Trials@uspto.gov
`571-272-7822
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` Paper No. 8
` Entered: November 7, 2018
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
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`AMNEAL PHARMACEUTICALS LLC,
`Petitioner,
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`v.
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`ALKERMES PHARMA IRELAND LIMITED,
`Patent Owner.
`____________
`
`Case IPR2018-00943
`Patent 7,919,499 B2
`____________
`Before CHRISTOPHER M. KAISER, JACQUELINE T. HARLOW, and
`KRISTI L. R. SAWERT, Administrative Patent Judges.
`
`SAWERT, Administrative Patent Judge.
`
`DECISION
`Granting Institution of Inter Partes Review
`35 U.S.C. § 314(a)
`
`APOTEX EXHIBIT 1058
`Apotex v. Alkermes
`IPR2025-00514
`
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`571-272-7822
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` Paper No. 8
` Entered: November 7, 2018
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
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`AMNEAL PHARMACEUTICALS LLC,
`Petitioner,
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`v.
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`ALKERMES PHARMA IRELAND LIMITED,
`Patent Owner.
`____________
`
`Case IPR2018-00943
`Patent 7,919,499 B2
`____________
`Before CHRISTOPHER M. KAISER, JACQUELINE T. HARLOW, and
`KRISTI L. R. SAWERT, Administrative Patent Judges.
`
`SAWERT, Administrative Patent Judge.
`
`DECISION
`Granting Institution of Inter Partes Review
`35 U.S.C. § 314(a)
`
`APOTEX EXHIBIT 1058
`Apotex v. Alkermes
`IPR2025-00514
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`IPR2018-00943
`Patent 7,919,499 B2
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`INTRODUCTION
`I.
`Amneal Pharmaceuticals LLC (“Petitioner”) requests an inter partes
`review of claims 1–13 of U.S. Patent No. 7,919,499 B2 (“the ’499 patent,”
`Ex. 1001). Paper 1 (“Pet.”). Alkermes Pharma Ireland Limited (“Patent
`Owner”) filed a Preliminary Response. Paper 7 (“Prelim. Resp.”).
`We have authority to determine whether to institute an inter partes
`review. 35 U.S.C. § 314(b); 37 C.F.R. § 42.4(a). We may not institute an
`inter partes review “unless . . . 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(a). On April 24, 2018, the Supreme Court
`held that a decision to institute under 35 U.S.C. § 314(b) may not institute
`review on less than all claims challenged in the petition. SAS Inst., Inc. v.
`Iancu, 138 S. Ct. 1348, 1355–56 (2018). Moreover, in accordance with
`USPTO Guidance, “if the PTAB institutes a trial, the PTAB will institute on
`all challenges raised in the petition.” See Guidance on the Impact of SAS on
`AIA Trial Proceedings (April 26, 2018) (available at
`https://www.uspto.gov/patents-application-process/patent-trial-and-appeal-
`board/trials/guidance-impact-sas-aia-trial) (“USPTO Guidance”).
`Applying those standards, and upon consideration of the information
`presented in the Petition and the Preliminary Response, we determine that
`Petitioner has demonstrated a reasonable likelihood of success in proving
`that at least one claim of the ’499 patent is unpatentable. Accordingly, we
`institute an inter partes review of all challenged claims (1–13) of the ’499
`patent, based on all grounds raised in the Petition.
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`II.
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`BACKGROUND
` Related Matters
`The parties state that there are no pending judicial proceedings
`involving the ’499 patent. Pet. 61; Paper 6, 1. Patent Owner states that U.S.
`Patent Application No. 15/486,869 claims priority to the ’499 patent and is
`currently pending before the Office. Paper 6, 1.
` The ’499 Patent
`The ’499 patent, titled “Naltrexone Long Acting Formulations and
`Methods of Use,” issued on April 5, 2011. Ex. 1001, at [45]. The ’499
`patent relates to “a method for treating an individual in need of naltrexone
`comprising the step of parenterally administering a long-acting formulation
`comprising naltrexone.” Id., at [57].
