ALKERMES EXHIBIT 2006
`Apotex Inc. v. Alkermes Pharma Ireland Limited
`IPR2025-00514
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`Page 1 of 29
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`Commissioner for Patents
`United States Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`www.uspto.gov
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`DO NOT USE IN PALM PRINTER
`
`(THIRD PARTY REQUESTER'S CORRESPONDENCE ADDRESS)
`
`CROWELL & MORING LLP
`
`Intellectual Property Group
`PO Box 14300
`
`Washington, DC 20044-4300
`
`EX PARTE REEXAMINATION COMMUNICATION TRANSMITTAL FORM
`
`REEXAMINATION CONTROL NO. 90/019,779 .
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`PATENT UNDER REEXAMINATION 7919499.
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`ART UNIT 3997 .
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`Enclosedis a copyof the latest communication from the United States Patent and Trademark
`Office in the above identified exparte reexamination proceeding (37 CFR 1.550(f)).
`
`Wherethis copy is supplied after the reply by requester, 37 CFR 1.535, or the timefor filing a
`reply has passed, no submission on behalf of the exoarfe reexamination requesterwill be
`acknowledged or considered (37 CFR 1.550(g)).
`
`PTOL-465 (Rev.07-04)
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`Page 2 of 29
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`Page 2 of 29
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`SUMMARY OF ACTION
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`Claims 1-13 are subject to reexamination.
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`Claims __ are not subject to reexamination.
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`Claims ___ have been canceledin the present reexamination proceeding.
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`Claims ___ are patentable and/or confirmed.
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`OQOOO0os80008 Acknowledgment is madeofthe priority claim under 35 U.S.C. 119(a)-(d) or (f).
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`Office Action in Ex Parte Reexamination
`Examiner Art Unit|AIA (First Inventorto File) Status
`
`LORA E DRISCOLL
`
`Control No.
`90/019,779
`
`Patent Under Reexamination
`7919499
`
`-- The MAILING DATEof this communication appears on the cover sheet with the correspondence address --
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`a. L) Responsiveto the communication(s)filed on
`(© Adeclaration(s)affidavit(s) under 37 CFR 1.130(b) was/werefiled on
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`.
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`b. L) This action is made FINAL.
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`Cc.
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`A statement under 37 CFR 1.530 has not been received from the patent owner.
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`A shortenedstatutory period for responseto this action is set to expire 2 month(s) from the mailing date ofthis letter.
`Failure to respond within the period for responsewill result in termination of the proceeding and issuance of an eygarfe reexamination
`certificate in accordance with this action. 37 CFR 1.550(d). EXTENSIONS OF TIME ARE GOVERNED BY 37 CFR 1.550(c).
`If the period for response specified aboveis less than thirty (30) days, a responsewithin the statutory minimum ofthirty (30) days
`will be consideredtimely.
`
`THE FOLLOWING ATTACHMENT(S) ARE PART OF THIS ACTION:
`Part!
`1. CJ Notice of References Cited by Examiner, PTO-892.
`3.[ Interview Summary, PTO-474.
`2. C Information Disclosure Statement, PTO/SB/08.
`4.0
`.
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`Part ||
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`ta.
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`1b.
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`2.
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`Claims 1-13 are rejected.
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`Claims __ are objectedto.
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`The drawings, filed on
`are acceptable.
`The proposed drawing correction, filed on
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`has been (7a)
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`C) approved (7b)
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`() disapproved.
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`a) CJ All
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`b)
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`(J Some* c)
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`(CJNone
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`of the certified copies have
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`1
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`(1) been received.
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`2 CJ not been received.
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`3 © been filed in Application No. _
`4 () been filed in reexamination Control No.
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`5 () been received by the International Bureau in PCT application No.
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`* See the attached detailed Office action for a list of the certified copies not received.
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`9. [) Since the proceeding appearsto be in condition for issuance of an exparle reexamination certificate except for formal
`matters, prosecution as to the merits is closed in accordancewith the practice under Exparte Quayle, 1935 C.D.
`11, 453 O.G. 213.
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`10.
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`(J Other:
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`cc: Requester (if third
`U.S. Patent and Trademark Office
`PTOL-466 (Rev. 08-13)
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`Page 3 of 29
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`Office Action in Ex Parte Reexamination
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`PartofPaperNo.
