Paper No. ______
`Filed: June 21, 2019
`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`AMNEAL PHARMACEUTICALS LLC,
`Petitioner
`v.
`ALKERMES PHARMA IRELAND LIMITED,
`Patent Owner
`______________________
`Case IPR2018-00943
`Patent 7,919,499
`______________________
`Patent Owner’s Sur-Reply
`
`
`
`
`
`Filed: June 21, 2019
`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`AMNEAL PHARMACEUTICALS LLC,
`Petitioner
`v.
`ALKERMES PHARMA IRELAND LIMITED,
`Patent Owner
`______________________
`Case IPR2018-00943
`Patent 7,919,499
`______________________
`Patent Owner’s Sur-Reply
`
`
`
`
`
`
`
`
`
`TABLE OF CONTENTS
`
`Case IPR2018-00943
`
`Page
`
`1.
`2.
`
`
`I.
`Introduction ........................................................................................1
`Petitioner’s Declarants Should Be Given Little or No Weight ....................2
`II.
`III. Claim Construction ..............................................................................6
`A.
`“the step of parenterally administering a long acting formulation
`comprising about 310 mg to about 480 mg of naltrexone” ................6
`“initial oral dose of naltrexone” ....................................................8
`B.
`IV. Amneal Failed to Establish That Any of the Claims Are Anticipated ..........9
`A. Neither Comer nor Nuwayser Discloses Administering a Single
`Injection ....................................................................................9
`B. Neither Comer nor Nuwayser Discloses the Claimed AUC
`Differential .............................................................................. 10
`Comer’s Data Is Incomplete .................................................. 12
`Comer’s Data Is Contaminated by Initial Oral Dosing ............... 14
`Comer Does Not Disclose Treating ............................................. 15
`C.
`D. Nuwayser Does Not Disclose the Claimed Dosage Range .............. 17
`E.
`Claims 10 and 11 Are Not Anticipated......................................... 17
`Comer Does Not Disclose Administration to an Individual
`Afflicted by Alcohol Dependency .......................................... 17
`Neither Comer nor Nuwayser Disclose Administration Without an
`Initial Oral Dose .................................................................. 17
`V. Amneal Failed to Establish That Any of the Claims Are Obvious ............. 18
`A. A POSA Would Not Have Pursued the Claimed AUC Differential .. 18
`
`1.
`
`2.
`
`i
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`
`
`
`
`TABLE OF CONTENTS
`(continued)
`
`Case IPR2018-00943
`
`Page
`
`B. Grounds 3 & 4: The Claims Are Not Obvious Over Comer,
`Nuwayser, Rubio, and Wright..................................................... 19
`Claims 2, 6–9, and 11 Are Not Obvious .................................. 20
`1.
`C. Ground 5: The Claims Are Not Obvious Over Nuwayser, Kranzler,
`Rubio, and Wright .................................................................... 22
`Claims 2, 6–9, and 11 Are Not Obvious .................................. 23
`1.
`D. Ground 6: The Claims Are Not Obvious Over Alkermes 10-K,
`Vivitrex Specimen, Rubio, and Wright ........................................ 23
`VI. Objective Indicia Show Nonobviousness............................................... 24
`VII. Conclusion........................................................................................ 26
`
`
`ii
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`
`
`
`
`
`TABLE OF AUTHORITIES
`
`Case IPR2018-00943
`
`Page(s)
`
`CASES
`Acorda Therapeutics, Inc. v. Roxane Labs., Inc.,
`903 F.3d 1310 (Fed. Cir. 2018) ................................................................ 24
`Finisar Corp. v. DirecTV Grp., Inc.,
`523 F.3d 1323 (Fed. Cir. 2008) .................................................................. 9
`Harari v. Lee, 656 F.3d 1331 (Fed. Cir. 2011). ................................................. 6
`In re Oelrich, 666 F.2d 578 (C.C.P.A. 1981) .................................................. 10
`In re Robertson, 169 F.3d 743 (Fed. Cir. 1999) ..........................................10–11
`Insite Vision Inc. v. Sandoz, Inc.,