`According to the ’499 patent, “[a]lcohol dependence is a chronic
`disorder that results from a variety of genetic, psychological and
`environmental factors.” Id. at 1:13–14. The ’499 patent states that, “[i]n the
`past, most rehabilitative treatments have been psychosocial.” Id. at 1:18–19.
`But, “[w]ith advances in neurobiology, there is increasing interest in drug
`therapy for alcohol dependence,” such as naltrexone therapy. Id. at 1:19–27.
`The ’499 patent states that “[t]he inventions described herein arose
`from unexpected discoveries made during clinical trials with a long acting
`formulation of naltrexone.” Id. at 1:31–33. Specifically, “[t]his invention
`arose from the unexpected discovery that substantially improved serum
`levels of naltrexone can be achieved by administering long acting
`formulations of naltrexone, such as the Alkermes, Inc. formulation,
`Vivitrex® injectable suspension, made employing its Medisorb® delivery
`system.” Id. at 2:29–34.
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`In one embodiment, the “invention includes a method for treating an
`individual in need of naltrexone comprising the step of parenterally
`administering a long acting formulation comprising naltrexone.” Id. at
`2:22–25. The formulation dosage preferably ranges from about 310 to about
`480 mg of naltrexone. Id. at 1:45–46. The ’499 patent states that the long
`acting formulation “may be achieved through the use of polymers
`(preferably poly-lactide or poly-lactide-co-glycolide polymers) to entrap or
`encapsulate the naltrexone.” Id. at 3:11–16. The ’499 patent identifies a
`preferred polylactide-co-glycolide (“PLGA”) polymer as MEDISORB®
`7525 DL polymer. Id. at 5:43–46; 6:44–51.
`The ’499 patent states that the disclosed method unexpectedly
`achieves a serum AUC of naltrexone that is “preferably at least about three
`times” that achieved by 50 mg/day oral administration of naltrexone. Id. at
`2:22–28. The ’499 patent provides a “semi-quantitative comparison” of the
`efficacy of long-acting naltrexone with oral naltrexone. See id. at 18:4–
`19:34 (Example 3). The ’499 patent states that “oral naltrexone significantly
`decreased the relapse rate by 36% relative to placebo,” whereas “Vivitrex
`suspension 380 mg significantly decreased the relapse rate by 45% relative
`to placebo.” Id. at 18:57–67.
`
` Illustrative Claim
`Petitioner challenges the patentability of claims 1–13, but not claims
`14 and 15, of the ’499 patent. Of the challenged claims, claim 1 is
`independent and illustrative of the claimed subject matter. Claim 1 recites:
` 1. A method for treating an individual in need of naltrexone
`comprising the step of parenterally administering a long acting
`formulation comprising about 310 mg to about 480 mg of
`naltrexone and a biocompatible polymer to the individual
`wherein the serum AUC of naltrexone is about three times
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`greater than that achieved by 50 mg/day oral administration and
`wherein the biocompatible polymer is a polylactide-co-glycolide
`polymer.
`Ex. 1001, 21:2–9.
`
` The Prior Art
`Petitioner advances the following references as prior art on which it
`relies for the asserted grounds challenging the claims of the ’499 patent:
`1. Sandra D. Comer et al., Depot naltrexone: long-lasting antagonism of
`the effects of heroin in humans, 159(4) PSYCHOPHARMACOLOGY 351–
`30 (2002) (“Comer,” Ex. 1010);
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`2. Elie S. Nuwayser, U.S. Patent No. 7,157,102 B1 (issued Jan. 2, 2007)
`(“Nuwayser,” Ex. 1014);
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`3. G. Rubio et al., Naltrexone versus acamprosate: one year follow-up of
`alcohol dependence treatment, 36(5) ALCOHOL & ALCOHOLISM 419–
`25 (2001) (“Rubio,” Ex. 1028);
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`4. Steven G. Wright et al., U.S. Patent No. 6,264,987 B1 (issued July 24,
`2001) (“Wright,” Ex. 1018);
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`5. Henry R. Kranzler et al., Sustained-Release Naltrexone for
`Alcoholism Treatment: A Preliminary Study, 22(5) ALCOHOLISM
`CLINICAL & EXPERIMENTAL RES. 1074–79 (1998) (“Kranzler,”
`Ex. 1011);
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`6. Alkermes, Inc., Form 10-K: Annual Report Pursuant to Section 13 or
`15(d) of the Securities Exchange Act of 1934 (July 2002) (“Alkermes
`10-K,” Ex. 1016); and
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`7. U.S. Trademark Application No. 76/271,990 for Vivitrex (Aug. 2002)
`(“Vivitrex Specimen,” Ex. 1017).