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`20250407
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`Page 3 of 29
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`Application/Control Number: 90/019,779
`Art Unit: 3991
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`Page 2
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`Notice of Pre-AlA or AIA Status
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`The present application is being examined underthe pre-AlAfirst to invent
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`provisions.
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`Reexamination—Non-Final Action
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`Procedural Posture
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`A third-party requesterfiled a request for ex parte reexamination of claims 1-13
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`of US Patent 7,419,499. Reexamination was ordered on 1/28/25.
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`The Challenged Patent Claims
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`Claims 1-13 of US Patent 7,419,499 are under reexamination in this proceeding.
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`Claim 1
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`is independent and representative:
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`A methodfor treating an individual in need of naltrexone comprising the step of
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`parenterally administering a long acting formulation comprising about 310 mg to
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`about 480 mg of naltrexone and a biocompatible polymerto the individual
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`wherein the serum AUCof naltrexone is about three times greater than that
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`achieved by 50 mg/day oral administration and wherein the biocompatible
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`polymer is a polylactide-co-glycolide polymer.
`
`Documents Submitted by Requester
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`Comeret al., 2002, “Depot Naltrexone: Long-Lasting Antagonism of the Effects
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`of Heroin in Humans,” Psychopharmacology 159(4): 351-360 (Ex. E)
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`Nuwayseret al., US Patent No. 7,157,102 (Ex. F)
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`Johnsonet al., 2004, “A Pilot Evaluation of the Safety and Tolerability of Repeat
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`Dose Administration of Long-Acting Injectable Naltrexone (Vivitrex®) in Patients with
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`Application/Control Number: 90/019,779
`Art Unit: 3991
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`Page 3
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`Alcohol Dependence,” Alcoholism:Clinical and Experimental Research 28(9): 1356-
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`1361 (Ex. G)
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`Rubio et al., 2001, “Naltrexone Versus Acamprosate: One Year Follow-Up of
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`Alcohol Dependence Treatment,” Alcohol & Alcoholism 36(5): 419-425 (Ex. W)
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`Wright et al., US Patent 6,264,987 (Ex. N)
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`Newly Cited Documents
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`Tice et al. (2001, US Patent 6,306,425; reference A on attached PTO-892)
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`Kaiko et al. (2002, US Patent 6,375,957; reference B on attached PTO-892)
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`Brederet al. (US 2003/0157168; reference C on attached PTO-892)
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`Priority
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`Application 11/083,167 wasfiled on 3/17/05 and claims benefit of US provisional
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`application 60/564,542, which wasfiled on 4/22/04. The ’499 patent issued from the
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`"167 application on 4/5/11. The ’499 patentlists no other domestic-benefit or foreign-
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`priority claims.
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`Patent Owner’s claim for the benefit of a prior-filed application under 35 U.S.C.
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`119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Patent Owner
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`has not complied with one or more conditions for receiving the benefit of an earlierfiling
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`date under 35 U.S.C. 112(e).
`
`The underlying 167 application adds material beyond the disclosure of the 542
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`provisional application (specifically, examples 3-5 at columns 18-20), so it is analogous
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`to a continuation-in-part of that provisional application. See MPEP 2152.01 (analysis of
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`effective filing date not changed by AIA and referencing MPEP 2133.01). “[A]ny claim
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`that contains a limitation that is only supported as required by pre-AlA 35 U.S.C. 112,
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`Application/Control Number: 90/019,779
`Art Unit: 3991
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`Page 4
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`first paragraph, by the disclosure of the CIP application will have the effectivefiling date
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`of the CIP application.” MPEP 2133.01. See also MPEP 2218:
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`[W]here the patent for which reexamination is requested is a continuation-in-part
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`of a parent application, the requester would notify the Office of the application
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`numberof the parent application andits status if the asserted substantial new
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`question of patentability relates to a proposed rejection based on an intervening
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`art and the question of whether the claimed subject matter in the patent has
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`support in the parent application is relevant.
