ALKERMES EXHIBIT 2002
`Apotex Inc. v. Alkermes Pharma Ireland Limited
`IPR2025-00514
`
`Page 1 of 68
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`

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`Request for Ex Parte Reexamination of
`U.S. Patent No. 7,919,499
`
`For the reasons set forth below, Requester respectfully submits that at least
`
`one Substantial New Question of Patentability exists based upon priorart references
`
`submitted herewith.
`
`Ex Parte Patent Reexamination Filing Requirements
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`Pursuant to 37 C.F.R. § 1.510(b)(1), statements pointing out at least one
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`substantial new question of patentability ("SNQ") based on material, non-cumulative
`
`reference patents and printed publications are provided in Section IV of this Request.
`
`Pursuant to 37 C.F.R. §§ 1510(b)(2)-(3), reexamination of the Challenged
`
`Claims is requested, and a detailed explanation of the pertinence and manner of
`
`applying the prior art references to the Challenged Claimsis provided in Section X
`
`of this Request. Copies of every patent or printed publication relied upon,or referred
`
`to, in the statement pointing out each SNQ and/orin the detailed explanation of the
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`pertinence and manner of applying the prior art references are provided with this
`
`Request.
`
`Pursuant to 37 C.F.R. §1.510(b)(4), a copy of the '499 Patent is provided as
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`Exhibit A, along with a copy of any disclaimer, certificate of correction, or
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`reexamination certificate issued in the patent. A copy ofthe file history of the '499
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`Patent is attached as Exhibit B.
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`Page 2 of 68
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`Request for Ex Parte Reexamination of
`U.S. Patent No. 7,919,499
`
`Pursuant to 37 C.F.R. §1.510(b)(5),
`
`the attached Certificate of Service
`
`indicates that a copy of this Request, in its entirety, includingall of the Exhibits, has
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`been served on Patent Ownerat the following correspondence address of record:
`
`Elmore Patent Law Group
`484 Groton Road
`Westford, MA 01886
`
`Pursuant to 37 C.F.R. §1.510(b)(6) Requester certifies that the statutory
`
`estoppel provisionsof 35 U.S.C. §§ 315(e)() and 325(e)(1)do not prohibit Requester
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`from filing this ex parte patent reexamination request.
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`The attached transmittal documentprovides the additional filing information
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`and acknowledgement of paymentof the fee under 37 C.F.R. § 120(c)().
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`Request for Ex Parte Reexamination of
`U.S. Patent No. 7,919,499
`
`TABLE OF CONTENTS
`
`INTRODUCTION00... ceccescceseceseceseceseeceeeeeaeeeseeeseecsaecsaeceseceseceseeeteeeeeeenes 8
`
`Il.
`
`LEGAL STANDARD0. cececcceccceseeeseeeseeeseeesaeceaeceaeceseceseceteeeeaeeeaeeeaeeenaes 12
`
`Il.
`
`IV.
`
`IDENTIFICATION OF THE PATENT AND CLAIMS FOR WHICH
`REEXAMINATION IS REQUESTED... ceccecccesecesecetecetceeeeeeeaeeeaeeenees 13
`
`STATEMENT POINTING OUT EACH SUBSTANTIAL NEW
`QUESTION OF PATENTABILITY... eee ceecceeceeeneeeneeeeeeneeenaeceaeeeaeens 15
`
`OVERVIEW OF THE °499 PATENT AND RELEVANT
`PROSECUTION HISTORY.00...eeceeceecceesceseeeseeceseceseceseceeeeteeseeeesaeeeaeeenaes 18
`
`A. Overview of the 499 Patent... ec ceeseeesseceeneeceeeeeeeeceseeeesaeeeteees 18
`
`B. Relevant Prosecution History of the ’499 Patent 0.0... eeeeceeeeeeeee21
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`C. Prior IPR Proceeding 0... cececccceesececesneeceessececeseeeceeaeceeseeeceeaeeceenaes22
`
`VI.
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`THIS REEXAMINATION REQUEST SHOULD NOT BE DENIED
`UNDER 35 U.S.C. § 325(d) wee ceeceeceseeeeseeeseeeseeceseceaecesecesecseeeseaeesaeeeaeeenaes24
`
`VIL.
`
`LEVEL OF ORDINARYSKILL IN THE ART... eee ceecceeeeeeneeeneeeneee 25
`
`VII.
`
`CLAIM CONSTRUCTIONuci cecceccceseceseceseceseceeeeeeaeeeaeeeaeeeaeenaeenaeeeseees 26
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`A. “along acting formulation” 00.0... ee eeeceeseeceesnececeteeeceenseceeeteeeceeaneeeen26
`
`B.
