`
`Case IPR2018-00943
`Patent No. 7,919,499
`Petition for Inter Partes Review
`Attorney Docket No. AMNEAL 7.1R-005
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________________
`
`AMNEAL PHARMACEUTICALS LLC,
`Petitioner,
`
`v.
`
`ALKERMES PHARMA IRELAND LIMITED,
`
`Patent Owner.
`
`Patent No. 7,919,499 to Elliot Ehrich
`Issue Date: May 19, 2015
`Title: NALTREXONE LONG ACTING
`FORMULATIONS AND METHODS OF USE
`____________________________
`Inter Partes Review No. IPR2018-00943
`____________________________
`
`PETITION FOR INTER PARTES
`REVIEW OF U.S. PATENT NO. 7,919,499
`
`
`
`
`
`5413465_1.docx
`
`

`

`
`Case IPR2018-00943 (Patent No. 7,919,499)
`Petition for Inter Partes Review
`
`
`TABLE OF CONTENTS
`
`Page
`
`TABLE OF AUTHORITIES ................................................................................... iii
`PETITIONER’S EXHIBIT LIST ............................................................................ vi
`OVERVIEW .................................................................................................... 1
`I.
`II.
`IDENTIFICATION OF THE CLAIMS
`BEING CHALLENGE (37 C.F.R. § 104(B)) ................................................. 4
`SUMMARY OF THE ARGUMENT .............................................................. 4
`III.
`IV. SUMMARY OF THE ’499 PATENT ............................................................. 6
`V.
`PERTINENT PROSECUTION
`HISTORY OF THE ’499 PATENT ................................................................ 9
`VI. TECHNICAL BACKGROUND
`AND STATE OF THE ART .........................................................................10
`VII. PERSON OF SKILL IN THE ART ..............................................................15
`VIII. CLAIM CONSTRUCTION ..........................................................................16
`A. “a long acting formulation” ....................................................................16
`B. “the serum AUC of naltrexone…than
`that achieved by 50 mg/day oral administration” ...................................17
`C. “about three” ...........................................................................................19
`D. “five or more days” .................................................................................19
`E. “initial oral dose” ....................................................................................20
`F. “about 35% by weight” ...........................................................................21
`IX. CLAIMS 1, 3-5, AND 10-12 ARE ANTICIPATED ....................................21
`A. Legal Background ...................................................................................21
`
`i
`
`

`

`
`Case IPR2018-00943 (Patent No. 7,919,499)
`Petition for Inter Partes Review
`
`
`X.
`
`B. Ground 1: Comer Teaches Every
`Element Of Claims 1, 3-5, And 10-12 ....................................................22
`C. Ground 2: Nuwayser Teaches Every
`Element Of Claims 1, 3-5, 11, And 12 ...................................................26
`THE CHALLENGED CLAIMS ARE OBVIOUS .......................................28
`A. Legal Background ...................................................................................28
`B. Ground 3: The Challenged Claims Are Obvious
`Over Comer In View Of Nuwayser, Rubio, And Wright .......................29
`C. Ground 4: The Challenged Claims Are Obvious
`Over Nuwayser In View Of Comer, Rubio, And Wright .......................36
`D. Ground 5: The Challenged Claims Are Obvious
`Over Nuwayser In View Of Kranzler, Rubio, And Wright ....................39
`E. Ground 6: The Challenged Claims Are Obvious
`Over Alkermes’ 10-K In View Of The Vivitrex
`Specimen, Rubio, And Wright ................................................................44
`XI. CLAIMS CHART ..........................................................................................51
`XII. SECONDARY CONSIDERATIONS ...........................................................57
`XIII. CONCLUSION ..............................................................................................60
`XIV. STATEMENT OF PRECISE RELIEF
`REQUESTED (37 C.F.R. § 42.22(A)) ..........................................................61
`XV. MANDATORY DISCLOSURES (37 C.F.R. § 42.8(a)(1)) ..........................61
`A. Notice Of Each Real Party-In-Interest (37 C.F.R. § 42.8(b)(1)) ............61
`B. Notice Of Related Matters (37 C.F.R. § 42.8(b)(2)) ..............................61
`C. Designation Of Lead And Backup
`Counsel (37 C.F.R. § 42.8(b)(3)) ............................................................61
`D. Notice Of Service Information (37 C.F.R. § 42.8(b)(4)) ........................62
`E. Grounds For Standing (37 C.F.R. § 42.104(a)) ......................................62
`
`ii
`
`