`783 F.3d 853 (Fed. Cir. 2015) .................................................................. 18
`Institut Pasteur v. Focarino,
`738 F.3d 1337 (Fed. Cir. 2013) ................................................................ 19
`K/S HIMPP v. Hear-Wear Techs., LLC,
`751 F.3d 1362 (Fed. Cir. 2014). ............................................................... 19
`Par Pharm., Inc. v. TWI Pharms., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) ................................................................ 18
`Pers. Web Techs., LLC v. Apple, Inc.,
`917 F.3d 1376 (Fed. Cir. 2019) ................................................................ 10
`Takeda Pharms. U.S.A., Inc. v. West-Ward Pharm. Corp.,
`785 F.3d 625 (Fed. Cir. 2015) .................................................................. 16
`Therasense, Inc. v. Becton, Dickinson & Co.,
`593 F.3d 1289 (Fed. Cir. 2010),
`vacated on other grounds,
`374 F. App’x 35 (Fed. Cir. 2010) ........................................................ 25, 26
`TiVo, Inc. v. Echostar Communs. Corp.,
`516 F.3d 1290 (Fed. Cir. 2008) .............................................................. 6–7
`
`iii
`
`
`
`TABLE OF AUTHORITIES
`(continued)
`
`Case IPR2018-00943
`
`Page(s)
`
`WBIP, LLC v. Kohler Co.,
`829 F.3d 1317 (Fed. Cir. 2016) ................................................................ 25
`Yorkey v. Diab, 601 F.3d 1279 (Fed. Cir. 2010) ................................................ 4
`
`Broad Ocean Techs., LLC v. Nidec Mot. Corp.,
`IPR2015-01617, Paper 70 (Apr. 25, 2019) ................................................... 5
`CaptionCall LLC v. Ultratec, Inc.,
`IPR2015-00636, Paper 97 (Sept. 7, 2016) .................................................... 4
`Celltrion, Inc. v. Biogen, Inc.,
`IPR2017-01095, Paper 12 (Oct. 6, 2017) ................................................................ 23
`eBay Inc. v. Global Equity Mgmt. (SA) Pty. Ltd.,
`IPR2016-01829, Paper 63 (Apr. 19, 2018). .................................................. 2
`Fox Factory, Inc. v. SRAM, LLC,
`IPR2016-01876, Paper 59 (Apr. 2, 2018). ............................................ 24, 25
`J.R. Simplot Co. v. McCain Foods Ltd.,
`IPR2018-00314, Paper 7 (June 29, 2018)............................................... 4, 12
`Luxshare Precision Indus. Co., Ltd. v. Bing Xu Precision Co., Ltd.,
`IPR2017-01492, Paper 52 (Jan. 11, 2019).................................................... 7
`
`
`OTHER AUTHORITES
`37 C.F.R. § 42.65.......................................................................................... 2
`
`iv
`
`
`
`
`
`
`
`Case IPR2018-00943
`
`Exhibit
`No.
`
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`
`2006
`
`2007
`
`LIST OF EXHIBITS
`
`Description
`
`Previously
`Submitted
`
`April 13, 2006 Vivitrol® Approval Letter for NDA No.
`21897 (https://www.accessdata.fda.gov/drugsatfda_docs
`/nda/2006/021897_toc_Vivitrol.cfm)
`October 12, 2010 Vivitrol® Approval Letter (New
`Indication) for NDA No. 21897
`(https://www.accessdata.fda.gov/drugsatfda_
`docs/nda/2006/021897_toc_Vivitrol.cfm)
`Vivitrol® Prescribing Information, revised 12/2015
`(https://www.accessdata.fda.gov/drugsatfda_docs/label/2
`015/021897s029lbl.pdf)
`“Drug Facts: Treatment Approaches for Drug Addiction”
`published by the National Institute on Drug Abuse
`(https://www.drugabuse.gov/
`publications/drugfacts/treatment-approaches-drug-
`addiction (revised January 2018))
`“Overdose Death Rates,” published by the National
`Institute on Drug Abuse
`(https://www.drugabuse.gov/related-topics/trends-
`statistics/overdose-death-rates)
`“Principles of Drug Abuse Treatment for Criminal Justice
`Populations | A Research Guide,” published by the
`National Institute on Drug Abuse, NIH Publication No.
`11-5316, (revised April 2014)
`(https://www.drugabuse.gov/publications/principles-drug-
`abuse-treatment-criminal-justice-populations/principles)
`November 21, 2005 Clinical Pharmacology and
`Biopharmaceutics Review for NDA No. 21897
`(https://www.accessdata.fda.gov/
`drugsatfda_docs/nda/2006/021897_toc_Vivitrol.cfm)
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`v
`
`
`
`
`
`
`
`Case IPR2018-00943
`
`LIST OF EXHIBITS
`(continued)
`Description
`
`Exhibit
`No.
