Paper No. ______
`Filed: February 7, 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 Response
`to Petition for Inter Partes Review
`of U.S. Patent No. 7,919,499
`
`APOTEX EXHIBIT 1060
`Apotex v. Alkermes
`IPR2025-00514
`
`

`

`
`
`
`
`Case IPR2018-00943
`
`TABLE OF CONTENTS
`
`Page
`
`I.
`
`Introduction ...................................................................................................... 1
`
`II.
`
`Claim Construction .......................................................................................... 4
`
`A.
`
`B.
`
`“the step of parenterally administering a long acting formulation
`comprising about 310 mg to about 480 mg of naltrexone” .................. 5
`
`“the serum AUC of naltrexone . . . achieved by 50 mg/day oral
`administration” ...................................................................................... 7
`
`C.
`
`“initial oral dose of naltrexone” ..........................................................10
`
`III. Amneal Has Not Established Anticipation ....................................................12
`
`A. Ground 1: The Claims Are Not Anticipated by Comer ......................13
`
`1. Comer Does Not Disclose a Single Injection of Naltrexone Within
`the Claimed Range of Doses ..........................................................13
`
`2. Comer Does Not Disclose the Claimed AUC Differential ............14
`
`3. Comer Does Not Disclose “Treating” ............................................20
`
`B. Ground 2: The Claims Are Not Anticipated by Nuwayser .................25
`
`1. Nuwayser Does Not Disclose a Single Injection of Naltrexone
`Within the Claimed Range of Doses ..............................................25
`
`2. Nuwayser Does Not Disclose the Claimed AUC Differential .......25
`
`3. Nuwayser Does Not Disclose the Claimed Range of Doses .........26
`
`C. At a Minimum, Dependent Claims 10 and 11 Are Not Anticipated ...26
`
`1. Claim 10: Comer Does Not Disclose Administration to an
`Individual Afflicted by Alcohol Dependency ................................27
`
`2. Claim 11: Neither Comer nor Nuwayser Disclose Administration
`Without an Initial Oral Dose ..........................................................28
`
`IV. Amneal Has Not Established Obviousness ...................................................29
`
`i
`
`

`

`
`
`
`
`Case IPR2018-00943
`
`TABLE OF CONTENTS
`(continued)
`
`Page
`
`A. Amneal’s Obviousness Grounds Rely on Improper Hindsight ...........30
`
`B. Grounds 3 & 4: The Claims Are Not Obvious Over Comer,
`Nuwayser, Rubio, and Wright .............................................................35
`
`1. The Asserted Combination Does Not Disclose a Single Injection of
`Naltrexone Within the Claimed Range of Doses ...........................35
`
`2. The Asserted Combination Does Not Disclose the Claimed AUC
`Differential .....................................................................................36
`
`3. A POSA Would Not Have Been Motivated or Had a Reasonable
`Expectation of Success in Combining the Asserted References....36
`
`4. At a Minimum, Dependent Claims 2, 6–9, and 11 Are Not Obvious
`Over Comer, Nuwayser, Rubio, and Wright ..................................38
`
`C. Ground 5: The Claims Are Not Obvious Over Nuwayser, Kranzler,
`Rubio, and Wright ...............................................................................43
`
`1. The Asserted Combination Does Not Disclose a Single Injection of
`Naltrexone Within the Claimed Range of Doses ...........................43
`
`2. The Asserted Combination Does Not Disclose the Claimed AUC
`Differential .....................................................................................44
`
`3. The Asserted Combination Does Not Disclose the Claimed Range
`of Doses ..........................................................................................44
`
`4. A POSA Would Not Have Been Motivated Or Had a Reasonable
`Expectation of Success in Combining the Asserted References....46
`
`5. At a Minimum, Dependent Claims 2, 6–9, and 11 Are Not Obvious
`Over Nuwayser, Kranzler, Rubio and Wright ...............................47
`
`D. Ground 6: The Claims Are Not Obvious Over Alkermes 10-K,
`Vivitrex Specimen, Rubio, and Wright ...............................................47
`
`1. Neither the Alkermes 10-K nor the Vivitrex Specimen Qualify as
`Prior Art ..........................................................................................47
`
`ii
`
`