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`The ’542 provisional application nowhere provides data demonstrating
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`possession of the claimed increased serum AUC from the claimed range of naltrexone
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`dose. Serum AUC is a calculation that depends on numerous factors. See, e.g., Tice et
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`al. (2001, US Patent 6,306,425) at columns 13-14 (calculating actual and extrapolated
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`AUC for various naltrexone formulations); Kaiko et al. (2002, US Patent 6,375,957) at
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`Figure 10A and column 38,lines 29-50 (showing different AUC patterns for different
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`doses of naltrexone); Brederet al. (US 2003/0157168) at paragraph 289 (Table 7,
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`showing varying AUC in different patients over time). The person of ordinary skill in the
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`art would therefore have understood the serum AUC of a given naltrexone formulation
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`to be unpredictable over time, with different dosages, andin different patients. In the
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`absenceof experimental data, then, the skilled artisan would not have concluded that
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`the 542 provisional application teaches the claimed three-fold (or 3.3-fold) increase
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`relative to 50 mg/dayoral administration of naltrexone.
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`Application/Control Number: 90/019,779
`Art Unit: 3991
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`Page 5
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`Because the ’542 provisional application does not provide support for the AUC
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`limitation in the mannersetforth in 35 U.S.C. 112, first paragraph, the ’499 patent's
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`effective filing date is its actualfiling date, 3/17/05.
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`Claim Rejections - 35 USC § 102
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`The following is a quotation of the appropriate paragraphs of pre-AlA 35 U.S.C.
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`102 that form the basis for the rejections under this section madein this Office action:
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`A personshall be entitled to a patent unless —
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`(a) the invention was knownor used by others in this country, or patented or described in a
`printed publication in this or a foreign country, before the invention thereof by the applicant for
`a patent.
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`(bo) the invention was patented or described in a printed publication in this or a foreign country
`or in public use or on sale in this country, more than one yearprior to the date of application
`for patent in the United States.
`
`Claims 1, 3-5, and 12 are rejected under pre-AlA 35 U.S.C. 102(b) as being
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`anticipated by Comer(2002, “Depot Naltrexone: Long-Lasting Antagonism of the Effects
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`of Heroin in Humans,” Psychopharmacology 159(4): 351-360; Ex. E) as evidenced by
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`Nuwayser(2007, US Patent No. 7,157,102; Ex. F).
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`Comerteaches a methodoftreating heroin addicts seeking recovery(individuals
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`in need of naltrexone) by injecting into the buttocks(i.e., parenterally administering) a
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`depot formulation of a total of 384 mg naltrexone, whichis within the 499 patent’s
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`claimed dosage range. (Page 351, column 2; page 352, column 2; page 354, column 1.)
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`Comer demonstrates that the depot formulation provides elevated plasma levels of
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`naltrexone for about 28 days, which is reasonably interpreted as a “long-acting
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`formulation.” (Figure 1; page 355, column 1.) Nuwayseris cited solely as evidencethat
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`Comer’s depot formulation, DEPOTREX, comprises poly-L-(—)-lactide-co-glycolide
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`(PLGA). (Figure 7; column 14, lines 26-49; column 19, lines 4-26.)
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`Application/Control Number: 90/019,779
`Art Unit: 3991
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`Page 6
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`Claim 1 requires that the long-acting formulation results in a serum area under
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`the curve (AUC)that is about three times greater than that achieved by 50 mg/dayoral
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`administration. Claim 5 requires an AUC about 3.3 times greater. Comer teaches
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`administering the same composition in the same wayasthat recited in the 499 patent.
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`As such, all results of that administration are inherent to the active step. MPEP
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`2112.02 (II) instructs:
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`Underthe principles of inherency,if a prior art device, in its normal and usual
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`operation, would necessarily perform the method claimed, then the method
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`claimedwill be considered to be anticipated by the prior art device. When the
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`prior art device is the same as a device described in the specification for carrying
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`out the claimed method, it can be assumedthe device will inherently perform the
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`claimed process.
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`Comertherefore inherently anticipates claims 1 and 5.
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`Regarding claims 3 and 4, Comer demonstrates release of naltrexone for about
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`four weeks, whichIs also “at least two weeks.” (Figure 1; page 355, column 1.)
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`Regarding claim 12, Comer teachesinjection. (Page 354, column 1.)