`
`Previously
`Submitted
`
`2008
`
`2009
`
`2010
`
`“Incorporating Alcohol Pharmacotherapies Into Medical
`Practice, Treatment Improvement Protocol (TIP) Series
`49 (2009) (‘TIP 49’),” published by Center for Substance
`Abuse Treatment (https://store.samhsa.gov/shin/content/
`/SMA13-4380/SMA13-4380.pdf)
`Leavitt, S.B., “Evidence for the Efficacy of Naltrexone in
`the Treatment of Alcohol Dependence (Alcoholism),”
`published by Addiction Treatment Forum, March 2002,
`(https://www.samhsa.gov/medication-assisted-treatment/
`treatment/naltrexone)
`Bartus et al., “Vivitrex®, in Injectable, Extended-Release
`Formulation of Naltrexone, Provides Pharmacokinetic
`and Pharmacodynamic Evidence of Efficacy for 1 Month
`in Rats,” Neuropsychopharmacology, 28, 1973-1982
`(2003)
`July 11, 2011 Alkermes Comment to Docket No. FDA-
`2007-D-0369, Draft Guidance for Industry Describing
`Product-Specific Bioequivalence Recommendations for
`Naltrexone Extended Release Suspension/Intramuscular
`(https://www.regulations.gov/document?D=FDA-2007-
`D-0369-0061)
`2012 U.S. Patent No. 7,919,499
`
`2011
`
`2013
`
`June 2, 2014 Alkermes Comment to Docket No. FDA-
`2007-D-0369, Draft Guidance for Industry Describing
`Product-Specific Bioequivalence Recommendations for
`Naltrexone Extended Release Suspension/Intramuscular
`(https://www.regulations.gov/document?D=FDA-2007-
`D-0369-0291)
`
`vi
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`
`
`
`
`
`
`Case IPR2018-00943
`
`LIST OF EXHIBITS
`(continued)
`Description
`
`Previously
`Submitted
`
`Orange Book: Approved Drug Products with Therapeutic
`Equivalence Evaluations, Patent Listing for Vivitrol®
`(https://www.accessdata.fda.gov/scripts/cder/ob/patent_in
`fo.cfm?Product_No=001&Appl_No=021897&Appl_type
`=N)
`“Practice Guidelines for the Pharmacological Treatment
`of Patients with Alcohol Use Disorder,” published by The
`American Psychiatric Association (January 2018)
`(https://psychiatryonline.org/doi/pdf/10.1176/appi.books.
`9781615371969)
`December 23, 2005 Division Director Approvable Memo
`for NDA No. 21897(https://www.accessdata.fda.gov/
`drugsatfda_docs/nda/2006/021897_toc_Vivitrol.cfm)
`Vereby et al., “Naltrexone: disposition, metabolism, and
`effects after acute and chronic dosing,” Clinical
`Pharmacology & Therapeutics, 20:315-329 (1976)
`“Medication for the Treatment of Alcohol Use Disorder:
`A Brief Guide,” published by National Institute on
`Alcohol Abuse and Alcoholism, Substance Abuse and
`Mental Health Services Administration (SAMHSA)
`(2015) (https://store.samhsa.gov/shin/content/SMA15-
`4907/SMA15-4907.pdf)
`American Psychiatric Association, “DSM-5 Frequently
`Asked Questions,” (https://www.psychiatry.org/
`psychiatrists /practice/dsm/feedback-and-
`questions/frequently-asked-questions)
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`Exhibit
`No.
`
`2014
`
`2015
`
`2016
`
`2017
`
`2018
`
`2019
`
`vii
`
`
`
`
`
`
`
`Case IPR2018-00943
`
`LIST OF EXHIBITS
`(continued)
`Description
`
`Exhibit
`No.
`
`Previously
`Submitted
`
`2020
`
`2021
`
`“An Introduction to Extended-Release Injectable
`Naltrexone for the Treatment of People with Opioid
`Dependence,” published by the Substance Abuse and
`Mental Health Services Administration (SAMHSA)
`(2012) (https://www.integration.samhsa.gov/
`Intro_To_Injectable_Naltrexone.pdf)
`Annual Report Pursuant to Section 13 or 15(d) of the
`Securities Exchange Act of 1934 for Alkermes PLC,
`Form 10-K, for the fiscal year ended December 31, 2017
`(http://phx.corporate-ir.net/External.File?item=
`UGFyZW50SUQ9NjkzNjEzfENoaWxkSUQ9NDA0OD
`MwfFR5cGU9MQ==&t=1)
`2022 Declaration of J. M. O’Malley
`Yun et al., “Controlled Drug Delivery: Historical
`2023
`perspective for the next generation,” Journal of
`Controlled Release, 219 2–7 (2015)
`2024 Kleber et al., “Nontolerance to the Opioid Antagonism of
`Naltrexone,” Biological Psychiatry, 20:66–72 (1985)
`Transcription of January 23, 2019 Deposition of Kinam
`2025
`Park, Ph.D.