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`“the serum AUCofnaltrexone...than that achieved by 50 mg/dayoral
`ACMINIStALION””’ ............cccceceeeseeseeeseeeseeeeeseseeeeeeeseeeeeseeeseeeeeeeeeeeeeeeeeeeeeeees 27
`
`C.
`
`“about three”oc ccccecccccccccrercrersseeeeeeseeeeeeeeeeeeeseaeaeaeaeaeaeaeaeaea 29
`
`D. “five Of More days”... eecececeeseeceetseeeceseeceesececeeeeeceeaeceeeteeeceeeaeeeens 30
`
`E.
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`“initial oral dose”... cececccsseesssssssessscsescsesescssscscsstesetcseestststeteteseeenea 31
`
`F.
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`“about 35% by weight?’ 00... ceceeccessececeeneceessececeseeeceeeeceeseeeecetaeeeens 31
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`IX.
`
`OVERVIEW OF THE PRIOR ARTuu... ..ccceeccecccccccccccccecsssssessscscsseeseseeeeeeees 32
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`A. Comeret al. (Exhibit E)........ ccc ccecccccccseeetesssesesessssssseeeeeeeneaenenea 32
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`B. Vivitrex Pilot Study (Exhibit G) oo. eee eesscccetneeceeneeeetteeeceteeeeees 33
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`Request for Ex Parte Reexamination of
`U.S. Patent No. 7,919,499
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`C. U.S. Patent No. 7,157,102 (‘Nuwayser’) (Exhibit F) oe eee 35
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`D. Rubio et al. (Exhibit W) .......cc i cccccccecsscscesccccessssesssssssseesesenseeeees 36
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`E. U.S. Patent No. 6,264,987 (“Wright”) (Exhibit N) ..... cee eeeeeeseceeeeee 37
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`X.
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`SUBSTANTIAL NEW QUESTIONS OF PATENTABILITY........0000. 38
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`A. SNQ Ground 1: Claims 1, 3-5, and 12 are anticipated by Comeras
`evidenced by NUWaYSEL...........ceccecesecccesseccestececesececeseeceesaeeeenseeeeneaaeees 38
`
`B. SNQ Ground 2: Claims 1, 3-5, and 10-12 are anticipated by Vivitrex
`Pilot Study oo... eeeecssecesscecssecsesseceseceesseceseceesseceseeeceseesesseceeeeeesseceeees45
`
`C. SNQ Ground3: The Challenged Claims Are Obvious Over Comerin
`View of Nuwayser, Rubio, and Wright ......... cece ceeseeceessececeseeeeeeneeees50
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`D. SNQ Ground 4: The Challenged Claims Are Obvious Over the
`Vivitrex Pilot Study In View Of Comer, Rubio, And Wright.............59
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`XI.
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`SECONDARY CONSIDERATIONS 2... ccccccseesscessessssssssssesseseeeeees 64
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`XII. CONCLUSION wo ccccccecssssesesessssssssssssssssssssssssssssssssssssssssssssssseeees 66
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`CERTIFICATE OF SERVICE... ccccccccccecceccserssersssssssssssssssssssssseesseeeees 68
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`Request for Ex Parte Reexamination of
`U.S. Patent No. 7,919,499
`
`TABLE OF EXHIBITS
`
`U.S. Patent No. 7,919,499 (“499 Patent’)
`
`File history of the '499 Patent
`
`U.S. Provisional Application No. 60/564,542 (“the Provisional
`Application’)
`
`Serial No. 11/083,167, Declaration Under 37 C.F.R. § 1.132 of Elliot
`Ehrich (undated)
`
`Sandra D. Comeret al., Depot naltrexone: long-lasting antagonism of the
`effects of heroin in humans, 159(4) Psychopharmacology (Feb. 2002), at
`351-360. (“Comer’’)
`
`U.S. Patent No. 7,157,102 (“Nuwayser’’)
`
`Decision Granting Joint Motion to Terminate (Paper 29) IPR2018-00943 U.S. Patent No. 6,306,425 (“Tice’’)
` Institution Decision (Paper 8) IPR2018-00943
`
`Johnsonet al., “A Pilot Evaluation of the Safety and Tolerability of
`Repeat Dose Administration of Long-Acting Injectable Naltrexone
`(Vivitrex®) in Patients With Alcohol Dependence,” Alcoholism: Clinical
`and Experimental Research, Vol. 28. No. 9, 2004: 1356-1361. (“Vivitrex
`Pilot Study”)
`
`Declaration of Kinam Park, Ph.D. of April 19, 2018 in IPR2018-00943
`
`Synopsis, Naltrexone HCl, ALZA Corporation (Nov. 3, 2003)
`
`In-hwan Baeket al., Evaluation of the Bioequivalence of Two Brands of
`Naltrexone 50 mg Tablet in Healthy Volunteers, 16(1) Kor. J. Clin. Pharm.