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`Reference(s)
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` The Asserted Grounds of Unpatentability
`Petitioner challenges the patentability of claims 1–13 of the ’499
`patent on the following grounds:
`Claims
`Basis
`1, 3–5, and 10–12 35 U.S.C. § 102 Comer
`1, 3–5, 11, and 12 35 U.S.C. § 102 Nuwayser
`1–13
`35 U.S.C. § 103 Comer, Nuwayser, Rubio, and
`Wright
`35 U.S.C. § 103 Nuwayser, Comer, Rubio, and
`Wright
`35 U.S.C. § 103 Nuwayser, Kranzler, Rubio, and
`Wright
`35 U.S.C. § 103 Alkermes 10-K, Vivitrex
`Specimen, Wright, and Rubio
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`1–13
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`1–13
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`1–13
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`Pet. 4. Petitioner also relies on the Declaration of Kinam Park, Ph.D. See
`id. (citing Exs. 1030; 1031). Patent Owner disputes that Petitioner’s asserted
`grounds render the challenged claims unpatentable. See generally Prelim.
`Resp.
`
`III. ANALYSIS
`We organize our analysis into four sections. First, we address the
`level of ordinary skill in the art. Second, we address claim construction.
`Third, we provide an overview of the asserted references. Fourth, taking
`account of the information presented, we consider whether the grounds
`asserted in the Petition meet the threshold showing for instituting an inter
`partes review under 35 U.S.C. § 314(a).
` Level of Ordinary Skill in the Art
`We consider the asserted grounds of unpatentability in view of the
`understanding of a person of ordinary skill in the art. Petitioner contends,
`and Dr. Park testifies, that a person of ordinary skill in the art would have a
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`doctorate level degree in pharmaceutics or related formulation sciences
`(such as a Pharm.D. or Ph.D.) and at least two years of experience in
`controlled release formulation. Pet. 15–16; Ex. 1030 ¶¶ 28–31. Petitioner
`and Dr. Park also contend that “[a] lesser degree of formal education
`balanced by additional practical experience could also qualify as a [person of
`ordinary skill in the art].” Id. In response, Patent Owner states that it “does
`not necessarily disagree with [Petitioner’s] proposed definition of a [person
`of skill in the art] and reserves the right to offer another definition should the
`Board institute trial.” Prelim. Resp. 15 n.8 (citations omitted).
`We adopt Petitioner’s definition for purposes of this decision. We
`also find, for purposes of this decision, that the prior art itself is sufficient to
`demonstrate the level of ordinary skill in the art at the time of the invention.
`See Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001) (the prior
`art, itself, can reflect the appropriate level of ordinary skill in art). Further,
`based on the information presented at this stage of the proceeding, we
`consider Petitioner’s declarant—Dr. Park—qualified to opine from the
`perspective of an ordinary artisan at the time of the invention. See Ex. 1031
`(Dr. Park’s curriculum vitae).
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` Claim Interpretation
`The Board interprets claims in an unexpired patent using the “broadest
`reasonable construction in light of the specification of the patent.” 37 C.F.R.
`§ 42.100(b) (2016); Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131,
`2144–46 (2016). “Under a broadest reasonable interpretation, words of the
`claim must be given their plain meaning, unless such meaning is
`inconsistent with the specification and prosecution history.” Trivascular,
`Inc. v. Samuels, 812 F.3d 1056, 1062 (Fed. Cir. 2016).
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`Petitioner proposes interpretations for claim terms: “a long acting
`formulation,” “the serum AUC of naltrexone . . . than that achieved by 50
`mg/day oral administration,” “about three,” “five or more days,” “initial oral
`dose,” and “about 35% by weight.” Pet. 16–21. In response, Patent Owner
`asserts that Petitioner’s claim interpretations are unnecessary or incorrect.