`Guidance for Industry. Bioequivalence Studies with
`Pharmacokinetic Endpoints for Drugs Submitted Under
`an ANDA. FDA CDER (December 2013)
`Reserved
`Meyer et al., “Bioequivalence, Dose-Proportionality, and
`Pharmacokinetics of Naltrexone after Oral
`Administration,” Journal of Clinical Psychiatry, 45:9
`(Sept. 1984)
`Reserved
`
`2026
`
`2027
`
`2028
`
`2029
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`
`
`X
`
`
`
`viii
`
`
`
`
`
`
`
`Case IPR2018-00943
`
`LIST OF EXHIBITS
`(continued)
`Description
`
`Exhibit
`No.
`
`2030
`
`2032
`
`2033
`
`Hamilton et al., “Pharmacokinetics and
`Pharmacodynamics of Hyaluronan Infused into Healthy
`Human Volunteers,” Open Drug Metabolism J. 3 43–55
`(2009)
`2031 Dale et al., “Bioavailability of Rectal and Oral Methadone
`in Healthy Subjects” British J. Clin. Pharmac., 58(2):156–
`162 (Aug. 2004)
`Saghir & Schultz, Low-Dose Pharmacokinetics and Oral
`Bioavailability of Dichloroacetate in Naïve and GSTζ-
`Depleted Rats, Environmental Health Perspectives,
`110(8) 757–763 (Aug. 2002)
`Swanson et al., Development of a New Once-a-Day
`Formulation of Methylphenidate for the Treatment of
`Attention-deficit/Hyperactivity Disorder, Arch Gen
`Psychiatry, 60 204–211 (Feb. 2003)
`Remington: The Science and Practice of Pharmacy,
`(2000)
`Berkland et al., “Precise control of PLG microsphere size
`provides enhanced control of drug release rate,” J.
`Controlled Release 82 137–138 (2002)
`Reserved
`“FDA Approves Injectable Drugs to Treat Opioid-
`Dependent Patients,” PR Newswire (Oct. 2010)
`(https://www.prnewswire.com/news-releases/fda-
`approves-injectable-drug-to-treat-opioid-dependent-
`patients-104818409.html)
`2038 Karl Verebey, “The Clinical Pharmacology of
`Naltrexone: Pharmacology and Pharmacodynamics,”
`NIDA Monograph Series, 28 147–158 (1980)
`
`2034
`
`2035
`
`2036
`
`2037
`
`ix
`
`Previously
`Submitted
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`
`
`X
`
`X
`
`
`
`
`
`
`
`Case IPR2018-00943
`
`LIST OF EXHIBITS
`(continued)
`Description
`
`2040
`
`2041
`
`Exhibit
`No.
`2039 Adam Bisaga, “XR-Naltrexone. As an Element of the
`Comprehensive Response to the Opioid Epidemic,”
`National Academies, Public Workshop on MAT
`(Oct. 2018) (http://www.nationalacademies.org/hmd/
`~/media/Files/Activity%20Files/MentalHealth/MATopioi
`dUseDisorder/BISAGA_MAT%20Public%20Workshop
`%20Final.pdf)
`“Medication Assisted Treatment for Opioid Addiction
`Phased Approach,” Quantum Units Education
`Comer et al., “Injectable, sustained-release naltrexone for
`the treatment of opioid dependence: a randomized,
`placebo-controlled trial,” Archives of General Psychiatry,
`63(2):210–18 (2006)
`Bardo et al., “Chronic naltrexone increases opiate binding
`in brain and produced supersenstitivty to morphine in the
`locus coeruleus of the rat,” Brain Res. 19 223–234 (1983)
`Lee et al., “Extended-Release Naltrexone to Prevent
`Opioid Relapse in Criminal Justice Offenders” N. Engl. J.
`Med. 374(13):1232–1242 (Mar. 2016)
`Reserved
`Lucey et al., “Hepatic Safety of Once-Monthly Injectable
`Extended-Release Naltrexone Administered to Actively
`Drinking Alcoholics,” Alcoholism: Clinical &
`Experimental Research, 32(3):498–504 (2008)
`Guidance for Industry: Expedited Programs for Serious
`Conditions – Drugs and Biologics. FDA CDER (May
`2014)
`Reserved
`Food and Drug Administration, “Kaopectate
`reformulation and upcoming labeling changes,” Drug
`Topics (2004)
`
`2042
`
`2043
`
`2044
`2045
`
`2046
`
`2047
`
`2048
`
`x
`
`Previously
`Submitted
`
`X
`
`X
`
`X
`
`X
`
`X
`
`
`
`X
`
`X
`
`
`
`X
`
`
`
`
`
`
`
`Case IPR2018-00943
`
`LIST OF EXHIBITS
`(continued)
`Description
`
`Exhibit
`No.