`(2006), at 69-74
`
`U.S. Patent No. 6,264,987 (“Wright’’)
`Z
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`Request for Ex Parte Reexamination of
`U.S. Patent No. 7,919,499
`
`U.S. Serial Number 11/083,167, Office Action, May 5, 2009
`
`U.S. Serial Number 11/083,167, Amendment and Response, Oct. 5, 2009
`
`U.S. Serial Number 11/083,167, Office Action, Jan. 6, 2010
`
`U.S. Serial Number 11/083,167, Amendment and Response, Apr. 5, 2010
`
`U.S. Serial Number 11/083,167, Final Rejection, July 20, 2010
`
`U.S. Serial Number 11/083,167, Amendment After Final, Oct. 20, 2010
`
`U.S. Serial Number 11/083,167, Notice of Allowance, Dec. 1, 2010
`
`Henry R. Kranzleret al., Sustained-Release Naltrexone for Alcoholism
`Treatment: A Preliminary Study, 22(5) Alcoholism: Clinical and
`Experimental Research (Aug. 1998), at 1074-79
`
`Claims Chart
` Joint Request to Treat Settlement and License Agreement as Business
`
`G. Rubio et al., Naltrexone Versus Acamprosate: One Year Follow-Up of
`Alcohol Dependence Treatment, 36(5) Alcohol& Alcoholism (2001), at
`419-425
`
`Filing Details for AlkermesInc. 10-K dated July 1, 2002 from the
`Security and Exchange Commission’s EDGAR Online Filing System
`
`U.S. Trademark Application Serial Number 76/271,990, Allegation of Use
`of a Mark & specimen of the mark as used in commerce, Aug. 15, 2002
`(“Vivitrex Specimen”or “Specimen’)
`
`AppealBrief, Application No. 13/871,534, Oct. 19, 2015
`
`Joint Motion to Terminate (Paper 27) IPR2018-00943
`
`Confidential (Paper 28) IPR2018-00943
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`Request for Ex Parte Reexamination of
`U.S. Patent No. 7,919,499
`
`I.
`
`INTRODUCTION
`
`The °499 Patent claims methods of treating addiction by parenterally
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`administering 310-480 mg of a long-acting formulation comprising naltrexone and
`
`the biocompatible polymer polylactide-co-glycolide (“PLGA”), also known as
`
`poly(lactic-co-glycolic acid). The application that issued as the ’499 Patent wasfiled
`
`on March 17, 2005, claiming priority to U.S. Provisional Application No.
`
`60/564,542 (“the Provisional Application”) (Ex. C). Critical to allowance was a
`
`declaration (Ex. D) presented by Patent Owner Alkermes Pharma Ireland Limited
`
`(“Alkermes”) by its sole named inventor, Dr. Ehrich, arguing that the crux of the
`
`invention resides in an “unexpected discovery” made duringclinical trials that a 380
`
`mg naltrexone formulation provided a greater area under the curve (“AUC”) than
`
`resulted from 50 mg/day oral administration. But this alleged “discovery” was
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`nothing new.
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`Naltrexone is an old compoundthat wasfirst investigated in the 1980sto treat
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`substance abuse. (Ex. E at 351-353.) The ability of naltrexone to treat alcoholism
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`was identified by 1986 andreported clinically by 1992. (/d.). As naltrexone therapy
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`commenced in human patients, and non-compliance problems began to arise based
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`on daily dosing requirements, it became clear that long-acting dosage forms could
`
`potentially improve patient outcomes significantly. U/d.). As a result, companies
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`Request for Ex Parte Reexamination of
`U.S. Patent No. 7,919,499
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`began investigating long-acting dosage forms, and in the early 2000s, BioTek
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`developed “Depotrex,” a long-acting naltrexone product
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`including 384 mg of
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`naltrexone in a biocompatible PLGA polymer, dosed once per month—1.e., the same
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`regimenasrecited in the Challenged Claims. A publication describing this Depotrex
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`product, Comer, anticipates the challenge claims, as described herein.
`
`The Challenged Claimsare also anticipated by a publication describing a pilot
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`study evaluating Alkermes’ Vivitrex (the original name for Vivitrol) (“Vivitrex Pilot
`
`Study”) (Ex. G). Although published after the filing date of the ’542 Provisional
`
`Application—1.e., the ’499 Patent’s alleged priority document—the Vivitrex Pilot
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`Study is nonetheless prior art because the Challenged Claims are not adequately
`
`supported or enabled bythe provisional application. “It is elementary patent law that
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`a patent application is entitled to the benefit of the filing date of an earlier filed
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`application only if the disclosure of the earlier application provides support for the
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`claimsof the later application, as required by 35 U.S.C. § 112.” PowerOasis, Inc. v.