`

`
`
`
`
`Case IPR2018-00943
`
`TABLE OF CONTENTS
`(continued)
`
`Page
`
`2. A POSA Would Not Have Been Motivated Or Had a Reasonable
`Expectation of Success in Combining the Asserted References....49
`
`3. The Asserted Combination Does Not Teach or Suggest All Claim
`Features ..........................................................................................50
`
`E.
`
`Objective Indicia Support a Finding of Nonobviousness ...................51
`
`1. Commercial success .......................................................................52
`
`2. Others Failed and There Was a Long-Felt, But Unsolved, Need ..53
`
`3. The Claimed Invention Provided Unexpected Results ..................55
`
`4. There Was Skepticism in the Industry ...........................................57
`
`5. Vivitrol® Has Received Industry Praise and Recognition .............59
`
`V.
`
`Conclusion .....................................................................................................60
`
`
`
`iii
`
`

`

`
`
`
`
`Case IPR2018-00943
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`CASES
`
`Graham v. John Deere Co. of Kan. City,
`383 U.S. 1 (1966). ......................................................................................... 29, 51
`
`KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007) .............................. 29, 35, 36, 50
`
`Nautilus, Inc. v. Biosig Instruments,
`134 S.Ct. 2120 (2014) ....................................................................................... 8, 9
`
`
`
`Apple Inc. v. ITC, 725 F.3d 1356 (Fed. Cir. 2013) .................................................. 51
`
`Brown & Williamson Tobacco Corp. v. Philip Morris Inc.,
`229 F.3d 1120 (Fed. Cir. 2000) .......................................................................... 53
`
`Cheese Sys., Inc. v. Tetra Pak Cheese & Powder Sys., Inc.,
`725 F.3d 1342 (Fed. Cir. 2013) .......................................................................... 30
`
`Continental Can Co. USA Inc. v. Monsanto Co.,
`948 F.2d 1264 (Fed. Cir. 1991) .......................................................................... 12
`
`Demaco Corp. v. F. Von Langsdorff Licensing Ltd.,
`851 F.2d 1387 (Fed. Cir. 1988) .......................................................................... 53
`
`DePuy Spine Inc. v. Medtronic Sofamor Danek, Inc.,
`567 F.3d 1314 (Fed. Cir. 2009) .......................................................................... 37
`
`Hansgirg v. Kemmer, 102 F.2d 212 (Fed. Cir. 1991) .............................................. 12
`
`In re Baxter Travenol Labs.,
`952 F.2d 388 (Fed. Cir. 1991) ............................................................................ 12
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule
`Patent Litig., 676 F.3d 1063 (Fed. Cir. 2012) .............................................. 30, 31
`
`In re Klopfenstein, 380 F.3d 1345 (Fed. Cir. 2004) .......................................... 48, 49
`
`In re Lister, 583 F.3d 1307 (Fed. Cir. 2009) ........................................................... 48
`
`iv
`
`

`

`
`
`
`
`Case IPR2018-00943
`
`TABLE OF AUTHORITIES
`(continued)
`
`Page(s)
`
`Insite Vision Inc. v. Sandoz, Inc.,
`783 F.3d 853 (Fed. Cir. 2015) ................................................................ 29, 30, 31
`
`Institut Pasteur v. Focarino,
`738 F.3d 1337 (Fed. Cir. 2013) .................................................................... 37, 59
`
`K/S HIMPP v. Hear-Wear Techs., LLC,
`751 F.3d 1362 (Fed. Cir. 2014) .............................................................. 36, 43, 50
`
`Millennium Pharm., Inc. v. Sandoz Inc.,
`862 F.3d 1356 (Fed. Cir. 2017) .......................................................................... 54
`
`Monarch Knitting Mach. Corp. v. Sulzer Moral GmbH,
`139 F.3d 877 (Fed. Cir. 1998) ............................................................................ 57
`
`Motorola, Inc. v. Interdigital Tech. Corp.,
`121 F.3d 1461 (Fed. Cir. 1997) .......................................................................... 12
`
`Orthopedic Equipment Co., Inc. v. United States,
`702 F.2d 1005 (Fed. Cir. 1983) .................................................................... 32, 50
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .................................................................... 31, 45
`
`Phillips v. AWH Corp., 415 F.3d 1303
`(Fed. Cir. 2005) (en banc) .................................................................................. 10
`
`PPG Indus. v. Guardian Indus. Corp.,
`75 F.3d 1558 (Fed. Cir. 1996) ............................................................................ 12
`
`Sonix Tech. Co., Ltd. v. Publ’ns.,
`844 F.3d 1370 (Fed. Cir. 2017) ............................................................................ 8
`
`Southwire Co. v. Cerro Wire LLC,
`870 F.3d 1306 (Fed. Cir. 2017). ......................................................................... 51
`
`Star Scientific Inc. v. R.J. Reynolds Tobacco Co.,
`655 F.3d 1364 (Fed. Cir. 2011) .................................................................... 30, 51
`
`v
`
`