`

`
`Case IPR2018-00943 (Patent No. 7,919,499)
`Petition for Inter Partes Review
`
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`CASES
`Alcon Research, LTD. v. Apotex Inc.,
`687 F.3d 1362 (Fed. Cir. 2012) ......................................................................... 28
`In re Aller,
`220 F.2d 454, 456 (C.C.P.A. 1955) ........................................................................ 28
`Asyst Techs., Inc. v. Emtrak, Inc.,
`544 F.3d 1310 (Fed. Cir. 2008) ......................................................................... 59
`Atlas Powder Co. v. IRECO Inc.,
`190 F.3d 1342 (Fed. Cir. 1999) ......................................................................... 21
`Baxter Travenol Labs,
`952 F.2d 388 (Fed. Cir. 1991) ........................................................................... 23
`Cuozzo Speed Techs., L.L.C. v. Lee,
`136 S. Ct. 2131 (2016) ...................................................................................... 16
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) ........................................................................... 59
`Hoffmann La. Roche, Inc. v. Apotex Inc.,
`748 F.3d 1326 (Fed. Cir. 2014) ......................................................................... 58
`In re Geisler,
`116 F.3d 1465 (Fed. Cir. 1997) ......................................................................... 29
`In re Harris,
`409 F.3d 1339 (Fed. Cir. 2005) ......................................................................... 59
`J.T. Eaton & Co. v. Atl. Paste & Glue Co. ,
`106 F.3d 1563 (Fed. Cir. 1997) ......................................................................... 59
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) .................................................................................... 28, 29
`Merck & Co. v. Teva Pharms. USA, Inc. ,
`395 F.3d 1364 (Fed. Cir. 2005) ......................................................................... 60
`
`iii
`
`

`

`
`Case IPR2018-00943 (Patent No. 7,919,499)
`Petition for Inter Partes Review
`
`Mintz v. Dietz & Watson, Inc. ,
`679 F.3d 1372 (Fed. Cir. 2012) ......................................................................... 15
`Newell Cos. v. Kenney Mfg. Co.,
`864 F.2d 757 (Fed. Cir. 1988) ........................................................................... 58
`Ohio Willow Wood Co. v. Alps S., L.L.C.,
`735 F.3d 1333 (Fed. Cir. 2013) ......................................................................... 58
`Par Pharm., Inc. v. TWi Pharms., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) ......................................................................... 28
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) ......................................................................... 58
`Sakraida v. Ag Pro, Inc.,
`425 U.S. 273 (1976) .......................................................................................... 29
`Santarus, Inc. v. Par Pharm., Inc.,
`694 F.3d 1344 (Fed. Cir. 2012) ........................................................................... 3
`Schering Corp. v. Geneva Pharms., Inc.,
`339 F.3d 1373 (Fed. Cir. 2003) ......................................................................... 21
`Steadymed Ltd. v. United Therapeutics Corp.,
`IPR2016-00006, Paper 82, Final Written Decision (Mar. 31, 2017), ................. 58
`In re Soni,
`54 F.3d 746 (Fed. Cir. 1995) ............................................................................. 58
`Titanium Metals Corp. v. Banner,
`778 F.2d 775 (Fed. Cir. 1985) ........................................................................... 29
`Verdegaal Bros. v. Union Oil Co.,
`814 F.2d 628, 2 U.S.P.Q.2d (BNA) (Fed. Cir. Mar. 12, 1987) ......................... 21
`In re Wertheim, ,
`541 F.2d 257 (C.C.P.A. 1976) ............................................................................ 29
`
`STATUTES, RULES & OTHER AUTHORITIES
`
`35 U.S.C. § 103 ....................................................................................................... 28
`
`iv
`
`

`

`
`Case IPR2018-00943 (Patent No. 7,919,499)
`Petition for Inter Partes Review
`
`37 C.F.R. § 42.100(b) ............................................................................................. 16
`
`MPEP § 2131.01 [I], [II] .......................................................................................... 23
`
`
`
`v
`
`