`
`Previously
`Submitted
`
`2049
`
`2050
`
`2051
`
`University of Michigan Comprehensive Cancer Center,
`“Intramuscular (IM) Self-Injection,” UMCCC Skills Lab
`(Aug. 2008) (http://www.med.umich.edu/cancer/files/im-
`self-injection.pdf)
`Reserved
`“Cephalon Agrees to Buy Alcohol-Treatment Drug,”
`Bloomberg News (June 2005)
`(https://www.deseretnews.com/article/600144016/Cephal
`on-agrees-to-buy-alcohol-treatment-drug.html)
`Enersen et al., “Beating Heroin With ‘Willpower in a
`Shot,’” USA Today (Feb. 2015)
`(https://www.usatoday.com/story/news/health/2015/02/12
`/addiction-heroin-vivitrol/23263073/)
`2017 Top Ten Awardees, Clinical Research Forum (2017)
`(https://www.clinicalresearchforum.org/page/2017TopTe
`n)
`2054 Merriam-Webster’s Collegiate Dictionary, Eleventh
`Edition (2003) (excerpt)
`2055 Declaration of Cory J. Berkland, Ph.D.
`2056 Declaration of Charles P. O’Brien, M.D., Ph.D.
`Transcription of May 24 Deposition of Sara K. Quinney,
`Pharm. D., Ph.D.
`
`2052
`
`2053
`
`2057
`
`X
`
`
`
`X
`
`X
`
`X
`
`X
`
`X
`X
`
`
`
`
`
`
`xi
`
`
`
`
`
`I.
`
`
`
`
`Case IPR2018-00943
`
`Introduction
`Amneal’s Reply is merely a failed attempt to patch holes in its grounds and
`
`prop up its discredited declarant with redundant testimony from his former student.
`
`But those efforts are too little, too late. Throughout its Reply, Amneal ignores
`
`declarant admissions and evidence that contradicts and undermines its arguments.
`
`Because Amneal has failed to establish unpatentability of the ’499 patent, the
`
`claims should be confirmed.
`
`Contrary to Amneal’s characterizations (see, e.g., Reply at 22–24), Vivitrol1
`
`is the first and only FDA-approved formulation to effectively address the patient-
`
`compliance problem that had vexed naltrexone formulators since the 1980s.
`
`(Ex. 2056, ¶¶ 16–17, 29.) Other naltrexone depots had fallen short due to problems
`
`like injection-site reactions and inadequate duration of release. (Id., ¶ 31.) Vivitrol,
`
`however, was shown to deliver safe and effective treatment for 28 days, via a
`
`single injection (id., ¶ 18) that provides an unexpectedly high AUC relative to oral
`
`naltrexone—even compared to other naltrexone depots (Ex. 1003 (contrasting Tice
`
`(Ex. 1015)). The contested method claims capture that AUC profile. Accordingly,
`
`the ’499 patent is listed in the Orange Book for Vivitrol.
`
`
`1 Vivitrol is the commercial embodiment of the contested claims. (POR at 52; Pet.
`
`at 49.)
`
`1
`
`
`
`
`
`
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`The asserted references do not disclose or suggest a single injection of about
`
`Case IPR2018-00943
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`310 mg to about 480 mg of naltrexone or the unexpected AUC profile, both of
`
`which are at the heart of the contested claims. The Petition also fails to establish
`
`motivation to combine the asserted references, much less with a reasonable
`
`expectation of success. Moreover, Amneal has not rebutted powerful objective
`
`indicia of nonobviousness.
`
`For at least these reasons, Amneal has not carried its burden for Grounds 1–
`
`6 and the claims should be confirmed.
`
`II. Petitioner’s Declarants Should Be Given Little or No Weight
`Amneal’s position hinges on the declaration testimony of Dr. Park, now
`
`mimicked by his former student, Dr. Quinney. But this duo’s largely conclusory
`
`opinions merit little or no weight—especially in light of Dr. Park’s conflict of
`
`interest and the well-grounded testimony of Patent Owner’s experts. 37 C.F.R.
`
`§ 42.65.
`
`The Board assesses the probative value of experts’ testimony by considering
`
`three factors: (1) their interest in the outcome of the case, (2) the presence or
`
`absence of factual support for their opinions, and (3) the strength of opposing
`
`evidence. eBay Inc. v. Global Equity Mgmt. (SA) Pty. Ltd., IPR2016-01829,
`
`Paper 63 at 14–15 (Apr. 19, 2018).
`
`2
`
`
`
`
`
`
`
`Regarding the first factor, an expert’s admitted personal and financial
`
`Case IPR2018-00943
`
`interest in case outcome is reason to give their testimony less weight. Id. Dr. Park
`
`admitted under cross-examination that he is developing and intends to seek FDA
`
`approval for a “cheap” naltrexone product. 2 (Ex. 2025 at 24:23–25:24.) Like
`
`Vivitrol, that product (i) will be used to treat individuals in need of naltrexone,
`
`(ii) is parenterally administered, (iii) is a long-acting formulation, (iv) comprises
`
`naltrexone, and (v) comprises PLGA. (Id. at 24:4–17.) In light of substantial
`
`overlap between the contested claims and Dr. Park’s product,3 his deposition
`
`testimony raises significant doubts that his opinions can fairly be accepted as
`
`unbiased. (See POR at 9, n.7.)