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`Claims 1, 3-5, and 7-12 are rejected under pre-AlA 35 U.S.C. 102(a) as being
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`anticipated by Johnsonet al., 2004, “A Pilot Evaluation of the Safety and Tolerability of
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`Repeat Dose Administration of Long-Acting Injectable Naltrexone (Vivitrex®) in Patients
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`with Alcohol Dependence,” Alcoholism: Clinical and Experimental Research 28(9):
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`1356-1361 (Ex. G).
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`Application/Control Number: 90/019,779
`Art Unit: 3991
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`Page 7
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`Regarding claim 1, Johnson administers 400 mg naltrexone to individuals
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`suffering from alcoholism and seeking at least temporary abstinence(i.e., in need of
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`naltrexone) intramuscularly (i.e., parenterally) in a formulation comprising PLGA.
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`(Abstract; page 1357, columns 1 and 2.)
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`Claim 1 requires that the long-acting formulation result in a serum area under the
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`curve (AUC) that is about three times greater than that achieved by 50 mg/dayoral
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`administration. Claim 5 requires an AUC about 3.3 times greater. Johnson teaches
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`administering the same composition in the same wayasthat recited in the ’499 patent.
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`As such, all results of that administration are inherent to the active step. See MPEP
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`2112.02(II). Johnson therefore inherently anticipates claims 1 and 5.
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`Regarding claims 3 and 4, Johnson administers depot naltrexone every month
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`for four months, whichis also “at least two weeks.” (Figure 1; page 355, column 1.)
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`Regarding claims 7-9, Johnson administers depot naltrexone every month for
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`four months, meaning each administration is provided “at least about 7 days after the
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`first administration.” Johnson provides the same formulation in all four administrations,
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`which meets the requirements of claims 8 and 9.
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`Regarding claim 10, Johnson’s treated individuals are afflicted by alcohol
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`dependency. (Page 1357, column 2, “Patient Enrollment... .”)
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`Regarding claim 11, Johnson doesnotteach providing aninitial oral dose of
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`naltrexone. (Page 1357, column 2, “Study Design .
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`.
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`.
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`.”)
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`Regarding claim 12, Johnson teachesinjection. (Page 1357, column 2, “Study
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`Design... .”)
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`Claim Rejections - 35 USC § 103
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`Application/Control Number: 90/019,779
`Art Unit: 3991
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`Page 8
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`The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis
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`for all obviousnessrejections set forth in this Office action:
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`(a) A patent may not be obtained though the invention is not identically disclosed or described
`as set forth in section 102, if the differences between the subject matter sought to be patented
`andthe prior art are such that the subject matter as a whole would have been obvious at the
`time the invention was madeto a person having ordinaryskill in the art to which said subject
`matter pertains. Patentability shall not be negated by the manner in which the invention was
`made.
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`The factual inquiries for establishing a background for determining obviousness
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`under pre-AlA 35 U.S.C. 103(a) are summarized as follows:
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`1. Determining the scope and contents of the prior art.
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`2. Ascertaining the differences betweenthe prior art and the claims at issue.
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`3. Resolving the level of ordinary skill in the pertinent art.
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`4. Considering objective evidence presentin the application indicating
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`obviousness or nonobviousness.
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`Claims 2, 6-11, and 13 are rejected underpre-AlA 35 U.S.C. 103(a) as being
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`unpatentable over Comer(Ex. E) in view of Nuwayser(Ex. F).
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`Comerteaches a methodoftreating heroin addicts seeking recovery(individuals
`
`in need of naltrexone) by injecting into the buttocks(i.e., parenterally administering) a
`
`depot formulation of a total of 384 mg naltrexone, which is within the ’499 patent’s
`
`claimed dosage range. (Page 351, column 2; page 352, column 2; page 354, column 1.)
`
`Comer demonstrates that the depot formulation provides elevated plasma levels of
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`naltrexone for about 28 days, whichis reasonably interpreted as a “long acting
`
`formulation.” (Figure 1; page 355, column 1.) Nuwayser is cited as evidencethat
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`Comer’s depot formulation, DEPOTREX, comprises poly-L-(—)-lactide-co-glycolide
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`(PLGA). (Figure 7; column 14, lines 26-49; column 19, lines 4-26.)