`

`
`Case IPR2018-00943 (Patent No. 7,919,499)
`Petition for Inter Partes Review
`
`
`
`
`PETITIONER’S EXHIBIT LIST
`
`1004
`
`1005
`1006
`
`1007
`1008
`
`1009
`1010
`
`Exhibit # Reference
`U.S. Patent No. 7,919,499 (“the ’499 Patent”)
`1001
`1002
`U.S. Serial Number 11/083,167, Office Action, May 5, 2009
`1003
`Serial No. 11/083,167, Declaration Under 37 C.F.R. § 1.132 of Elliot
`Ehrich (undated)
`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
`Sandra D. Comer et al., Depot naltrexone: long-lasting antagonism
`of the effects of heroin in humans, 159(4) Psychopharmacology
`(Feb. 2002), at 351-360
`Henry R. Kranzler et al., Sustained-Release Naltrexone for
`Alcoholism Treatment: A Preliminary Study, 22(5) Alcoholism:
`Clinical and Experimental Research (Aug. 1998), at 1074-79
`C.N. Chiang et al., Clinical Evaluation of A Naltrexone
`Sustained-Release Preparation, 16 Drug & Alcohol Dependence
`(1985), at 1-8
`T.N. Alim et al., Tolerability Study of A Depot Form of Naltrexone
`Substance Abusers, Problems of Drug Dependence,
`1994: Proceedings of the 56th Annual Scientific Meeting, The
`College on Problems of Drug Dependence, Inc., Vol. II: Abstracts,
`National Institute on Drug Abuse Research Monograph 153 (1995),
`at 253
`U.S. Patent No. 7,157,102 (“the ’102 Patent” or “Nuwayser”)
`U.S. Patent No. 6,306,425 (“Tice”)
`U.S. Securities and Exchange Commission, FORM 10-K, Annual
`Report Pursuant to Section 13 or 15(d) of the Securities Exchange
`Act of 1934 for the fiscal year ended March 31, 2002. Alkermes, Inc.
`(July 2002)
`
`1014
`1015
`1016
`
`1011
`
`1012
`
`1013
`
`vi
`
`

`

`
`Case IPR2018-00943 (Patent No. 7,919,499)
`Petition for Inter Partes Review
`
`
`1018
`1019
`
`Exhibit # Reference
`U.S. Trademark Application Serial Number 76/271,990, Allegation
`1017
`of Use of a Mark & specimen of the mark as used in commerce,
`Aug. 15, 2002 (“Vivitrex Specimen” or “Specimen”)
`U.S. Patent No. 6,264,987 (“the ’987 Patent” or “Wright”)
`S.J. Heishman et al., Safety And Pharmacokinetics of a New
`Formulation of Depot Naltrexone, Problems of Drug Dependence,
`1993: Proceedings of the 55th Annual Scientific Meeting, The
`College on Problems of Drug Dependence, Inc.,
`Volume II: Abstracts, National Institute on Drug Abuse Research
`Monograph 141 (1994)
`U.S. Patent and Trademark Office, 1265(2) Official Gazette of the
`United States Patent and Trademark Office, Trademarks, Dec. 10,
`2002
`Intentionally Left Blank
`Stewart B. Leavitt, PhD, ed., Evidence for the Efficacy of Naltrexone
`in the Treatment of Alcohol Dependence (Alcoholism), Addition
`Treatment Forum Naltrexone Clinical Update (2002 Clinco
`Communications, Inc.), at 1-8
`ReVia, Physicians’ Desk Reference 936-938 (53rd ed. 1999)
`(“PDR”)
`U.S. Patent No. 4,882,335 (“Sinclair”)
`Chiang et al., Kinetics of a naltrexone sustained-release preparation,
`36(5) Clin. Pharmacol. Ther. (Nov. 1984), at 704-08 “Kinetic of a
`naltrexone sustained-release preparation.”
`Reuning et al., Pharmacokinetic Quantitation of Naltrexone
`Release From Several Sustained-Release Delivery Systems,
`Naltrexone: Research Monograph 28 (R. E. Willette and G. Barnett,
`eds. National Institute on Drug Abuse 1980)
`Appeal Brief, Application No. 13/871,534, Oct. 19, 2015
`G. Rubio et al., Naltrexone Versus Acamprosate: One Year
`Follow-Up of Alcohol Dependence Treatment, 36(5) Alcohol &
`Alcoholism (2001), at 419-425
`Intentionally Left Blank
`Declaration of Kinam Park Ph.D in Support of Inter Partes Review
`of U.S. Patent No. 7,919,499
`Curriculum Vita of Kinam Park
`
`1020
`
`1021
`1022
`
`1023
`
`1024
`1025
`
`1026
`
`1027
`1028
`
`1029
`1030
`
`1031
`
`vii
`
`