`

`
`
`
`
`Case IPR2018-00943
`
`TABLE OF AUTHORITIES
`(continued)
`
`Page(s)
`
`Studiengesellschaft Kohle, m.b.H. v. Dart Indus., Inc.,
`726 F.2d 724 (Fed. Cir. 1984) ............................................................................ 12
`
`Tempo Lighting, Inc. v. Tivoli, LLC,
`742 F.3d 973 (Fed. Cir. 2014) .............................................................................. 7
`
`Toro Co. v. White Consol. Indus., Inc.,
`199 F.3d 1295 (Fed. Cir. 1999) ............................................................................ 7
`
`Trivascular, Inc. v. Samuels,
`812 F.3d 1056 (Fed. Cir. 2016) .......................................................................... 10
`
`Verdegaal Bros., Inc. v. Union Oil Co. of Cal.,
`814 F.2d 628 (Fed. Cir. 1987) ............................................................................ 12
`
`Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc.,
`200 F.3d 795 (Fed. Cir. 1999) .............................................................................. 7
`
`WBIP, LLC v. Kohler Co.,
`829 F.3d 1317 (Fed. Cir. 2016) .......................................................................... 52
`
`
`
`Aventis Pharma S.A. v. Hospira,
`743 F. Supp. 2d 305 (D. Del. 2010).............................................................. 41, 42
`
`Eisai v. Glenmark Pharms. Ltd., No. 13-1279,
`2015 U.S. Dist. LEXIS 32462 (D. Del. Mar. 17, 2015) ..................................... 41
`
`Shire LLC v. Mylan Pharms., Inc., No. 11-55,
`2013 U.S. Dist. LEXIS 5279
`(N.D.W.Va. Jan. 14, 2013) ................................................................................. 41
`
`
`
`10X Genomics, Inc. v. Univ. of Chi.,
`IPR2015-01157, Paper 14 (Nov. 16, 2015) .......................................................... 7
`
`Celltrion, Inc. v. Biogen, Inc.,
`IPR2017-01095, Paper 12 (Oct. 6, 2017) ........................................................... 48
`
`vi
`
`

`

`
`
`
`
`Case IPR2018-00943
`
`TABLE OF AUTHORITIES
`(continued)
`
`Page(s)
`
`Coal. For Affordable Drugs XI LLC v. Insys Pharma, Inc.,
`IPR2015-01797, Paper 9 (Mar. 10, 2016) .................................................... 41, 42
`
`Coal. For Affordable Drugs XI LLC v. Insys Pharma, Inc.,
`IPR2015-01799, Paper 9 at 12 (Mar. 10, 2016) ................................................. 41
`
`Coal. For Affordable Drugs XI LLC v. Insys Pharma, Inc.,
`IPR2015-01800, Paper 9 (Mar. 10, 2016) .................................................... 31, 32
`
`Dr. Reddy’s Labs., Inc. v. Pozen Inc.,
`IPR2015-00802, Paper 28 (Oct. 9, 2015) ........................................................... 50
`
`Endo Pharms., Inc. v. Depomed, Inc.,
`IPR2014-00652, Paper 68 (Sept. 16, 2015) ........................................................ 31
`
`Endo Pharms. Inc. v. Depomed, Inc.,
`IPR2014-00656, Paper 66 (Sept. 21, 2015) ........................................................ 41
`
`Gen. Elec. Co. v. United Tech. Corp.,
`IPR2016-00534, Paper 9 (Aug. 12, 2016) ............................................................ 4
`
`Intri-Plex Techs., Inc. v. Saint-Gobain Performance Plastics Rencol
`Ltd., IPR2014-00309, Paper 83 (Mar. 23, 2015) .......................................... 30, 51
`
`Liberty Mut. Ins. Co. v. Progressive Cas. Ins. Co.,
`CBM2013-00009, Paper 68 (Feb. 11, 2014) ...................................................... 48
`
`Luxshare Precision Indus. Co., Ltd. v. Bing Xu Precision Co., Ltd.,
`IPR2017-01404, Paper 51 (Jan. 10, 2019) ............................................................ 6
`
`Nike, Inc. v. Mayfonk Athletic, LLC,
`IPR2015-00656, Paper 8 (Aug. 10, 2015) ............................................................ 6
`
`Purdue Pharma LP v. Depomed, Inc.,
`IPR2014-00378, Paper 73 (July 8, 2015) ........................................................... 31
`
`vii
`
`