`
`T-Mobile USA, Inc., 522 F.3d 1299, 1306 (Fed. Cir. 2008).
`
`Specifically, the °542 Provisional Application omits the critical data necessary
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`to show possession and enablementof the subject matter recited in the Challenged
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`Claims. Challenged claim 1 of the ’499 patent requires a “serum AUCof naltrexone
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`[that]
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`is about
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`three times greater
`
`than that achieved by 50 mg/day oral
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`administration” for a dose containing “about 310 mg to about 480 mgof naltrexone
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`Request for Ex Parte Reexamination of
`U.S. Patent No. 7,919,499
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`and a biocompatible polymer.” But the provisional application (and the ’499 Patent
`
`specification) contains no serum AUC data for a 50 mg/day oral administration,
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`which is essential to compare a long-acting formulation to the 50 mg/day form as
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`required by the claim. (Ex. H at PP 35-36, 42.)
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`The choice of this comparator data is critical. When assessing whether some
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`value X is three times greater than a value Y,it is axiomatic that the value of Y must
`
`be knownto make the assessment. Without Y, the answer is unknowable.
`
`During prosecution, Patent Owner relied on data presented in the Ehrich
`
`declaration, which uses a specific 50 mg/day oral administration for comparator
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`data, i.e. the value of “Y.” But when using other publicly available 50 mg/day
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`comparator data,
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`in other words, different values for “Y,”’ the same Alkermes
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`formulation is no longer “aboutthree times greater,” and, therefore, no longer meets
`
`the claim. (Ex. H at PP 39, 82; Ex. I; Ex. J.) In other words, the choice of “Y” makes
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`all the difference.
`
`Although the Patent Trial and Appeal Board (‘Board’)
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`tangentially
`
`encounteredthis issue before in IPR2018-00943, finding the related claim term was
`
`at least broad enough “to create a reasonable likelihoodthatit reads onthe priorart,”
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`the Office has not yet considered whether the full scope of the claim is properly
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`supported and enabled by the underlying provisional application. (Ex. K at 10-12.)
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`If the Ehrich declaration data is used to limit the claim to specific 50 mg/day
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`Request for Ex Parte Reexamination of
`U.S. Patent No. 7,919,499
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`oral administration data,
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`this limitation is not supported in the provisional
`
`application because the Ehrich declaration wasnotavailable at that time. If, instead,
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`the claims are read more broadly to encompass other 50 mg/day oral administration
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`data, yet again the provisional application (and the ’499 Patent) does not support or
`
`enable the full scope of the Challenged Claims.
`
`In either case, the Vivtrex Pilot Study is priorart.
`
`Finally,
`
`the prior art
`
`in SNQ Grounds
`
`1 and 3 in this Request for
`
`Reexamination were the subject of the prior IPR2018-00943 petition filed by a
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`different party (Amneal Pharmaceuticals LLC) than the Requester here, which the
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`Boardinstituted on all grounds. (Ex. K.) Thus, through instituting that prior petition,
`
`the Board has already determined that there is a reasonable likelihood that SNQ
`
`Grounds 1 and 3 would successfully render the claims unpatentable. See 35 U.S.C.
`
`§314(a). That prior Board decision, which applies a more rigorous standard of
`
`“reasonable likelihood”necessarily establishes that the same grounds would meet
`
`the less rigorous standard required for reexamination whereit is merely required that
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`an examiner would considerthe art “important” in deciding patentability. Alkermes
`
`and the Petitioner in that proceeding settled before the oral hearing was held, and the
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`Board terminated the proceeding on the basis of settlement. (Ex. L) (see Section
`
`V(C) below).)
`
`Below, Requester establishes that the Challenged Claims of the ’499 Patent
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`Request for Ex Parte Reexamination of
`U.S. Patent No. 7,919,499
`
`are unpatentable under 35 U.S.C. §§ 102 and 103 as shown by Comer, the Vivitrex
`
`Pilot Study, and otherart.
`
`Il.
`
`LEGAL STANDARD
`
`In general, a "substantial question of patentability" exists when “there is a
`
`substantial likelihood that a reasonable examiner would considerthe prior art patent
`
`or printed publication important in deciding whetheror not the claim is patentable.”
`
`MPEP § 2242 (emphasis added).
