit teachings of Keck (Ex. 1007, 2) and the Otsuka Press Release
`(Ex. 1008, 2) concerning the unique mechanism of action of aripiprazole, a
`relevant skilled artisan would have had a reasonable expectation of success
`in using aripiprazole and lithium combination therapy to treat bipolar
`
`14
`
`
`
`IPR2017-00287
`Patent 9,125,939 B2
`
`
`patients in general, much less bipolar patients refractory to mood stabilizer
`monotherapy, as required by the challenged claims. In this regard, we
`observe that Alkermes’ conclusory statements concerning the existence of an
`expectation of success in treating bipolar disorder with aripiprazole and
`lithium combination therapy (Pet. 27) are not persuasive. Dr. Frances’
`nearly identical, unsupported opinions on this issue (Ex. 1002 ¶ 64), to
`which we give little weight (37 C.F.R. § 42.65(a)), are similarly
`unpersuasive.
`Neither Keck nor the Otsuka Press Release contemplates the use of
`aripiprazole to treat refractory bipolar disorder, or as a component of
`combination therapy. Nor do these references compare the efficacy of
`aripiprazole to that of other antipsychotic medications. Moreover, Keck and
`the Otsuka Press Release each explicitly disclose aripiprazole as having a
`mechanism of action different from that of all other known atypical
`antipsychotics—including olanzapine and risperidone. Ex. 1007, 2;
`Ex. 1028, 2. In this context, Alkermes only explains how the APA
`Guidelines’ suggests that atypical antipsychotics in general may be useful in
`combination therapy. Pet. 25–27; see also Ex. 1002 ¶ 61; Ex. 1009, 15.
`Further, olanzapine and risperidone are the only specific atypical
`antipsychotics identified in the APA Guidelines as useful in combination
`therapy. Ex. 1009, 31. As noted above, however, evidence before us
`indicates that aripiprazole was known to have a different mechanism of
`action from all other atypical antipsychotics. Petitioner does not explain
`adequately why an ordinary artisan would have reasonably expected that
`
`15
`
`
`
`IPR2017-00287
`Patent 9,125,939 B2
`
`
`administration of aripiprazole—having a different mechanism of action than
`olanzapine and risperidone—in combination with mood stabilizers, would
`have worked to treat patients partially nonresponsive to mood stabilizer
`monotherapy. Petitioner’s lack of adequate explanation is fatal to this
`asserted ground of unpatentability.
`Alkermes asserts that an ordinarily skilled artisan would have
`understood from Keck or the Otsuka Press Release that aripiprazole “was
`safe and effective in treating bipolar disorder and, in fact, showed a
`beneficial side effect profile that made it more desirable than other atypical
`antipsychotics available” (Pet. 27; see also Ex. 1002 ¶ 64). That assertion
`has little bearing, however, on whether an ordinarily skilled artisan would
`have had a reasonable expectation of success in using aripiprazole in
`combination with a mood stabilizer to treat bipolar disorder in a patient
`partially nonresponsive to mood stabilizer monotherapy. Neither evidence
`of the efficacy of aripiprazole monotherapy as a first-line treatment for acute
`bipolar mania, nor the beneficial side effects of aripiprazole monotherapy,
`such as reduced weight gain relative to other atypical antipsychotics, would
`have been sufficient to create a reasonable expectation of success in treating
`patients partially refractory to mood stabilizer monotherapy with
`aripiprazole and mood stabilizer cotherapy. This is particularly so where, as
`here, the record indicates that aripiprazole has a different mechanism of
`action than other known atypical antipsychotics.
`Stated plainly, Alkermes has not adequately explained why a relevant
`skilled artisan would have had a reasonable expectation of success in using
`
`16
`
`
`
`IPR2017-00287
`Patent 9,125,939 B2
`
`
`aripiprazole in combination with a mood stabilizer to treat refractory bipolar
`disorder. Specifically, Alkermes does not address evidence of record
`indicating that ordinarily skilled artisans knew that aripiprazole worked
`differently from other antipsychotics and had only been shown to be
`effective as a monotherapy relative to placebo.3
`Accordingly, we determine that Alkermes has not established
`sufficiently for purposes of this Decision that claims 2, 6, 7, and 9 would
`have been unpatentable as obvious over the APA Guidelines and Keck or the
`Otsuka Press Release. Because we determine that Alkermes has not shown a
`reasonable likelihood in prevailing on its assertion that the challenged claims
`would have been obvious in view of the APA Guidelines and Keck, we do
`not need to address Otsuka’s assertions regarding the status of Keck and the
`Otsuka Press Release as a printed publications. We likewise decline to
`address Otsuka’s contentions regarding the exercise of our discretion under
`35 U.S.C. § 325(d) and the purported redundancy of this ground of
`unpatentability.
`
`D. Obviousness Ground of Unpatentability
`Based on Tohen and Keck or Otsuka Press Release
`
`Alkermes asserts that claims 2, 6, 7, and 9 are unpatentable under
`35 U.S.C. § 103(a) as obvious in view of Tohen and Keck or the Otsuka
`
`
`3 To the extent Alkermes attempts to rely on the ’939 patent specification to
`support its reasonable expectation of success argument (see Pet. 27, n.4), we
`observe that such reliance is improper. See Dow Chemical, 837 F.2d at 473.