`
`
`2 Dr. Park failed to disclose this in his CV and declarations.
`
`3 Dr. Park refused to disclose the dose of naltrexone in his product and claimed to
`
`be unaware of its AUC. (Ex. 2025 at 28:9–11, 32:19–22.) His NIH grant, however,
`
`uses 380 mg, which is within the range of claim 1. (See
`
`https://projectreporter.nih.gov/project info description.cfm?aid=9796274&icde=4
`
`5016813.)
`
`3
`
`
`
`
`
`
`
`Amneal’s second declarant, Dr. Quinney, recently began serving as an
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`Case IPR2018-00943
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`adjunct assistant faculty member at Purdue University, 4 where Dr. Park holds the
`
`title of “Distinguished Professor.” She has no prior experience (and thus no
`
`expertise) with any formulations—let alone long-acting injectables—that comprise
`
`either naltrexone or PLGA. (Ex. 2057 at 11:9–15, 87:15–17.) As such, her
`
`testimony merits little or no weight. 5
`
`For the second factor, a “lack[] [of] sufficient technical analysis and . . .
`
`support[] by objective evidence” is further reason to give little weight to Amneal’s
`
`declaration testimony. J.R. Simplot Co. v. McCain Foods Ltd., IPR2018-00314,
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`Paper 7 at 22 (June 29, 2018). Here, the testimony of Drs. Park and Quinney is
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`deficient regarding key aspects of the case. For instance, Dr. Park alleges that a
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`POSA would not have understood the claims to be directed to a single injection,
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`based on his unsupported attempt (as a non-clinician) to liken swallowing multiple
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`4 This role is absent from Dr. Quinney’s CV, though it began months before her
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`CV was last updated. (Ex. 2057 at 9:25–11:3.)
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`5 The Board has broad discretion to accord less weight to declarants testifying
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`outside their area of expertise. See CaptionCall LLC v. Ultratec, Inc., IPR2015-
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`00636, Paper 97 at 11–12 (Sept. 7, 2016) (citing Yorkey v. Diab, 601 F.3d 1279,
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`1284 (Fed. Cir. 2010)).
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`4
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`
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`aspirin to receiving multiple PLGA-microsphere injections in one sitting.
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`Case IPR2018-00943
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`(Ex. 1061, ¶¶ 17–20.)
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`With respect to AUC, Dr. Park incorrectly opines that a POSA would have
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`viewed Comer’s two-day washout as “more than adequate” to disregard the
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`influence of previously administered oral naltrexone because it lasts “more than
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`five half-lives.” (See, e.g., id., ¶¶ 54–57 (alleging that “reported naltrexone half-
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`li[ves]” range from 1.1 to 8.9 hours).) But that opinion is based on mean half-lives
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`in healthy volunteers (see id. (citing, e.g., Exhibits 1068, 1039, and 2028)),
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`whereas the prior art showed much longer half-lives in heroin-dependent men (like
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`those disclosed in Comer and Nuwayser). Dr. Quinney made a similar mistake
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`(Ex. 1062, ¶ 82) and acknowledged it during her deposition. (Ex. 2057 at 62:11–15
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`(“Sorry. . . . So it does appear that in heroin-dependent individuals, the half-life
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`may be 14 hours.”)).
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`Regarding the third factor, expert testimony deserves less weight if opposing
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`testimony—even regarding what is absent from asserted art—“is more directly
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`grounded in the actual disclosure of” that art. Broad Ocean Techs., LLC v. Nidec
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`Mot. Corp., IPR2015-01617, Paper 70 at 27 (Apr. 25, 2019). Here, Petitioner chose
`
`not to depose Patent Owner’s experts and has not identified any objective
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`inconsistencies between their testimony and other record evidence.
`
`5
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`Petitioner’s experts, however, have based their testimony on
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`Case IPR2018-00943
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`misapprehensions of the asserted references. For example, their declarations each
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`incorrectly assume that Comer used just one oral administration (see, e.g.,
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`Exs. 1061, ¶ 33; 1062, ¶ 82), when it in fact used three (Ex. 1010 at 353).
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`Moreover, Dr. Park incorrectly assumed that Comer took daily blood draws
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`(Ex. 1061, ¶¶ 41, 62), though it did not (Ex. 1010 at 354). Dr. Quinney said she
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`would expect more frequent sampling from an inpatient study, not realizing that
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`Comer is such a study. (Ex. 2057 at 95:23–25.) She also failed to appreciate (until
`
`her deposition) that Comer’s study participants were heroin-dependent males, not
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`healthy volunteers (id. at 62:7–13).