`

`
`
`
`
`Case IPR2018-00943
`
`TABLE OF AUTHORITIES
`(continued)
`
`Page(s)
`
`STATUTES
`
`35 U.S.C.
`§ 103 .............................................................................................................. 29, 35
`§ 316(e) ............................................................................................................... 20
`
`OTHER AUTHORITIES
`
`37 C.F.R.
`§ 42.1(d) .............................................................................................................. 20
`§ 42.65(a) ............................................................................................................ 41
`§ 42.100(b) ............................................................................................................ 4
`
`
`
`viii
`
`

`

`
`
`
`
`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
`
`ix
`
`

`

`
`
`
`
`Case IPR2018-00943
`
`LIST OF EXHIBITS
`(continued)
`
`Description
`
`Previously
`Submitted
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`Exhibit
`No.
`
`2008
`
`2009
`
`2010
`
`2011
`
`“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 Parmacokinetic 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
`
`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)
`
`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
`
`xi
`
`

`

`
`
`
`
`Case IPR2018-00943
`
`LIST OF EXHIBITS
`(continued)
`
`Description
`
`Previously
`Submitted
`
`X
`
`X
`
`X
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Exhibit
`No.
`
`2020
`
`2021
`
`2022
`
`2023
`
`2024
`
`2025
`
`2026
`
`“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)
`
`Declaration of J. M. O’Malley
`Yun et al., “Controlled Drug Delivery: Historical
`perspective for the next generation,” Journal of
`Controlled Release, 219 2–7 (2015)
`Kleber et al., “Nontolerance to the Opioid Antagonism of
`Naltrexone,” Biological Psychiatry, 20:66–72 (1985)
`Transcription of January 23, 2019 Deposition of Kinam
`Park, Ph.D.
`
`Guidance for Industry. Bioequivalence Studies with
`Pharmacokinetic Endpoints for Drugs Submitted Under
`an ANDA. FDA CDER (December 2013)
`
`2027
`
`Reserved
`
`2028
`
`Meyer et al., “Bioequivalence, Dose-Proportionality, and
`Pharmacokinetics of Naltrexone after Oral
`Administration,” Journal of Clinical Psychiatry, 45:9
`(Sept. 1984)
`
`2029
`
`Reserved
`
`xii
`
`

`

`
`
`
`
`Case IPR2018-00943
`
`LIST OF EXHIBITS
`(continued)
`
`Description
`
`Previously
`Submitted
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Exhibit
`No.
`
`2030
`
`2031
`
`2032
`
`2033
`
`2034
`
`2035
`
`Hamilton et al., “Pharmacokinetics and
`Pharmacodynamics of Hyaluronan Infused into Healthy
`Human Volunteers,” Open Drug Metabolism J. 3 43–55
`(2009)
`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)
`
`2036
`
`Reserved
`
`2037
`
`2038
`
`“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)
`Karl Verebey, “The Clinical Pharmacology of
`Naltrexone: Pharmacology and Pharmacodynamics,”
`NIDA Monograph Series, 28 147–158 (1980)
`
`xiii
`
`