`

`
`Case IPR2018-00943 (Patent No. 7,919,499)
`Petition for Inter Partes Review
`
`
`1034
`
`1035
`
`1036
`
`1037
`
`Exhibit # Reference
`U.S. Provisional Application No. 60/564,542
`1032
`1033 Manit Srisurapanont & Ngamwong Jarusuraisin, Naltrexone for the
`treatment of alcoholism: a meta-analysis of randomized controlled
`trials, 8 Int’l J. of Neuropsychopharmacology (2005), at 267-280
`Bouza Carmen et al., Efficacy and safety of naltrexone and
`acamprosate in the treatment of alcohol dependence: a systematic
`review, 99(7) Addiction (July 2004), at 811-828
`J.S. Hopkins et al., Naltrexone and Acamprosate Meta-Anaylsis of
`Two Medical Treatments for Alcoholism, 26(5) Alcoholism Clinical
`and Experimental Research, 2002 Scientific Meeting of the Research
`Society on Alcoholism and the 11th Congress of the Int’l Society for
`Biomedical Research on Alcoholism, June 28-July 3, 2002, San
`Francisco, California (Suppl. May 2002)
`Orange Book: Approved Drug Products with Therapeutic
`Equivalence Evaluations, Product Details for NDA 018932, REVIA
`(NALTREXONE HYDROCHLORIDE) 50MG
`Bioequivalence, Center for Drug Evaluation and Research,
`Application Number: 75-434, Naltrexone Hydrochloride Tablets,
`Eon Labs Manufacturing, Inc., at 1-8
`Synopsis, Naltrexone HCl, ALZA Corporation (Nov. 3, 2003)
`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. (2006), at 69-74
`TREXAN™, Physicians’ Desk Reference 936-938 (46 ed. 1992)
`(“PDR”), at 937-939
`Trademark Manual of Examining Procedure (TMEP) (3rd ed. Jan.
`2002), at 100-5 to 100-11
`Orange Book: Approved Drug Products with Therapeutic
`Equivalence Evaluations, NALTREXONE (VIVITROL) FOR
`SUSPENSION, EXTENDED RELEASE 380MG/VIAL
`General Notices and Requirements, USP 32/NF 27 (2009) at 8
`Bertil Abrahamsson and Anna-Lena Ungell, Biopharmaceutical
`support in formulation development:A Practical Guide from
`Candidate Drug Selection to Commercial Dosage Form,
`Pharmaceutical Preformulation and Formulation (Mark Gibson ed.,
`Interpharm/CRC) (2004), 239-291, at 262
`
`1043
`1044
`
`1038
`1039
`
`1040
`
`1041
`
`1042
`
`viii
`
`