`
`A substantial new question of patentability exists when a reasonable examiner
`
`would consider the prior art relied upon in the request for reexamination to be
`
`“important” and “the same question of patentability” has not already been decided
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`by: (1) a federal court in a final holding of invalidity (after all appeals), or (2) the
`
`Office in an earlier examination,
`
`review,
`
`reexamination, or
`
`supplemental
`
`examination. (/d.)
`
`An SNQ can exist even when some(orall) of the prior art relied upon in the
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`reexamination request was previously before the Office (“old art’): “In a decision to
`
`order reexamination made on or after November 2, 2002, reliance on “old art’ does
`
`not necessarily preclude the existence of a substantial new question of patentability.”
`
`(Id.) Moreover, the MPEP expressly states that a rejection is proper when the
`
`proposedrejection combines “old art” with prior art that was not previously before
`
`the Office. MPEP § 2258.01 (citing In re Hiniker, 150 F.3d 1362, 1362 (Fed. Cir.
`
`Page 12 of 68
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`Request for Ex Parte Reexamination of
`U.S. Patent No. 7,919,499
`
`1998)) (“If the rejection to be made by the examinerwill be based on a combination
`
`of “old art” and art newly cited during the reexamination proceeding, the rejection
`
`is proper, and should be made.” (emphasis added)).
`
`A request only needsto identify an SNQ with respect to one challenged claim
`
`for reexamination to be ordered. (/d.) Furthermore,it is not necessary that a request
`
`for reexamination establish a prima facie case of unpatentability with respect to the
`
`challenged claims. (/d.) A SNQ can exist, “even if the examiner would not
`
`necessarily reject the claim[s] as either fully anticipated by, or obvious in view of
`
`the prior art” applied in a request. (MPEP § 2242 (citing In re Etter, 756 F.2d 852,
`
`857 n.5 (Fed. Cir. 1985))).
`
`Nevertheless, as shownin detail below,the priorart relied upon in eachof the
`
`Grounds presented herein discloses each and every limitation of the Challenged
`
`Claims and thus would be “important in deciding whether or not the claim is
`
`patentable.”
`
`I.
`
`IDENTIFICATION OF THE PATENT AND CLAIMS FOR WHICH
`REEXAMINATION IS REQUESTED
`
`According to 35 U.S.C. § 302 and 37 C.F.R. § 1.510(B)(2), reexamination of
`
`claims 1-13 of the ’499 Patent is requested in view of the prior art references listed
`
`below. These claims may be referred to herein individually, or collectively as the
`
`“Challenged Claims” subject to reexamination.
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`Request for Ex Parte Reexamination of
`U.S. Patent No. 7,919,499
`
`The °499 Patent issued on April 5, 2011, from U.S. Application Serial No.
`
`11/083,167 (“the ’167 Application’), filed on March 17, 2005, and claimsthe benefit
`
`of U.S. Provisional Application No. 60/564,542, filed April 22, 2004. (Ex. C.)
`
`Accordingly, the earliest possible effective filing date for the 499 Patent is April
`
`22, 2004, but as explained at Sections I and V, the challenged claimsare not entitled
`
`to the priority date of the provisional application.
`
`Reexamination of claims 1-13 of the '499 Patent is requested in view of the
`
`
`
`Comer, Sandra D. et al., "Depot Naltrexone: Long-lasting Antagonism
`of the Effects of Heroin in Humans," Psychopharmacology, 159:351-
`360 (2002). (“Comer”) A copy of Comerbearing a library date stamp
`of February 18, 2002, and declaration of the British Library Board are
`provided. Comeris 35 U.S.C. § 102(b) prior art. Comer wasof record
`but was not applied.
`
`U.S. Patent No. 7,157,102 (‘Nuwayser’”). Nuwayser was filed on May
`31, 2002, with a nonpublication request. Nuwayseris prior art under 35
`U.S.C. § 102(e). Nuwayser wasnotof record.
`
`Johnsonetal., “A Pilot Evaluation of the Safety and Tolerability of
`Repeat Dose Administration of Long-Acting Injectable Naltrexone
`(Vivitrex®) in Patients With Alcohol Dependence,” Alcoholism:
`Clinical and Experimental Research, Vol. 28. No. 9, 2004: 1356-1361.
`(“Vivitrex Pilot Study”)
`
`24, 2001. It is prior art under 35 U.S.C. § 102(e). Wright wasofrecord,
`but not discussed during prosecution.