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`Application/Control Number: 90/019,779
`Art Unit: 3991
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`Page 9
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`Regarding claims 2 and 6, Comer does not exemplify administering the depot
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`formulation every four weeks for at least about 24 weeks. Regarding claims 7-9, Comer
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`does not exemplify administration at least every week of a substantially similar or
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`identical formulation. Regarding claim 10, Comer does not exemplify treating individuals
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`afflicted by alcohol dependency with depot naltrexone. Regarding claim 11, Comer does
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`not exemplify omitting a preliminary doseof oral naltrexone before beginning treatment.
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`Regarding claim 13, Comer does not specify that the long-acting formulation contains
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`about 35%naltrexone by weight.
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`Regarding claims 2 and 6, Comer teaches administering naltrexone for over a
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`year doesnot result in the developmentof toleranceto its antagonist effects. (Page 351,
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`column 2.) The person of ordinary skill in the art would therefore have found it obvious
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`to administer Comer’s depot naltrexone for about 24 weeks or morein orderto provide
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`prolonged antagonism of the effects of heroin.
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`Regarding claims 7-9, Comerdiscloses that the depot formulation provides
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`increased mean plasma levels of naltrexone for 28 days (Figure 1, left panel) and also
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`teaches that compliance with oral-dosage regimens is low (page 351, column 1, through
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`page 352, column 2). Comer discloses, however, that providing naltrexone for over a
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`year can help manage heroin dependence. (Page 351, column 1.) The person of
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`ordinary skill in the art would therefore have found it obvious to repeat Comer’s
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`administration of depot naltrexone in PLGA, for example every 28 days (whichis “at
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`least about 7 days’), in order to provide prolonged management of heroin dependence.
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`Regarding claim 10, Comerdiscloses that depot naltrexone is useful for treating
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`individuals afflicted with alcohol dependency and thatit “significantly reduced the
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`Application/Control Number: 90/019,779
`Art Unit: 3991
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`Page 10
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`percentage of heavy drinking days in alcoholics” in an earlier study. (Page 352, column
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`1.) The personof ordinary skill in the art would therefore have found it obvious to use
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`Comer’s method to treat an individual afflicted by alcohol dependencyin order to assist
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`that individual with managing his or her addiction.
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`Regarding claim 11, Comerdiscloses “a treatment setting where oral naltrexone
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`may not be given prior to depot naltrexone administration” and teaches methods for
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`avoiding heroin-withdrawal symptoms whenno preliminary dose of oral naltrexone is
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`provided. (Page 359, column 2.) The person of ordinary skill in the art would therefore
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`have understoodaninitial oral dose of naltrexone to be optional and would have foundit
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`obvious to omit thatinitial dose.
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`Regarding claim 13, Nuwayser teaches that DEPOTREX is made by mixing 10
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`grams of PLGA and 30 grams of naltrexone base in 120mL methylene chloride, then
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`mixing with 2.7L of 10%polyvinyl alcohol (PVA) to make microspheres with 68.2%
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`naltrexone. (Column 14, lines 26-49.) Nuwayser teachesthat the microspheres are then
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`coated with additional 1% PLGAsolution for a “target coating level’ of 14% to generate
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`microcapsules with 54.4%naltrexone. (Column 19, lines 4-25.) Nuwayser teachesthat
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`the microparticle-manufacture method can makeparticles containing 0.1-80%of active
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`ingredient or more by weight. (Column 4, lines 24-32.) The person of ordinary skill in the
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`art would have understood that the concentration of naltrexone within the microparticles
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`could be modified by changing the parameters of the manufacture method
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`(concentration of reagents, desired coating level, etc.). Since these parameters are
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`result-effective variables, it would have been obvious for the person of ordinary skill in
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`Application/Control Number: 90/019,779
`Art Unit: 3991
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`Page 11
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`the art to optimize them through routine experimentation in order to arrive ata
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`formulation containing about 35% naltrexone by weight. See MPEP 2144.05(II)(A).