`Prelim. Resp. 62–63.
`To determine whether to institute an inter partes review, we need not
`explicitly interpret every claim term for which Petitioner proposes a
`construction. See 35 U.S.C. § 314(a); Vivid Techs., Inc. v. Am. Sci. & Eng’g,
`Inc., 200 F.3d 795, 803 (Fed. Cir. 1999) (“[O]nly those terms need be
`construed that are in controversy, and only to the extent necessary to resolve
`the controversy.”). We determine that, to resolve whether Petitioner has
`demonstrated a reasonable likelihood of prevailing, we need only address
`Petitioner’s proposed interpretations of “the serum AUC of naltrexone . . .
`than that achieved by 50 mg/day oral administration” and “about three.”
` “the serum AUC of naltrexone . . . than that achieved by 50 mg/day
`oral administration”
`Claim 1 recites that “the serum AUC of naltrexone is about three
`times greater than that achieved by 50 mg/day oral administration.”
`Ex. 1001, 21:6–7. Petitioner asserts that the ’499 patent does not define
`“AUC,” but, relying on the declaration testimony of Dr. Park, asserts that an
`ordinarily skilled artisan would understand serum “AUC” to refer to “area
`under the curve.” Pet. 17 (citing Ex. 1030 ¶¶ 36, 37, 56–59). Petitioner also
`asserts that an ordinarily skilled artisan would understand that serum AUC
`“is merely the area under the curve created by plotting plasma drug
`concentration versus time.” Id. (citing Ex. 1030 ¶¶ 38, 60).
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`We agree with Petitioner’s interpretation of serum “AUC.” As the
`record reflects, AUC is a well-known pharmacokinetic parameter referring
`to area under the curve. We also agree with Petitioner that serum AUC is
`represented by a plasma concentration-time curve. See, e.g., Ex. 1012, 3
`(referring to “AUC” as “area under plasma concentration-time curve”);
`Ex. 1044, 261–62 (accord); see also Ex. 1044, 261 (stating that AUC is used
`to evaluate the extent of drug absorption).
`By its plain terms, claim 1 requires that the serum AUC achieved by
`parenterally administering the long-acting formulation of naltrexone (i.e., a
`long-acting formulation comprising about 310 mg to about 480 mg
`naltrexone and a polylactide-co-glycolide polymer as a biocompatible
`polymer) is about three times the serum AUC achieved by administration of
`a 50 mg/day oral naltrexone formulation. Ex. 1001, 21:3–9. Petitioner
`asserts that the ’499 patent “does not define or specify the AUC of the
`claimed formulation or oral dosing.” Pet. 17. Because of this lack of
`information, Petitioner asserts, “a POSA must look to the art” but “would
`find . . . that there is no single accepted data set, particularly for the AUC
`resulting from administering 50 mg/day orally.” Pet. 17–18. Petitioner
`asserts therefore that “the BRI . . . allows the use of any data for the AUC of
`the claimed naltrexone dose compared to any data for the AUC of a 50
`mg/day oral dose.” Id. at 18–19 (citing Ex. 1030 ¶ 43) (emphases added).
`We agree with Petitioner that the ’499 patent does not provide a value
`(or underlying data) for the serum AUC of the disclosed long-acting
`formulation of naltrexone, or a value (or underlying data) for the serum
`AUC of the 50 mg/day oral formulation. See Pet. 17–18. We observe,
`instead, that the written description describes the serum AUC of the
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`disclosed long-acting formulation of naltrexone in comparative terms: as
`“preferably at least about three times . . . greater over the course of the
`month than that achieved by 50 mg/day oral administration” of naltrexone.
`Ex. 1001, 1:37–40.1
`Even so, we disagree with Petitioner on this record that the broadest
`reasonable interpretation allows for the use of any available data set for the
`claimed serum AUCs. Pet. 18–19. Petitioner does not address the ’499
`patent’s prosecution history in its claim construction analysis. But in
`interpreting claims, “[a] patent’s specification, together with its prosecution
`history, constitutes intrinsic evidence to which the Board gives priority when
`it construes claims.” WesternGeco LLC v. ION Geophysical Corp., 889 F.3d
`1308, 1323 (Fed. Cir. 2018) (emphasis added). Thus, we must “consult the
`patent’s prosecution history in proceedings” such as this one, “in which the
`patent has been brought back to the agency for a second review.” Microsoft
`Corp. v. Proxyconn, Inc., 789 F.3d 1292, 1298 (Fed. Cir. 2015), overruled
`on other grounds by Aqua Prods., Inc. v. Matal, 872 F.3d 1290 (Fed. Cir.