`

`
`Case IPR2018-00943 (Patent No. 7,919,499)
`Petition for Inter Partes Review
`
`
`1046
`
`1047
`
`1048
`1049
`
`Exhibit # Reference
`Guidance for Industry. Bioavailability and Bioequivalence Studies
`1045
`for Orally Administered Products—General Considerations. FDA
`CDER (March 2003)
`Riddle et al., Anxiolytics, adrenergic agents, and naltrexone, 38(5) J.
`Am. Acad. Child. Adolesc. Psychiatry, 546-556 (May 1999)
`Food and Drug Administration, FDA PSYCHOPHARMACOLOGIC
`DRUGS ADVISORY COMMITTEE MEETING VIVITROL®
`(naltrexone for extended-release injectable suspension),
`NDA 21-897 (Sept. 16 2010)
`Intentionally Left Blank
`Rothenberg et al., Behavioral naltrexone therapy: an integrated
`treatment for opiate dependence, 23 J. of Substance Abuse
`Treatment (2002), at 351-360
`B.A. Johnson, Naltrexone long-acting formulation in the treatment of
`alcohol dependence, 3(5) Ther. Clin. Risk Manag., 741-749 (2007),
`at 742.
`Food and Drug Administration, Guidance for Industry,
`Exposure-response relationships – study design, data analysis, and
`regulatory applications, FDA CDER (April 2003)
`Food and Drug Administration, Guidance for Industry, Statistical
`approaches to establishing bioequivalence, FDA CDER (April 2003)
`Schenker et al., Antecedent liver disease and drug toxicity, 31 J. of
`Hepatology 1098-1105 (1999)
`Résumé of Mike Ramstack, as obtained from LinkedIn
`Résumé of Richard Reuning, as obtained from LinkedIn
`Résumé of Steve Wright, as obtained from LinkedIn
`U.S. Patent No. 3,332,950
`Filing Details for Alkermes Inc. 10-K dated July 1, 2002 from the
`Security and Exchange Commission’s EDGAR Online Filing System
`1059 WayBack Machine capture of Security and Exchange Commission’s
`Information Page regarding the Electronic Data Gathering, Analysis,
`and Retrieval System (EDGAR), June 6, 2002
`1060 WayBack Machine capture of Security and Exchange Commission’s
`Regulatory Overview of the Electronic Data Gathering, Analysis, and
`Retrieval System (EDGAR), June 6, 2002
`
`1054
`1055
`1056
`1057
`1058
`
`1050
`
`1051
`
`1052
`
`1053
`
`ix
`
`

`

` Patent No. 7,919,499
`
`
`
`
`
`
`Case IPR2018-
`Petition for Inter Partes Review Attorney Docket No. AMNEAL 7.1R-005
`
`Pursuant
`
`to 35 U.S.C. §§ 311-319 and 37 C.F.R. § 42, Amneal
`
`
`
`Pharmaceuticals LLC (“Amneal” or “Petitioner”) petitions for Inter Partes Review
`
`(“IPR”) seeking cancellation of claims 1-13 (“the challenged claims”) of U.S.
`
`Patent No. 7,919,499 (“the ’499 Patent”) (Ex. 1001). The Statement of Precise
`
`Relief Requested and Mandatory Notices follow the Conclusion of this Petition.
`
`I.
`
`OVERVIEW
`The ’499 Patent claims a method of treating alcoholics, among others, using
`
`310-480 mg of parenterally-administered naltrexone in a long-acting formulation
`
`comprising the biocompatible polymer polylactide-co-glycolide (“PLGA”), also
`
`known as poly(lactic-co-glycolic acid). According to Patent Owner Alkermes
`
`Pharma Ireland Limited (“Alkermes”), the alleged invention resides in an
`
`“unexpected discovery” made during clinical trials that its 380 mg naltrexone
`
`formulation provided a greater area under the curve (“AUC”) than resulted from
`
`50 mg/day oral administration. (Exs. 1001 Abstract, 1:31-33; 21:6-7; 1003, at 1.)
`
`In reality, Alkermes’ AUC “discovery” argument is flawed, inconsequential,
`
`and irrelevant. It is flawed because comparisons made to oral naltrexone
`
`treatments, and even those made during prosecution to the depot injection
`
`formulation of Tice (Ex. 1015), are not comparisons to the closest prior art. The
`
`closest prior art actually includes identical PLGA formulations containing about
`
`380 mg of naltrexone, administered in monthly depot injections.
`
`
`
`

`

`Case IPR2018-00943 (Patent No. 7,919,499)
`Petition for Inter Partes Review
`
`
`The “discovery” is inconsequential because it is not linked to any
`
`meaningful improvement in therapeutic efficacy. Alkermes had ample motive and
`
`opportunity to establish superior efficacy, if it could, but chose not to do so.
`
`Perhaps that is because the preponderance of the evidence, in fact, suggests that
`
`any way of maintaining therapeutic blood levels of naltrexone of at least 1 ng/ml
`
`will be effective. And 50 mg/day oral administration did just that. Whether that
`
`AUC is a fraction of that resulting from some other dose or protocol, or multiples
`
`of it, is quite beside the point.
`
`Finally Alkermes’ “discovery” is irrelevant. Alkermes acknowledges that
`
`pharmacokinetic results are dose dependent in this system. The claimed dose
`
`(about 380 mg), delivered from a PLGA depot injection, over the same time
`
`period, was known. The resulting AUC, a pharmacokinetic property, must
`
`therefore be the same as, or sufficiently similar to the AUC of the claimed
`
`formulation so as to render it unpatentable. The same is true for any AUC
`
`differential between depot injection and oral dosing.
`
`This assumes, however, that the same oral data is used for the comparison.
`
`Alkermes presented no data in its specification, either for the AUC of its protocol
`
`or for 50 mg/daily oral dosing, making the analysis of any AUC differential a
`
`moving target. Using some, but not all, available oral data will result in the claimed
`
`AUC differential. Alkermes also never explained that no matter what the AUC
`
`2
`
`