`
`Page 14 of 68
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`14
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`
`
` U.S. Patent No. 6,264,987 (“Wright”). Wright was published on July
`
`following prior art patents and printed publications:
`
`Exhibit
`
`Description
`
` E
`
`Page 14 of 68
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`Request for Ex Parte Reexamination of
`U.S. Patent No. 7,919,499
`
`
`
`
`
`WwW
`
`
`
`Rubio, G.et al. NALTREXONE VERSUS ACAMPROSATE: ONE
`YEAR FOLLOW-UP OF ALCOHOL DEPENDENCE TREATMENT,
`Alcohol and Alcoholism, Volume 36, Issue 5, September 2001, Pages
`419-425 (“Rubio”) A copy of Rubio bearing a library date stamp of
`September28, 2001, is provided. Rubio is 35 U.S.C. § 102(b)priorart.
`Rubio wasnot of record or considered by the Examiner during
`prosecution.
`
`A Form SB-08and copies of the foregoing references are submitted herewith.
`
`Reexamination of the challenged claimsis requested in view of the following
`
`grounds:
`
`
`
`102(b)|1, 3-5, 12
`
`102(a)|1, 3-5, 10-12|Vivitrex Pilot Study
`
`
`= 103(a) meComerinviewofNuwayser,Rubio,and
`
`103(a)|1-13 Vivitrex Pilot Study in view of Comer,
`
`Rubio, and Wright.
`
`
`Wright
`
`IV.
`
`STATEMENT POINTING OUT EACH SUBSTANTIAL NEW
`QUESTION OF PATENTABILITY
`
`For claims 1, 3-5, and 12 this Request presents a substantial new question of
`
`patentability based on anticipation under 35 U.S.C. § 102(b) over Comer, as
`
`evidenced by Nuwayser (“SNQ 1”). Comer describes each element claimed,
`
`including the allegedly unexpected AUC. Nuwayser supports what a person of
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`Request for Ex Parte Reexamination of
`U.S. Patent No. 7,919,499
`
`ordinary skill in the art (“POSA”) would understand from Comer’s reference to
`
`“Depotrex.”
`
`Asset forth in greater detail below, this Request presents a second substantial
`
`new question of patentability because the Vivitrex Pilot Study (“SNQ 2”) anticipates
`
`claims 1, 3-5, and 10-12 under 35 U.S.C. § 102(a). The Vivitrex Pilot Study similarly
`
`describes each element claimed. Additionally, the Vivitrex Pilot Studyis priorart to
`
`the ’499 Patent becausethe patentis notentitled to the priority date of the provisional
`
`application. The Vivitrex Pilot Study describes each element claimed and would
`
`have anticipated the claims for the same reasons as Comer.
`
`Furthermore, combinations of the primary references with secondary priorart
`
`references render claims of the ’499 Patent obvious. This Request presents a third
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`substantial new question of patentability of claims 1-13 based on obviousness under
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`35 U.S.C. § 103 over Comer in view of Nuwayser, Rubio, and Wright (“SNQ 3”).
`
`This Request presents a fourth substantial new question of patentability of claims 1-
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`13 based on obviousness over The Vivitrex Pilot Study in view of Comer, Rubio,
`
`and Wright (“SNQ 4’). The addition of Rubio and Wright to each of these SNQs
`
`establish that the dependent claims not challenged as being anticipated would have
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`been obvious.
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`Requester submits that the prior art references raise a new “substantial
`
`question of patentability” because “the teaching of the (prior art) patents and printed
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`Request for Ex Parte Reexamination of
`U.S. Patent No. 7,919,499
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`publications is such that a reasonable examiner would consider the teaching to be
`
`important in deciding whether or not the claim is patentable.” MPEP § 2242. As
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`noted above, the Board in a prior IPR has already concluded that SNQ Grounds 1
`
`and 3 are reasonably likely to render the claims unpatentable. Those same grounds
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`here, in a reexamination context, would thus meet the lessened standard of being
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`“important” in determining patentability.
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`Further, the additional grounds and references, discussed in further detail
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`below, when considered independently (Vivitrex Pilot Study) or as a combination in
`
`view of their shared disclosures, teach each limitation of the claims. The Vivitrex
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`Pilot Study disclosesall limitations of the independent claim. Additionally, it would
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`have been obviousto adjust the naltrexone dose in the Vivitrex Pilot Study (400 mg)
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`to the dose used in Comer (384 mg) to arrive at yet another long-acting naltrexone
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`formulation that produces the claimed AUC differential. The dependent claims are
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`obvious based on the combination with Rubio and Wrightas detailed further below.
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`Further, these prior art references are new because the “same question of
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`patentability as to the claim has not been decided by the Office in an earlier
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`concluded examination or review of the patent.”
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`(/d.) Although some of the
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`references(i.e., Comer and Wright) are of record, they were either not considered or
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`not discussed by the Examiner during prosecution. On the other hand, neither
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`Vivitrex Pilot Study, Rubio nor Nuwayser were raised, considered, or formed the
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`Request for Ex Parte Reexamination of
`U.S. Patent No. 7,919,499
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`basis of a rejection during the original prosecution of the ’499 Patent.