`2017) (en banc).
`During prosecution of the ’499 patent, applicants filed a Declaration
`under 37 C.F.R. § 1.132 (“the Ehrich Declaration”) purporting to show
`unexpected results for the serum AUC of the claimed long-acting naltrexone
`formulation over that of a 50 mg/day oral formulation (i.e., an unexpected
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`1 The written description of the ’499 patent also refers to the claimed
`serum AUC of the long-acting naltrexone formulation as “unexpected,”
`Ex. 1001, 2:29, and further states that “the pharmacokinetic profile of long-
`acting injectable naltrexone differs substantially from that of the oral
`formulation,” id. at 17:49–51.
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`serum AUC differential). Ex. 1003, 1–18. The Ehrich Declaration provides
`two data sets (Cohort A and Cohort B) for the serum AUCs of the claimed
`long-acting naltrexone formulation and the 50 mg/day oral naltrexone. See
`id. at 6 (Table 8). For Cohort A, the serum AUC of the 380 mg dose of the
`claimed long-acting naltrexone formulation is 4.307,2 which is 3.37 times
`the serum AUC value of 1.278 for the 50 mg oral naltrexone dose. Id. at 2.
`Similarly, for Cohort B, the serum AUC of the 380 mg dose of the claimed
`long-acting naltrexone formulation is 4.921, which is 3.35 times the 1.468
`serum AUC value for the 50 mg oral naltrexone dose. Id. In her Statement
`of Reasons for Allowance, the Examiner referenced this data as showing “an
`AUC about three times greater than that achieved by 50 mg/day oral
`administration,” and explained that “no prior art disclos[es]” this effect.
`Ex. 1009, 4.
`Because these serum AUC data points were presented during
`prosecution and were relied on by the Examiner in allowing the application
`issuing as the ’499 patent, an ordinarily skilled artisan would understand that
`the serum AUC achieved by 50 mg/day oral administration encompasses
`these data points. Indeed, Dr. Park admits that “[b]ecause the patent
`provides no data, a POSA would look at the Ehrich Declaration.” Ex. 1030
`¶ 72. For purposes of this decision, therefore, we interpret the reference to a
`“50 mg/day” AUC in “than that achieved by 50 mg/day oral administration”
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`2 The Declaration explains that the AUC0-t (AUC0-28days) for a single
`dose of 380 mg long-acting naltrexone formulation on a per day basis can be
`calculated for Cohort A by dividing 120.6 ng•day/ml (the AUC0-t for Cohort
`A) by 28 days (120.6÷28=4.307), and by dividing 137.8 ng•day/ml (the
`AUC0-t for Cohort B) by 28 days (137.8÷28=4.921). Ex. 1003, 2.
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`as encompassing at least serum AUCs of 1.278 ng•day/ml and 1.468
`ng•day/ml.
`We acknowledge Petitioner’s arguments and evidence suggesting that
`the comparative AUC values for the claimed long-acting naltrexone
`formulation and the 50 mg/day oral naltrexone render the claims difficult to
`understand. For example, Petitioner asserts that “the art reports varying data
`sets for oral dosing, none of which is consistent.” Pet. 18 (citing Ex. 1030
`¶¶ 41, 81–86). Dr. Park cites to Baek3 for showing a serum AUC of 1.80
`ng•day/ml and 1.810 ng•day/ml for the 50 mg/day oral naltrexone
`formulations having the trade names Levia and Traxone, respectively.
`Ex. 1030 ¶ 82 (citing Ex. 1039, 72 (Table 1)). And Dr. Park points out that
`the serum AUC of the 380 mg long-acting naltrexone formulation would not
`be about three times the serum AUC of either Levia or Traxone. See id. ¶ 83
`(calculating the serum AUC of the claimed 380 mg long-acting naltrexone
`formulation as 2.4 times the serum AUC of the Traxone 50 mg/day oral
`formulation).