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`Claims 2 and 6 are rejected under pre-AlA 35 U.S.C. 103(a) as being
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`unpatentable over Johnson (Ex. G) in view of Rubio et al., 2001, “Naltrexone Versus
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`Acamprosate: One Year Follow-Up of Alcohol Dependence Treatment,” Alcohol &
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`Alcoholism 36(5): 419-425 (Ex. W).
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`Johnson teaches administering 400 mg naltrexone to individuals suffering from
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`alcoholism and seeking at least temporary abstinence(i.e., in need of naltrexone)
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`intramuscularly (i.e., parenterally) in a formulation comprising PLGA monthly for four
`
`months (a total of four injections). (Abstract; page 1357, columns 1 and 2.)
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`Regarding claims 2 and 6, Johnson does not exemplify administering the depot
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`formulation every four weeksfor at least about 24 weeks.
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`Rubio teaches a randomized 12-month naltrexone treatment protocol in
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`alcoholics. (Page 419, column 2, through page 420, column 1.) Rubio teaches that
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`subjects who received the 12-month treatment showed improved abstinence, lack of
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`relapse, and later relapse compared to those who received acamprosate. (Page 421,
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`column 2; page 422, column 2.)
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`It would have been obvious for the person of ordinary skill in the art to continue
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`administering Johnson’s depot naltrexone for at least about 24 weeks because Rubio
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`teaches that naltrexone can be administered for a year to provide prolonged assistance
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`with managing alcohol dependence.
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`Application/Control Number: 90/019,779
`Art Unit: 3991
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`Page 12
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`Claim 13 is rejected under pre-AlA 35 U.S.C. 103(a) as being unpatentable over
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`Johnson (Ex. G) in view of Wright et al., US Patent 6,264,987 (Ex. N).
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`Johnson teaches administering 400 mg naltrexone to individuals suffering from
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`alcoholism and seeking at least temporary abstinence(i.e., in need of naltrexone)
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`intramuscularly (i.e., parenterally) in a formulation comprising PLGA monthly for four
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`months (a total of four injections). (Abstract; page 1357, columns 1 and 2.) Johnson’s
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`formulation is knownby the trade name MEDISORB. (Page 1357, column 1.)
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`Regarding claim 13, Johnson doesnot specify that the long-acting formulation
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`contains about 35%naltrexone by weight.
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`Wright teaches methods for making MEDISORB naltrexone-loaded polymer
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`containing 30-70%naltrexone by weight. (Column 7, line 63, through column 8,line 1.)
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`Wright teachesthat the drug-loading range is modified by selecting different amounts of
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`drug and polymer. (Column 7, line 65, through column 8, line 1.)
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`The person of ordinary skill in the art would have understood that the
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`concentration of naltrexone within Johnson’s and Wright’s microparticles could be
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`modified by changing the parameters of the manufacture method (concentration of
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`reagents.). Since these parameters are result-effective variables, it would have been
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`obvious for the person of ordinary skill in the art to optimize them through routine
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`experimentation in orderto arrive at a formulation containing about 35%naltrexone by
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`weight. See MPEP 2144.05(II)(A).
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`Double Patenting
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`The nonstatutory double patenting rejection is based on a judicially created
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`doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the
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`Application/Control Number: 90/019,779
`Art Unit: 3991
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`Page 13
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`unjustified or improper timewise extension of the “right to exclude” granted by a patent
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`and to prevent possible harassment by multiple assignees. A nonstatutory double
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`patenting rejection is appropriate where the conflicting claims are not identical, but at
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`least one examined application claim is not patentably distinct from the reference
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`claim(s) because the examined application claim is either anticipated by, or would have
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`been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46
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`USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed.
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`Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum,
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`686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619
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`(CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
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`A timelyfiled terminal disclaimer in compliance with 37 CFR 1.321 (c) or 1.321 (d)
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`may be used to overcome an actualor provisional rejection based on nonstatutory
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`double patenting provided the reference application or patent either is shown to be
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`commonly owned with the examined application, or claims an invention made as a
`
`result of activities undertaken within the scopeof a joint research agreement. See
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`MPEP § 717.02 for applications subject to examination underthe first inventor to file
`
`provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146et seq.for
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`applications not subject to examination underthe first inventor to file provisions of the
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`AlA. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
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`The filing of a terminal disclaimerbyitself is not a complete reply to a
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`nonstatutory double patenting (NSDP)rejection. A complete reply requires that the
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`terminal disclaimer be accompanied by a reply requesting reconsideration of the prior
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`Office action. Even where the NSDP rejection is provisional the reply must be complete.