`
`This Request provides the detailed mapping and explanation regarding the
`
`combination of references and raises a SNQ because the Office hasn’t previously
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`considered the teaching of the combinations of references in SNQ 1, SNQ 2, SNQ
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`3, or SNQ 4.
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`While Requester is not providing a separate declaration by an expert, given
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`the overlapping grounds and positions presented herein, Requester cites to
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`supportive testimony in the Park Declaration of April 19, 2018, from a prior IPR
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`Petition in IPR2018-00943. (Ex. H.)
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`V.
`
`OVERVIEW OF THE °499 PATENT AND RELEVANT
`PROSECUTION HISTORY
`
`A.
`
`Overview of the ’499 Patent
`
`The °499 Patent issued on April 5, 2011, from U.S. Application Serial No.
`
`11/083,167 (“the ’167 Application’), filed on March 17, 2005, and claimsthe benefit
`
`of U.S. Provisional Application No. 60/564,542, filed April 22, 2004. Accordingly,
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`the earliest possible effective filing date for the ’499 Patent is April 22, 2004, but as
`
`explained herein, the challenged claims are not entitled to the priority date of the
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`provisional application.!
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`The ’499 Patent purports to describe a methodoftreating an individual in need
`
`' Title 35 as it existed before adoption of the AIA is applicable here.
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`Request for Ex Parte Reexamination of
`U.S. Patent No. 7,919,499
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`of naltrexone by parenterally administering a long-acting formulation that includes
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`310-480 mg of naltrexone and PLGAto the individual, where the serum AUC of
`
`naltrexone is about three times greater than what is achieved by administration of 50
`
`mg/day oral administration. (Ex. A at 1:30-46.)
`
`The ’499 Patent alleges that the “inventions described herein arose from
`
`unexpected discoveries made during clinical trials with a long-acting formulation of
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`naltrexone.” (Ex. A at Abstract, 1:31-33; Ex. H at P 15.) It provides no direct data
`
`for the AUC ofany claimed formulation or the comparator—50 mg/day oral dosing.
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`(Ex. A at 18:10-12; Ex. H at P 35.) Nor does it discuss the duration under which the
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`comparison should be made—one day, one week, one month, or something else.
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`During prosecution, comparisons were made using data from an Alkermes’ study
`
`referenced in the ’499 Patent and from Tice (Ex. M), but such comparisons were
`
`limited to a single duration, which is not includedin the claims. In any event, none
`
`of this data could be determined from the patent or priority documentitself.
`
`The specification discusses the need for improving naltrexone therapies,
`
`based on patient compliance. (Ex. A at 1:13-26, 17:24-29; Ex. H at J 16.) In some
`
`embodiments,
`
`the naltrexone is combined with well-known polymers, such as
`
`PLGA,
`
`to “entrap or encapsulate” the naltrexone and provide a long-acting
`
`formulation. (Ex. A at 3:14-15; Ex. H at J 17.)
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`The specification describes
`
`its
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`long-acting formulations
`
`as_
`
`releasing
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`Request for Ex Parte Reexamination of
`U.S. Patent No. 7,919,499
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`naltrexone over a period of at least one week. (Ex. A at 3:59-64, 4:42-44.) It then
`
`describes “Vivitrex” as a monthly administration that releases naltrexone for four
`
`weeks, and that the therapy can be maintained for 24 weeks or more. (/d. 4:54-64.).
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`Five examples are included, three of which (Examples 3-5) were not present
`
`in the provisional application. (Compare Ex. A (499 Patent) and Ex. C (Provisional
`
`Application).) Example 1 describes how to manufacture Vivitrex formulations. The
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`microparticles portion of this example is virtually identical to the preparation
`
`described in Example 3 of Wright. (Compare Ex. A, 3:3-33, 5:35-8:2 and Ex. N,
`
`7:50-8:60; Ex. H at P 18.) The remaining examples describe various aspects of a
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`clinical trial and meta-analysis. Example 2 describes screening, eligibility, and
`
`adverse events.
`
`(Ex. A at 8:5-18:2.) Newly added Example 3 compares the
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`“efficacy” of oral versus injectable naltrexone but clearly states that ‘“‘a direct head-
`
`to-head comparison of efficacy has not been studied” and thus “a definitive
`
`comparison of efficacy between Vivitrex and oral naltrexone cannot be made.” (Ex.
`
`A at 18:10-12; Ex. H at PP 19, 61.)