`Although Petitioner’s arguments may raise issues of claim clarity—or
`even indefiniteness—that are beyond the scope of this inter partes review,
`because we discern, based on the present record, that the serum AUC of a
`50 mg/day oral formulation encompasses at least the values reported in the
`Ehrich Declaration, we determine, for purposes of this decision, that the
`phrase is broad enough to create a reasonable likelihood that it reads on the
`prior art that is asserted here. See infra §§ III.D., III.E. Thus, it is
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`3 In-hwan Baek et al., Evaluation of the Bioequivalence of Two
`Brands of Naltrexone 50 mg Tablet in Healthy Volunteers, 16(1) KOR. J.
`CLIN. PHARM. 69–74 (2006) (“Baek,” Ex. 1039).
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`unnecessary at this point to determine the precise contours of the claim
`limitation for purposes of this decision. Vivid Techs., 200 F.3d at 803. We
`leave for trial the issue of whether, on a fully developed record, this term is
`capable of construction, as well as the final construction it should be given.
`Accordingly, the parties are encouraged to explore this issue further at trial.
` “about three”
`Turning to the claim language “about three,” we agree with Petitioner
`that—although not defined in the ’499 patent—“about three necessarily
`encompasses at least 3.3” and “at least about 2.7.” Pet. 19 (citing Ex. 1030
`¶¶ 45–47) (quotations omitted). As Petitioner points out, the Ehrich
`Declaration provides data of a serum AUC for long-acting naltrexone
`formulation that is 3.3 times greater than that achieved by oral dosing. Id.;
`Ex. 1003, 2. Dr. Park also testifies, and supports with evidence, that the
`term “about” as used in the art “indicate[s] a quantity within 10%.”
`Ex. 1030 ¶ 47 (citing Ex. 1043, 8). For these reasons, we agree with
`Petitioner that the broadest reasonable interpretation of “about three”
`encompasses values as high as 3.3 and as low as 2.7.
` Asserted References
`Before turning to Petitioner’s asserted grounds of unpatentability, we
`provide a brief summary of the asserted references.
` Comer
`Comer describes a study “designed to evaluate the time course, safety,
`and effectiveness of a depot formulation of naltrexone (Depotrex®)” in
`subjects dependent on heroin. Ex. 1010, 351 (Abstract). Comer states that
`the results of the study “suggest that th[e] depot formulation of naltrexone
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`provides a safe, effective, long-lasting antagonism of the effects of heroin.”
`Id.
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`As background, Comer states that, although approved as a treatment
`for heroin dependence, “naltrexone is generally not well accepted by
`patients, and medication non-compliance is a difficult obstacle to treatment.”
`Id. at 351 (Abstract). Comer states, however, that “[s]ustained-release forms
`of naltrexone could increase compliance and ultimately improve treatment
`effectiveness.” Id. at 352. In particular, “[a] new depot formulation of
`naltrexone (Depotrex®) has been developed that provides a stable, long-
`lasting elevation in plasma naltrexone levels with either no or minimal side
`effects.” Id. Comer states that “[a]lthough this formulation of depot
`naltrexone appears to be safe and effective in treating alcohol dependence, it
`has not yet been tested with heroin.” Id. Thus, “[t]he purpose of the current
`study was 1) to determine whether the new formulation of depot naltrexone
`will antagonize the effects of heroin at doses comparable to those used on
`the streets today, and 2) to assess the duration of antagonist effect of 192 mg
`and 384 mg depot naltrexone.” Id.
`Comer states that naltrexone microcapsules were reconstituted in a
`suspending medium and 2.4 ml of the suspension was injected into study
`participants. Id. at 354. Participants given a “low dose” received one
`placebo injection and one naltrexone injection (192 mg naltrexone base)
`subcutaneously into the buttocks using an 18 gauge needle. Id. Participants
`given a “high dose” received two naltrexone injections (384 naltrexone
`base). Id. Figure 1 of Comer, reproduced below, provides mean plasma
`levels of naltrexone as a function of depot naltrexone dosage and dates after
`administration of depot naltrexone. Id.