`

`Case IPR2018-00943 (Patent No. 7,919,499)
`Petition for Inter Partes Review
`
`differential is, there is no established meaningful effect on performance—whether
`
`AUC was equal to that of oral, or 50 times greater. Because AUC is dependent on
`
`dose, as Alkermes admitted, and the art dosed the same amount of the same drug
`
`from the same vehicle on the same protocol, it must result in the same or at least
`
`highly similar AUCs and differentials. The resulting AUC of its parenteral
`
`formulation compared to some other protocol might be interesting, but it is
`
`certainly not a credible reason to grant a patent. As the Federal Circuit has
`
`previously held in similar circumstances, “an obvious formulation cannot become
`
`nonobvious simply by administering it to a patient and claiming the resulting
`
`serum concentrations.” Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344, 1354
`
`(Fed. Cir. 2012). The same should be true of the otherwise known method claimed
`
`here.
`
`Admittedly, the discovery of a new property of any known or obvious
`
`product can be the basis of patentability when a new method results from that
`
`discovery. But here the method merely resulted in the discovery; the discovery did
`
`not lead to some unobvious change in a method. The claimed method is not new or
`
`unobvious.
`
`3
`
`

`

`Case IPR2018-00943 (Patent No. 7,919,499)
`Petition for Inter Partes Review
`
`II.
`
`IDENTIFICATION OF THE CLAIMS
`BEING CHALLENGE (37 C.F.R. § 104(b))
`The Board should find the challenged claims unpatentable on the following
`
`grounds:
`
`Ground
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`35 U.S.C.
`102(b)
`
`102(b)
`
`103(a)
`
`103(a)
`
`103(a)
`
`103(a)
`
`Claims
`1, 3-5, 10-12
`
`1, 3-5, 11, 12
`
`All challenged
`claims
`
`All challenged
`claims
`
`All challenged
`claims
`
`All challenged
`claims
`
`References
`Comer
`
`Nuwayser
`
`Comer in view of
`Nuwayser, Rubio,
`and Wright
`Nuwayser in view
`of Comer, Rubio,
`and Wright
`Nuwayser in view
`of Kranzler, Rubio,
`and Wright
`Alkermes’ 10-K in
`view of the
`Vivitrex Specimen
`Wright, and Rubio
`
`A copy of each reference is filed herewith. The grounds for unpatentability
`
`are supported by the Declaration of Kinam Park, Ph.D. (Exs. 1030; 1031.)
`
`III. SUMMARY OF THE ARGUMENT
`First, claims 1, 3-5, and 10-12 are anticipated by Comer (Ex. 1010), as
`
`evidenced by Nuwayser (Ex. 1014) (Ground 1). Comer describes each element
`
`claimed, including the allegedly unexpected AUC. Nuwayser evidences what a
`
`POSA would understand from Comer’s reference to “Depotrex.”
`
`4
`
`