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`Page 15 of 29
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`Page 15 of 29
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`

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`Application/Control Number: 90/019,779
`Art Unit: 3991
`
`Page 14
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`See MPEP § 804, subsection |.B.1. For a reply to a non-final Office action, see 37 CFR
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`1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A requestfor
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`reconsideration while not provided for in 37 CFR 1.113(c) may befiled after final for
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`consideration. See MPEP §§ 706.07(e) and 714.13.
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`The USPTOInternet website contains terminal disclaimer forms which may be
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`used. Please visit www.uspto.gov/patent/patents-forms. The actualfiling date of the
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`application in which the form is filed determines what form (e.g., PTO/SB/25,
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`PTO/SB/26, PTO/AIA/25, or PTO/AIA/26) should be used. A web-based eTerminal
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`Disclaimer maybefilled out completely online using web-screens. An eTerminal
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`Disclaimer that meets all requirements is auto-processed and approved immediately
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`upon submission. For more information about eTerminal Disclaimers, refer to
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`www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
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`Claims 1-13 are rejected on the ground of nonstatutory double patenting as being
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`unpatentable overclaims 1 and 14-18 of U.S. Patent No. 10,799,496in view of Comer
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`(2002, “Depot Naltrexone: Long-Lasting Antagonism of the Effects of Heroin in
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`Humans,” Psychopharmacology 159(4): 351-360; Ex. E) and Nuwayser(2007, US
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`Patent No. 7,157,102; Ex. F). The ’496 patent is assigned to Alkermes Pharma Ireland
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`Ltd., as is the application under reexamination.
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`The ’496 patent claims a pharmaceutical composition comprising naphthalene-
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`containing prodrugs of naltrexone and a pharmaceutically acceptable carrier. (Claims 1
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`and 14.) The 496 patent’s composition is adapted for parenteral administration, for
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`example intramuscular injection. (Claims 15 and 18.) The 496 patent’s composition
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`provides naltrexone release for about 9 or about 13 weeks, i.e., it is long-acting.
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`Page 16 of 29
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`Page 16 of 29
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`

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`Application/Control Number: 90/019,779
`Art Unit: 3991
`
`Page 15
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`The ’496 patent doesnot specify that the composition comprises about 310-480
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`mg of naltrexone. The ’496 patent does notspecify that the pharmaceutically acceptable
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`carrier is PLGA. The ’496 patent doesnotindicate that the composition, upon
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`administration, gives a serum AUC aboutthree times greater than that achieved by 50
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`mg/day oral administration.
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`Comerteaches a methodoftreating heroin addicts seeking recovery(individuals
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`in need of naltrexone) by injecting into the buttocks(i.e., parenterally administering) a
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`depot formulation of a total of 384 mg naltrexone, which is within the reexamined ’499
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`patent’s claimed dosage range. (Page 351, column 2; page 352, column 2; page 354,
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`column 1.) Comer demonstrates that the depot formulation provides elevated plasma
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`levels of naltrexone for about 28 days, which is reasonably interpreted as a “long-acting
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`formulation.” (Figure 1; page 355, column 1.) Nuwayser teaches that Comer’s depot
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`formulation, DEPOTREX, comprises poly-L-(—)-lactide-co-glycolide (PLGA). (Figure 7;
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`column 14, lines 26-49; column 19, lines 4-26.)
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`The person of ordinary skill in the art would have found it obvious to substitute
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`Comer’s naltrexone depot formulation for the composition of the ’496 patent because
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`both provide long-acting administration of naltrexone. The skilled artisan would have
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`understood these formulations as being functional equivalents for each other. See
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`MPEP 2144.06(II).
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`Comer’s composition is identical to that recited in the ’499 patent and is
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`administered the same way.As such, all results of that administration are inherent to
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`the active step. See MPEP 2112.02(II).