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`In sum, Petitioner’s declaration evidence is tainted by bias, unsupported
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`analysis, and misunderstanding of key evidence. Moreover, it is directly
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`contradicted by powerful opposing testimony that Petitioner chose not to cross-
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`examine. For at least these reasons, the Board should accord little or no weight to
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`Petitioner’s experts.
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`III. Claim Construction
`“the step of parenterally administering a long acting formulation
`A.
`comprising about 310 mg to about 480 mg of naltrexone”
`Contrary to Amneal’s argument (Reply at 2), “Baldwin . . . does not set a
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`hard and fast rule that ‘a’ always means one or more.” Harari v. Lee, 656 F.3d
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`1331, 1340–42 (Fed. Cir. 2011). Rather, “the question whether [an article] is
`
`6
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`
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`treated as singular or plural depends heavily on the context of its use.” TiVo, Inc. v.
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`Case IPR2018-00943
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`Echostar Communs. Corp., 516 F.3d 1290, 1303 (Fed. Cir. 2008); see also
`
`Luxshare Precision Indus. Co., Ltd. v. Bing Xu Precision Co., Ltd., IPR2017-
`
`01492, Paper 52 at 29–32 (Jan. 11, 2019) (finding “an insulating layer” to be
`
`“limited to a single layer of insulation” based on intrinsic evidence, including its
`
`importance to the invention).
`
`Here, “the step of parenterally administering a long acting formulation
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`comprising about 310 mg to about 480 mg of naltrexone” refers to a single
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`injection. (POR at 5–7.) First, the claims recite singular terms, “the step of” and “a
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`long acting formulation.” (Ex. 1001 at 21:3–4.) As the specification makes clear,
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`the benefits of the claimed methods flow from the fact that they are carried out via
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`a single injection. (Id. at 2:34–36.) Moreover, all of the working examples disclose
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`single-injection regimens, and Amneal has not identified anything in the
`
`specification that refers to multiple injections. (Reply at 2.) Amneal also fails to
`
`consider that the Ehrich Declaration—on which the Office relied to distinguish
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`“the closest art” (Ex. 1009 at 4)—further confirms that the claims are limited to a
`
`single injection (see, e.g., Ex. 1003 at 1).
`
`Despite the intrinsic evidence, Amneal attempts to downplay the benefits of
`
`a single-injection regimen, comparing it to swallowing one ibuprofen tablet versus
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`two (Reply at 2–3). This comparison is irrelevant and inapt. Depot injections are
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`7
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`
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`
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`associated with a distinct set of adverse events, such as indurations and injection-
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`Case IPR2018-00943
`
`site reactions. (Ex. 1050 at 742.) Accordingly, guidelines state that that Vivitrol
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`injections “should be administered into alternating buttocks . . . each month” in
`
`order “[t]o reduce the risk of serious injection site reactions.” (Ex. 2020 at 4; see
`
`also Ex. 2056, ¶ 31.) As Dr. O’Brien explained, part of the reason that Vivitrol
`
`faced industry skepticism is that prior art reported indurations in 73% of treated
`
`subjects and suggested decreasing the amount of naltrexone per injection. (Ex.
`
`2056, ¶ 34.) Given these potential side effects, there is clear benefit in a higher-
`
`dose formulation that can be administered via a single injection.
`
`“initial oral dose of naltrexone”
`B.
`Amneal takes the erroneous position that Alkermes’ construction of “initial
`
`oral dose” refers to any oral dose ever taken prior to receiving depot naltrexone.
`
`(Reply at 4.) Not so. Though the broadest reasonable interpretation of this term is
`
`blind to the purpose of the oral dose and encompasses “any oral dose of naltrexone
`
`prior to the parenteral administration of a long acting formulation comprising about
`
`310 mg to about 480 mg of naltrexone” (Ex. 2055, ¶ 53), it is not divorced from
`
`common-sense temporal restrictions as set out in the specification. For example,
`
`the specification indicates that inventions described therein include treatments
`
`wherein the individual “has not used oral naltrexone within five days, such as
`
`within ten days, before . . . administration.” (Ex. 1001 at 1:67–2:2.) As another
`
`8
`
`
`
`
`
`
`
`example, the specification describes administration “to individuals who did not
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`Case IPR2018-00943
`
`receive a prior oral dose of naltrexone, for example, within 3, such as within about
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`5 days or about 10 days of commencing therapy.” (Id. at 2:49–53.)
`
`Amneal’s proposed construction for this term ignores the intrinsic record
`
`and instead attempts to rely on Comer (Reply at 4, 14), but it is illogical to rely
`
`solely on Comer to shape the meaning of a claim term that Comer allegedly lacks.