`

`Case IPR2018-00943 (Patent No. 7,919,499)
`Petition for Inter Partes Review
`
`
`Second, claims 1, 3-5, and 11-12 are anticipated by Nuwayser (Ground 2),
`
`which similarly describes each element claimed and discloses the claimed dose to a
`
`POSA by integration of the blood level plot in Figure 7.
`
`Next, all of the challenged claims are obvious over Comer in view of
`
`Nuwayser, Rubio (Ex. 1028), and Wright (Ex. 1018) (Ground 3); and Nuwayser in
`
`view of Comer, Rubio, and Wright (Ground 4). Comer does not discuss the
`
`specifics of the Depotrex formulation used. But a POSA interested in Depotrex
`
`would find Nuwayser, which describes it fully. Taken from the opposite direction,
`
`Nuwayser identifies a naltrexone/PLGA depot injection formulation, a treatment
`
`protocol, and the pharmacokinetic plot that results from its administration.
`
`Nuwayser is not explicit as to the dose providing that plot. But in seeking to
`
`determine that dose, a POSA would find Comer, which used the same protocol,
`
`resulting in an identical plasma level plot, and used about 380 mg of Depotrex to
`
`do so.
`
`The challenged claims are also obvious in view of Nuwayser in view of
`
`Kranzler (Ex. 1011), Rubio, and Wright (Ground 5). As Dr. Park explains, it would
`
`be obvious to establish a dose using a standard curve. (Ex. 1030 ¶¶ 116-117.)
`
`Rubio and Wright are applicable to dependent claims 2, 6, and 13 in Grounds 3-5.
`
`Finally, all of the challenged claims are obvious over Alkermes’ 10-K
`
`(Ex. 1016) in view of the Vivitrex® Trademark Specimen (Ex. 1017), Rubio, and
`
`5
`
`

`

`Case IPR2018-00943 (Patent No. 7,919,499)
`Petition for Inter Partes Review
`
`Wright (Ex. 1018) (Ground 6). Alkermes’ 10-K describes the claimed method and
`
`the use of Alkermes’ Vivitrex depot injection of naltrexone and Medisorb®
`
`technology to treat alcoholism—and opioid addicts. The Specimen confirms the
`
`use of its Medisorb technology with naltrexone and provides the dose found in
`
`Vivitrex. Wright fully describes the Medisorb microparticles. The result, in terms
`
`of AUC and differential, should be the same as claimed because this ground is
`
`based on the use of the very same formulation used by Alkermes in the claimed
`
`study described in the ’499 Patent. Wright and Rubio are also applicable to
`
`dependent claims 2, 6, and 13.
`
`IV. SUMMARY OF THE ’499 PATENT
`The ’499 Patent (Ex. 1001)1 issued on April 5, 2011, from U.S. Application
`
`Serial No. 11/083,167 (“the ’167 Application”), filed on March 17, 2005, and
`
`claims the benefit of U.S. Provisional Application No. 60/564,542, filed April 22,
`
`2004 (the “Provisional Application”) (Ex. 1032.) Accordingly, the earliest possible
`
`effective filing date for the ’499 Patent is April 22, 2004.
`
`The ’499 Patent describes a method of treating an individual in need of
`
`naltrexone by parenterally administering a long acting formulation that includes
`
`310-480 mg of naltrexone and PLGA to the individual, where the serum AUC of
`
`
`1 Title 35 as it existed before adoption of the AIA is applicable here.
`
`6
`
`

`

`Case IPR2018-00943 (Patent No. 7,919,499)
`Petition for Inter Partes Review
`
`naltrexone is about three times greater than what is achieved by administration of
`
`50 mg/day oral administration. (Ex. 1001, 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 naltrexone.” (Exs. 1001 Abstract, 1:31-33; 1030 ¶ 15.) It provides no direct data
`
`for the AUC of any claimed formulation or the comparator—50 mg/day oral
`
`dosing. (Ex. 1001, 18:10-12; 1030 ¶ 15.) During prosecution, comparisons were
`
`made using data from an Alkermes’ study referenced in the ’499 Patent and from
`
`Tice. (Exs. 1003; 1015.) But none of this data could be determined from the patent
`
`itself.
`
`The specification discusses the need for improving naltrexone therapies,
`
`based on patient compliance. (Exs. 1001, 1:13-26, 17:24-29; 1030 ¶ 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. (Exs. 1001, 3:14-15; 1030 ¶ 17.)
`
`The specification describes its long-acting formulations as releasing
`
`naltrexone over a period of at least one week. (Ex. 1001, 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. (Id. 4:54-64.)
`
`7
`
`