`17
`
`
`
`IPR2017-00287
`Patent 9,125,939 B2
`
`
`Press Release. Pet. 30–32, 41–49. Alkermes relies upon the Frances
`Declaration (Ex. 1002) and the Au Declaration (Ex. 1004) to support its
`positions.
`Otsuka reiterates its contention that Alkermes has not established that
`either Keck or the Otsuka Press Release qualifies as a publicly accessible
`printed publication (Prelim. Resp. 3–16), and asserts that an ordinarily
`skilled artisan would not have had reason to combine, or a reasonable
`expectation of success in combining the cited references to arrive at the
`claimed invention (id. at 16–33). Otsuka also reasserts its position that the
`Petition should be denied under 35 U.S.C. § 325(d) (id. at 33–59), and
`argues that the asserted ground of unpatentability based on Tohen and Keck
`or Otsuka Press Release is both horizontally and vertically redundant of
`other grounds set forth in the Petition (id. at 59–62).
`
`1. Overview of Tohen
`Tohen describes a study conducted to determine “the efficacy of
`combined therapy with olanzapine and either valproate or lithium compared
`with valproate or lithium alone in treating acute manic or mixed bipolar
`episodes.” Ex. 1006, 1. Tohen reports that “[o]lanzapine cotherapy
`improved patients’ YMRS total scores significantly more than
`monotherapy” with either lithium or valproate. Id. Tohen additionally
`reports that weight gain was observed with cotherapy, but the amount of
`weight gain was similar to that seen with olanzapine monotherapy. Id. at 7.
`Tohen notes that olanzapine is an atypical antipsychotic that has been
`shown in prior studies to have acute anti-maniac effects, and to be “effective
`18
`
`
`
`IPR2017-00287
`Patent 9,125,939 B2
`
`
`when used in combination with other psychotropic agents.” Id. at 1. Tohen
`observes that the finding that olanzapine and mood stabilizer cotherapy
`results in improved patient Y-MRS scores versus mood stabilizer
`monotherapy is consistent with others’ findings evaluating the efficacy of
`cotherapy using typical antipsychotics and mood stabilizers, as well as
`preliminary results obtained with cotherapy using the atypical antipsychotic
`risperidone and mood stabilizers. Id. at 7. Tohen does not discuss
`aripiprazole.
`
`2. Discussion
`Alkermes relies on Tohen in much the same way that it relies on the
`APA Guidelines in the preceding asserted ground of unpatentability.
`Indeed, Alkermes’ argument concerning whether a relevant skilled artisan
`would have had a reasonable expectation of success in treating patients
`refractory to mood stabilizer monotherapy using a combination of
`aripiprazole and lithium closely mirrors that discussed above concerning the
`combination of the APA Guidelines and Keck or the Otsuka Press Release.
`Pet. 30–32. Namely, Alkermes asserts that Tohen’s teachings with regard to
`the treatment of refractory bipolar disorder using combination therapy
`employing atypical antipsychotics in general, and using olanzapine and
`lithium cotherapy in particular, considered together with teachings by Keck
`and the Otsuka Press Release regarding the efficacy and beneficial side
`effect profile of aripiprazole monotherapy, would have created a reasonable
`expectation of success in the claimed method. Pet. 30–32.
`
`19
`
`
`
`IPR2017-00287
`Patent 9,125,939 B2
`
`
`
`Alkermes discusses disclosures concerning the treatment of refractory
`illness with a combination therapy that employs atypical antipsychotics in
`general (Ex. 1006, 1), and the use of olanzapine and mood stabilizer
`combination therapy in particular (id.). Pet. 30–32. Alkermes does not
`explain sufficiently, however, why an ordinary artisan would have had a
`reasonable expectation of success in using aripiprazole––which had only
`been evaluated as a monotherapy, and was explicitly disclosed as having a
`mechanism of action that differed from that of all other known atypical
`antipsychotics (Ex. 1007, 1; Ex. 1028, 2)––in combination with mood
`stabilizers to treat patients partially nonresponsive to mood stabilizer
`monotherapy.
`Moreover, the fact that olanzapine combination therapy is associated
`with weight gain, while aripiprazole monotherapy is not, does not provide
`evidence of a reasonable expectation of success in relation to the subject
`matter of the challenged claims. The essential question is whether a relevant
`skilled artisan would have had a reasonable expectation of success in
`treating a patient partially nonresponsive to mood stabilizer monotherapy
`with aripiprazole and lithium combination therapy. Evidence that an
`ordinary artisan expected aripiprazole to exhibit a side effect profile superior
`to that of olanzapine does not sufficiently establish that an ordinarily skilled
`artisan would have had a reasonable expectation of success in treating
`refractory bipolar disorder using aripiprazole combination therapy.
`Improved side effects are immaterial to the reasonable expectation of
`
`20
`
`
`
`IPR2017-00287
`Patent 9,125,939 B2
`
`
`success analysis, absent evidence that one would have expected the recited
`method to treat a refractory bipolar disorder in the first place.
`Accordingly, we determine that Alkermes has not established
`sufficiently for purposes of this Decision that claims 2, 6, 7, and 9 would
`have been unpatentable as obvious over Tohen and Keck or the Otsuka Press
`Release. Because we deny institution of inter partes review with respect to
`this asserted ground of unpatentability, we do not need to address Otsuka’s
`arguments concerning the prior art status of Keck and the Otsuka Press
`Release. We l
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