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`Figure 1 shows mean plasma levels of depot naltrexone over time
`following either a 192 mg depot dose (○) or a 384 mg depot dose
`(●). Ex. 1010, 354.
`Comer states that “[a]cross the time points measured, the highest
`naltrexone plasma levels attained after administration of 192 mg and 384 mg
`of depot naltrexone were 3.8 (±0.2) and 8.9 (±1.4) ng/ml, respectively.” Id.
`at 358. Comer states that a comparative study “reported that daily
`administration of 50 mg oral naltrexone resulted in naltrexone plasma
`concentrations of approximately 30 ng/ml, while daily administration of 12.5
`mg oral naltrexone resulted in naltrexone plasma concentrations of
`approximately 10 ng/ml (plasma samples were collected 30 min after
`administration of naltrexone).” Id. Thus, Comer states, “the amount of drug
`found in plasma after depot naltrexone administration is lower than the
`amount found after a standard dose of naltrexone used clinically for treating
`heroin dependence (50 mg/day).” Even so, “antagonism of heroin’s effects
`occurred, despite negligible plasma levels of naltrexone.” Id.
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`Comer summarizes that “the data presented in the current study
`demonstrate that this formulation of naltrexone produced a long-lasting
`antagonism of the effects of intravenous heroin, with minimal side-effects.”
`Id. at 359. And thus, “a formulation of naltrexone that requires only once-a-
`month administration has important and exciting treatment implications.”
`Id.
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` Nuwayser
`Nuwayser teaches a multi-layered microcapsule containing one or
`more active ingredients and a process for preparing the microcapsule.
`Ex. 1014, Abstract. In Example IV, Nuwayser teaches the preparation of
`naltrexone microcapsules by coating naltrexone microspheres with the
`polymer poly-L-(–)-lactide-co-glycolide (PLGA). Id. at 19:3–25. Nuwayser
`teaches that the microcapsules contain a final naltrexone content of 54.4%.
`Id. “This formulation delivered a therapeutic level of naltrexone in six
`heroin addicts for a period of 30 days.” Id. Figure 7 of Nuwayser,
`reproduced below, provides mean plasma levels of naltrexone “after single
`and double [subcutaneous] injections of Depotrex™.” Id.
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`Figure 7 shows mean plasma levels of naltrexone over time
`following either a single dose (○) or a double dose (●) of
`naltrexone. Ex. 1014.
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` Rubio
`Rubio states that both naltrexone and acamprosate “reduce relapse in
`alcohol dependence,” but they “have not yet been compared in a published
`trial.” Ex. 1028, 419 (Abstract). Rubio describes a study designed “to
`compare the efficacy of these compounds in conditions similar to those in
`routine clinical practice.” Id. Recently detoxified alcohol-dependent men
`were administered either one year of treatment with 50 mg/day of naltrexone
`(i.e., one tablet per day) or 1665–1998 mg/day of acamprosate (i.e., six
`tablets per day). Id.; see also id. at 420. Rubio found that, at the end of the
`year, “[n]altrexone was associated with reducing relapse, achieving more
`days of accumulated abstinence, reducing the number of drinks consumed at
`any one time and reducing craving, compared to acamprosate.” Id. at 422.
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` Wright
`Wright teaches a method for preparing microparticles having a
`selected polymer molecular weight. Ex. 1018, Abstract. In Example 3,
`Wright teaches the preparation of microparticles containing naltrexone. Id.
`at 7:50–8:60. Wright teaches that the polymers used were “MEDISORB®
`7525 DL polymer, MEDISORB® 8515 DL polymer and MEDISORB®
`6535 DL polymer.” Id. at 7:56–58.