`

`Case IPR2018-00943 (Patent No. 7,919,499)
`Petition for Inter Partes Review
`
`
`Five examples are included, three of which (Examples 3-5) were not present
`
`in the provisional application. (Compare Exs. 1001 and 1032; 1030 ¶ 18.)
`
`Example 1 describes how
`
`to manufacture Vivitrex
`
`formulations. The
`
`microparticles portion of this example is virtually identical to the preparation
`
`described in Example 3 of Wright. (Compare Exs. 1001, 3:3-33, 5:35-8:2 and
`
`1018, 7:50-8:60; 1030 ¶¶ 132-133.) The remaining examples describe various
`
`aspects of a clinical trial and meta-analysis. Example 2 describes screening,
`
`eligibility, and adverse events. (Ex. 1001, 8:5-18:2.) Example 3 compares the
`
`“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.”
`
`(Exs. 1001, 18:10-12 (emphases added); 1030 ¶¶ 19, 61.) Instead the specification
`
`admits to using data from three nonrelated studies for a “semi-quantitative”
`
`comparison that resulted in efficacy “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 improved efficacy to
`
`a POSA. (Exs. 1030 ¶¶ 16, 61; 1001, 18:12-29, 19:30-33.) Finally, Examples 4
`
`and 5 are directed to “quality of life” and “durability of effect and tolerability” of
`
`long acting naltrexone formulations.
`
`8
`
`

`

`Case IPR2018-00943 (Patent No. 7,919,499)
`Petition for Inter Partes Review
`
`V.
`
`PERTINENT PROSECUTION HISTORY OF THE ’499 PATENT
`The ’499 Patent was filed under 37 C.F.R. § 1.102(e) on March 17, 2005, as
`
`the ’167 Application. On September 5, 2007, Alkermes filed a preliminary
`
`amendment, which merely canceled original claims 24 and 25. A restriction
`
`requirement was mailed on February 20, 2009, and Alkermes responded on
`
`March 20, 2009, electing Group 1, i.e., claims 1, 2, and 6-23, with traverse.
`
`A nonfinal rejection was mailed on May 5, 2009 (Ex. 1002), which rejected
`
`the claims as allegedly being anticipated by Tice and, in the alternative, as being
`
`obvious over the combination of Tice and Chandrashekar. Alkermes responded on
`
`October 5, 2009 (Ex. 1004), with claim amendments and a declaration under 37
`
`C.F.R. § 1.132 by Elliot Ehrich (the “Ehrich Declaration” (Ex. 1003)), 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/day oral dosing. In contrast, the claimed invention
`
`allegedly resulted in 3.3 times the oral AUC. Alkermes also argued the existence of
`
`this AUC differential using its own oral data from a clinical trial. (Ex. 1030 ¶¶ 23,
`
`63, 72-74.)
`
`The Examiner issued a second office action on January 6, 2010, which
`
`withdrew the anticipation and obviousness rejections over Tice in view of the
`
`Ehrich Declaration but nevertheless rejected the claims for lack of enablement.
`
`9
`
`

`

`Case IPR2018-00943 (Patent No. 7,919,499)
`Petition for Inter Partes Review
`
`(Ex. 1005.) Alkermes responded on April 5, 2010, by amending the claims to
`
`require a biocompatible polymer. (Ex. 1006.) A final rejection was mailed on
`
`July 20, 2010, maintaining the enablement rejection. (Ex. 1007.) Alkermes filed a
`
`response after final on October 20, 2010, amending the claims further to require
`
`that the biocompatible polymer be PLGA. (Exs. 1008; 1030 ¶ 23.)
`
`A Notice of Allowance was mailed on December 1, 2010, which
`
`acknowledged a telephone interview of November 19, 2010, where Alkermes
`
`agreed to an Examiner’s Amendment to insert certain language into the claims,
`
`e.g., “about 310 mg to about 480 mg” into claim 1. (Ex. 1009.) The Examiner also
`
`included reasons for allowance. According to the Examiner, Tice was the closest
`
`prior art and reported that its injectable formulation was comparable to taking
`
`50 mg tablets orally. (Id.) But, as discussed below, Tice is not the closest prior art.
`
`(Ex. 1030 ¶ 24.)
`
`VI. TECHNICAL BACKGROUND AND STATE OF THE ART
`The challenged claims are directed to treating certain conditions, such as
`
`alcoholism. Naltrexone as a treatment for patients suffering from alcoholism and
`
`opioid addiction dates back to at least the 1980s. (Exs. 1010, at 351-352; 1011,
`
`at 1075; 1012 Summary; 1013; 1014, 19:22-25; 1016, at 3; 1022 Abstract; 1023,
`
`at 936; 2024, 1:55-2:50; 1026, at 173; 1030 ¶¶ 52-53.) Indeed, naltrexone in an
`
`amount of 50 mg/day delivered orally was a known effective treatment