`
`IV. Amneal Failed to Establish That Any of the Claims Are Anticipated
`A. Neither Comer nor Nuwayser Discloses Administering a Single
`Injection
`“To anticipate a claim, a single prior art reference must expressly or
`
`inherently disclose each claim limitation.” Finisar Corp. v. DirecTV Grp., Inc.,
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`523 F.3d 1323, 1334 (Fed. Cir. 2008). As previously discussed (POR at 13, 25),
`
`Comer and Nuwayser each administered two injections. Neither discloses “a long
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`acting formulation comprising about 310 mg to about 480 mg of naltrexone,” as
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`construed to require a single injection. (POR at 13–14, 25.)
`
`9
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`
`
`
`
`
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`B. Neither Comer nor Nuwayser Discloses the Claimed AUC
`Differential6
`Amneal concedes that “the AUC of Comer Fig. 1/Nuwa[s]yer Fig. 7 and its
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`Case IPR2018-00943
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`differential versus the AUC of oral naltrexone” are “not expressly” disclosed by
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`the asserted references. (Reply at 16 (emphasis in original); see also, e.g., Ex. 2057
`
`at 96:19–21.) Consequently, Amneal attempts to rely on inherency. (See, e.g.,
`
`Reply at 7 (“Comer and Nuwayser include a pharmacokinetic profile from which
`
`an AUC can necessarily be calculated”); 16 (“AUC and the differential are simply
`
`a necessary consequence of administering what is disclosed by the combination of
`
`Comer and Nuwayser.”).)
`
`Importantly, inherency “may not be established by probabilities or
`
`possibilities,” and “[t]he mere fact that a certain thing may result from a given set
`
`of circumstances is not sufficient” to establish that it is necessarily true. In re
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`Oelrich, 666 F.2d 578, 581 (C.C.P.A. 1981) (quotation omitted); see also Pers.
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`Web Techs., LLC v. Apple, Inc., 917 F.3d 1376, 1382 (Fed. Cir. 2019) (reversing
`
`the Board’s inherency finding because “mere possibility is not enough”); In re
`
`
`6 If, as Amneal alleges, Comer and Nuwayser are two accounts of the same study
`
`(Reply at 5–6), then they have the same protocol and are similarly deficient
`
`regarding AUC (POR at 29).
`
`10
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`
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`Robertson, 169 F.3d 743, 745 (Fed. Cir. 1999) (reversing the Board’s inherent
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`Case IPR2018-00943
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`anticipation finding because it rested upon probability or possibility).
`
`Amneal has not met the high bar for inherency. For instance, a POSA would
`
`have recognized Comer’s and Nuwayser’s data to be incomplete and contaminated
`
`by non-depot sources of naltrexone. (See §§ IV.B.1 and 2, infra.)
`
`Unable to mitigate deficiencies in the asserted art, Petitioner accuses
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`Alkermes of being “wrong and disingenuous—if not outright hypocritical.” (Reply
`
`at 7.) Specifically, Amneal alleges that Alkermes “hold[s] itself to a different
`
`standard” because “nothing in the ’499 Patent or Ehrich Declaration suggest[s] that
`
`a T zero reading was, or must be, taken.” (Id. at 9–10.) Amneal also complains that
`
`Alkermes has not “criticize[d] Tice for not reporting a T zero.” (Id. at 9.) But those
`
`attacks are misplaced because the ’499 patent’s file history (via, for example, the
`
`Ehrich Declaration) and Tice expressly disclose AUC for tested depot
`
`formulations, 7 beginning from time zero. (See e.g., Exs. 1003 at 6 (reporting
`
`“AUC0–∞”); 1015 at 15 (reporting “AUC0–LAST”).)
`
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`7 Reporting AUC values without reporting underlying data is common. (See
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`Ex. 2057 at 95:6–11.)
`
`11
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`Comer’s Data Is Incomplete
`1.
`As Petitioner’s declarant admitted, “PK profile[s] must start from time
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`Case IPR2018-00943
`
`zero.”8 (Ex. 2025 at 66:25–67:5 (emphasis added); see also Exs. 2055, ¶ 59; 1044
`
`at 263; 1045 at 9; 2026 at 6.) Failure to obtain a time zero measurement is
`
`particularly problematic when the highest drug plasma level is observed upon the
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`first blood draw, as in Comer’s Figure 1. (POR at 16.)
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`Attempting to downplay the incompleteness of Comer’s Figure 1, Dr. Park
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`purports to calculate the area from time zero to two hours, assuming that plasma
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`levels of naltrexone peaked at 12 ng/mL or 30 ng/mL (proposed Cmax values), after
`
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