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`Page 17 of 29
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`Page 17 of 29
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`

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`Application/Control Number: 90/019,779
`Art Unit: 3991
`
`Page 16
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`Regarding claims 2 and 6, Comer teaches administering naltrexone for over a
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`year doesnot result in the developmentof toleranceto its antagonist effects. (Page 351,
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`column 2.) The person of ordinary skill in the art would therefore have found it obvious
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`to administer Comer’s depot naltrexone for about 24 weeks or morein orderto provide
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`prolonged antagonism of the effects of heroin.
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`Regarding claims 3 and 4, both the ’496 patent and Comer demonstrate release
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`of naltrexone for about four weeks, whichis also “at least two weeks.” (Figure 1; page
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`355, column 1.)
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`Regarding claims 7-9, Comerdiscloses that the depot formulation provides
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`increased mean plasma levels of naltrexone for 28 days (Figure 1, left panel) and also
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`teaches that compliance with oral-dosage regimens is low (page 351, column 1, through
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`page 352, column 2). Comerdiscloses, however, that providing naltrexone for over a
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`year can help manage heroin dependence. (Page 351, column 1.) The person of
`
`ordinary skill in the art would therefore have found it obvious to repeat Comer’s
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`administration of depot naltrexone in PLGA, for example every 28 days (whichis “at
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`least about 7 days”), in order to provide prolonged managementof heroin dependence.
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`Regarding claim 10, Comerdiscloses that depot naltrexone is useful for treating
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`individuals afflicted with alcohol dependency and thatit “significantly reduced the
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`percentage of heavy drinking days in alcoholics” in an earlier study. (Page 352, column
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`1.) The person of ordinary skill in the art would therefore have found it obvious to use
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`Comer’s method to treat an individual afflicted by alcohol dependencyin order to assist
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`that individual with managing his or her addiction.
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`Page 18 of 29
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`Page 18 of 29
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`Application/Control Number: 90/019,779
`Art Unit: 3991
`
`Page 17
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`Regarding claim 11, Comer discloses “a treatment setting where oral naltrexone
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`may not be given prior to depot naltrexone administration” and teaches methods for
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`avoiding heroin-withdrawal symptoms whenno preliminary dose of oral naltrexone is
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`provided. (Page 359, column 2.) The person of ordinary skill in the art would therefore
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`have understoodaninitial oral dose of naltrexone to be optional and would have foundit
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`obvious to omit thatinitial dose.
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`Regarding claim 12, both the ’496 patent and Comerteachinjection. (Page 354,
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`column 1.)
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`Regarding claim 13, Nuwayser teaches that DEPOTREXis made by mixing 10
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`grams of PLGA and 30 grams of naltrexone base in 120mL methylene chloride, then
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`mixing with 2.7L of 10%polyvinyl alcohol (PVA) to make microspheres with 68.2%
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`naltrexone. (Column 14, lines 26-49.) Nuwayser teachesthat the microspheresare then
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`coated with additional 1% PLGAsolution for a “target coating level” of 14% to generate
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`microcapsules with 54.4%naltrexone. (Column 19, lines 4-25.) Nuwayser teaches that
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`the microparticle-manufacture method can makeparticles containing 0.1-80%of active
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`ingredient or more by weight. (Column 4, lines 24-32.) The person of ordinary skill in the
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`art would have understood that the concentration of naltrexone within the microparticles
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`could be modified by changing the parameters of the manufacture method
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`(concentration of reagents, desired coating level, etc.). Since these parameters are
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`result-effective variables, it would have been obvious for the person of ordinary skill in
`
`the art to optimize them through routine experimentation in order to arrive ata
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`formulation containing about 35% naltrexone by weight. See MPEP 2144.05(II)(A).
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`Page 19 of 29
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`Page 19 of 29
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`

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`Application/Control Number: 90/019,779
`Art Unit: 3991
`
`Page 18
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`Claims 1-13 are rejected on the ground of nonstatutory double patenting as being
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`unpatentable over claims 1 and 9-13 of U.S. Patent No. 10,807,995 in view of Comer
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`(2002, “Depot Naltrexone: Long-Lasting Antagonism of the Effects of Heroin in
`
`Humans,” Psychopharmacology 159(4): 351-360; Ex. E) and Nuwayse