` Kranzler
`Kranzler describes a “preliminary study” of the use of sustained-
`release naltrexone for alcoholism treatment. Ex. 1011, 1074 (Abstract). In
`Kranzler’s study, twenty alcohol-dependent subjects received 50 mg/day
`oral naltrexone for two weeks, followed by a medication-free two-week
`“washout period.” Id. at 1074–75. Fifteen of those subjects then received a
`single subcutaneous injection of 206 mg of a sustained-release preparation
`(SRP) of naltrexone, and five received placebo. Id. The SRP of naltrexone
`comprises biodegradable, injectable microcapsules. Id. at 1074. Kranzler
`states that “[a]fter injection, [naltrexone] concentrations exceeded a mean of
`1 ng/ml for 21 days,” and that “[a]dverse effects produced by the SRP of
`[naltrexone] were comparable with those resulting from oral [naltrexone]
`therapy.” Id. at 1074, Abstract. Kranzler concludes that “[t]he results of this
`preliminary study support the potential clinical utility of the SRP of
`[naltrexone] for treatment of alcohol dependence.” Id.
` Alkermes 10-K
`Alkermes 10-K states that “we are developing Vivitrex™, a Medisorb
`formulation of naltrexone, for the treatment of alcoholism and opiate
`dependence.” Ex. 1016, 3. Alkermes 10-K states that naltrexone is “an
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`FDA-approved drug used for the treatment of alcohol and opioid
`dependence, which is currently available in daily oral dosage form.” Id. at 5.
`Alkermes 10-K states that “Vivitrex is based on our Medisorb injectable
`extended-release technology and is designed to provide once-a-month
`dosing to enhance patient adherence by removing the need for daily dosing.”
`Id.
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` Vivitrex Specimen
`The “Vivitrex Specimen” consists of an “Allegation of Use of a Mark
`under 15 U.S.C. §§ 1051(c) or (d),” filed in U.S. Trademark Application No.
`76/271,990 for “Vivitrex,” accompanied by one specimen of the mark as
`used in commerce, a transmittal letter, and a fee. Ex. 1017, 1–5. The
`Allegation states that the mark was “first used at least as early as August 7,
`2002; and was first used in commerce at least as early as August 7, 2002.”
`Id. at 4. The specimen of the mark appears to be a label for Vivitrex, which
`identifies the contents as “Medisorb® Naltrexone (190 mg or 380 mg) (for
`injectable suspension).” Id. at 5.
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` Asserted Anticipation Grounds
`Petitioner contends that Comer, as evidenced by Nuwayser,
`anticipates claims 1, 3–5, and 10–12 of the ’499 patent. Pet. 22–26.
`Petitioner also contends that Nuwayser anticipates claims 1, 3–5, 11, and 12.
`Id. at 26–27. A claim is anticipated, and therefore unpatentable under 35
`U.S.C. § 102, if all of its limitations are disclosed either explicitly or
`inherently in a single prior art reference. In re Schreiber, 128 F.3d 1473,
`1477 (Fed. Cir. 1997). That single prior art reference must disclose all the
`limitations of the claim “arranged or combined in the same way as in the
`claim.” Net MoneyIN, Inc. v. VeriSign, Inc., 545 F.3d 1359, 1370 (Fed. Cir.
`2008). We address each asserted anticipation ground individually below.
` Anticipation by Comer as Evidenced by Nuwayser
`Petitioner argues that Comer “teaches the method of claim 1—treating
`patients in need of naltrexone (heroin dependent patients) by parenterally
`administering (depot injection into the buttocks) a long-acting (1 ng/ml
`blood levels for four weeks) formulation of about 310 mg to about 480 mg
`(384 mg) [naltrexone] and PLGA (evidenced by Nuwayser).” Pet. 23–24
`(citing Ex. 1030 ¶ 89). Petitioner argues that Comer teaches the claimed
`serum AUC differential of about 3, by comparing Comer’s serum AUC
`values with the Ehrich Declaration’s serum AUC values for 50 mg/day oral
`naltrexone in Cohort A. Pet. 24 (citing Ex. 1030 ¶¶ 67–74, 81, 89).
`Petitioner also argues that Comer inherently teaches the claimed AUC
`differential because (1) Comer’s dose is 384 mg, which is about the claimed
`dose of 380 mg, and (2) Patent Owner admitted before the Office during
`prosecution of a related patent application that serum AUC is dose
`dependent. Id. at 24–25 (citing Ex. 1030 ¶¶ 81, 89). Having considered the
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`IPR2018-00943
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