`
`Instead, the specification admits to using data
`
`from three nonrelated studies for a “‘semi-quantitative” comparison that resulted in
`
`efficacy that “compares favorably with oral naltrexone.” “Favorably”in this context
`
`would be understood by a POSA to mean comparable or equivalent to, as the °499
`
`Patent’s data would not establish improvedefficacy to a POSA.(Ex. H at {J 16, 61;
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`Ex. A at 18:12-29, 19:30-33.) Finally, newly added Examples 4 and 5 are directed
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`Request for Ex Parte Reexamination of
`U.S. Patent No. 7,919,499
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`to “quality of life’ and “durability of effect and tolerability” of long-acting
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`naltrexone formulations.
`
`B.—_Relevant Prosecution History of the ’499 Patent
`
`The ’499 Patent wasfiled with a request for prioritized examination under 37
`
`C.F.R. § 1.102(e) on March 17, 2005, as the ’167 Application. On September5,
`
`2007, Alkermes filed a preliminary amendment, which merely canceled original
`
`claims 24 and 25. A restriction requirement was mailed on February 20, 2009, and
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`Alkermes responded on March 20, 2009, electing Group 1, i.e., claims 1, 2, and 6-
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`23, with traverse.
`
`A nonfinal rejection was mailed on May 5, 2009 (Ex. O), which rejected the
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`claimsas allegedly being anticipated by Tice and,in the alternative, as being obvious
`
`over the combination of Tice and Chandrashekar. Alkermes responded on October
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`5, 2009 (Ex. P), with claim amendments and a declaration under 37 C.F.R. § 1.132
`
`by Elliot Ehrich (the “Ehrich Declaration” (Ex. D)), the sole inventor of the ’499
`
`Patent. The Ehrich Declaration argued that Tice used polylactic acid (“PLA’’), not
`
`PLGA,and that the AUC of Tice’s formulation was about the same as that of 50
`
`mg/dayoral dosing. In contrast, the claimed invention allegedly resulted in 3.3 times
`
`the oral AUC. Alkermesalso argued the existence of this AUC differential using its
`
`ownoral data from a clinical trial, not information from the patent specification. (Ex.
`
`H atPP 23, 63, 72-74.)
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`Request for Ex Parte Reexamination of
`U.S. Patent No. 7,919,499
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`The Examiner issued a second office action on January 6, 2010, which
`
`withdrewthe anticipation and obviousnessrejections over Tice in view of the Ehrich
`
`Declaration but nevertheless rejected the claims for lack of enablement. (Ex. Q.)
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`Alkermes responded on April 5, 2010, by amending the claims to require a
`
`biocompatible polymer. (Ex. R.) A final rejection was mailed on July 20, 2010,
`
`maintaining the enablementrejection. (Ex. S.) Alkermes filed a response after final
`
`on October 20, 2010, amending the claims further to require that the biocompatible
`
`polymer be PLGA.(Ex. T; Ex. H at P 23.)
`
`A Notice of Allowance was mailed on December
`
`1, 2010, which
`
`acknowledged a telephone interview of November19, 2010, where Alkermesagreed
`
`to an Examiner’s Amendmentto insert certain language into the claims, e.g., “about
`
`310 mg to about 480 mg”into claim 1. (Ex. U.) The Examineralso included reasons
`
`for allowance. According to the Examiner, Tice wasthe closestprior art and reported
`
`that its injectable formulation was comparable to taking 50 mg tablets orally. (/d.)
`
`But, as discussed below,Tice is not the closest prior art. (Ex. H at P 24.)
`
`C.
`
`Prior IPR Proceeding
`
`On April 20, 2018, Amneal Pharmaceuticals LLC (“Amneal”) filed and
`
`served an IPR petition against Alkermes Pharma Ireland Limited (“Alkermes’’)
`
`regarding U.S. Patent No. 7,919,499 (IPR2018-00943 (“the *943 IPR’’)). Finding
`
`that Petitioner had had demonstrated a reasonable likelihood of success in proving
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`Request for Ex Parte Reexamination of
`U.S. Patent No. 7,919,499
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`at least one claim of the ‘499 patent was unpatentable and to that end that the
`
`elements of the claims were taughtbythepriorart, the Board instituted the ‘943 IPR
`
`on November7, 2018. (Ex. K at 2.)
`
`Amneal’s “943 IPR petition identified six grounds that purported to renderthe
`
`claims of the *499 patent unpatentable as anticipated or obvious in view of the cited
`
`references. Amnealalleged that the *499 patentis anticipated. Specifically, the 943
`
`IPR identified claims 1, 3-5, and 10-12 as anticipated by Comer, as evidenced by
`
`Nuwayser and additionally identified claims 1, 3-5,