`

`
`
`
`
`Case IPR2018-00943
`
`LIST OF EXHIBITS
`(continued)
`
`Description
`
`Previously
`Submitted
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Exhibit
`No.
`2039
`
`2040
`
`2041
`
`2042
`
`2043
`
`2044
`2045
`
`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)
`
`2046
`
`Guidance for Industry: Expedited Programs for Serious
`Conditions – Drugs and Biologics. FDA CDER (May
`2014)
`
`2047
`
`Reserved
`
`2048
`
`Food and Drug Administration, “Kaopectate
`reformulation and upcoming labeling changes,” Drug
`Topics (2004)
`
`xiv
`
`

`

`
`
`
`
`Case IPR2018-00943
`
`LIST OF EXHIBITS
`(continued)
`
`Description
`
`Previously
`Submitted
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Exhibit
`No.
`
`2049
`
`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)
`
`2050
`
`Reserved
`
`2051
`
`2052
`
`2053
`
`“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.
`
`
`
`xv
`
`

`

`
`
`
`I.
`
`Introduction
`
`
`
`Case IPR2018-00943
`
`U.S. Patent No. 7,919,499 (“the ’499 patent”) claims inventions relating to
`
`Vivitrol®,1 an extended-release injectable formulation of naltrexone developed by
`
`Alkermes Pharma Ireland Limited (“Alkermes”). The FDA approved Vivitrol in
`
`2006 for the treatment of alcohol dependence and in 2010 for the prevention of
`
`relapse to opioid dependence following opioid detoxification. (Ex. 2001; Ex. 2002;
`
`Ex. 2003.)
`
`Vivitrol is a breakthrough in the treatment of alcohol and opioid addiction. It
`
`is the first FDA-approved, long-acting injectable formulation of naltrexone (a non-
`
`opioid, non-addictive active ingredient), having 380 mg of the drug in a single
`
`injection. (Ex. 2020 at 1–2; Ex. 2003.) So significant was the development of this
`
`long-acting (“depot”) formulation of naltrexone that the FDA “merited [Vivitrol]
`
`priority review,” indicating that Vivitrol is a “significant improvement” over
`
`existing treatments. (Ex. 2016 at 1; Ex 2046 at 24.) Since approval, Vivitrol has
`
`received significant praise, including in the prestigious New England Journal of
`
`Medicine. (Ex. 2043.) It has enjoyed significant commercial success, with 2017
`
`sales of about $270 million. (Ex. 2021 at 56.)
`
`
`1 Vivitrol was previously called Vivitrex. (Ex. 1050 at 742.)
`
`1
`
`

`

`
`
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`
`
`Case IPR2018-00943
`
`Ignoring the breakthrough that the ’499 patented invention represents,
`
`Petitioner asserts invalidity based on prior art largely consisting of publications
`
`from parties that failed in their own attempts to develop a FDA-approved depot
`
`injection of naltrexone. (e.g., Ex. 1010; Ex. 1011; Ex. 1014.)
`
`Specifically, the Petition asserts that claims 1–13 of the ’499 patent (“the
`
`contested claims”) were either (i) anticipated by Comer (Ex. 1010) or Nuwayser
`
`(Ex. 1014), as addressed in Grounds 1 and 2, or (ii) obvious over various
`
`combinations of at least one of those references in view of Rubio (Ex. 1028),
`
`Wright (Ex. 1018), Kranzler (Ex. 1011), Alkermes’s 10-K (Ex. 1016), and the
`
`Vivitrex Specimen (Ex. 1017), as addressed in Grounds 3–6. (Pet. at 4.)
`
`As a threshold matter, the claims should be confirmed because the asserted
`
`grounds fail to disclose “the step of parenterally administering a long acting
`
`formulation,” which requires a single injection of about 310 mg to about 480 mg of
`
`naltrexone. The ’499 patent’s specification and prosecution history make clear that
`
`this is a key claim limitation, and it cannot be ignored. Yet Petitioner’s primary
`
`references, Comer and Nuwayser, each require two injections to reach the claimed
`
`range of doses. Kranzler, which actually “tested a single injection of the same
`
`formulation” used by Comer (Ex. 1010 at 359 (emphasis added)2), suggested
`
`
`2 All emphasis in this brief is added unless otherwise noted.
`
`2
`
`

`

`
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`
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`Case IPR2018-00943
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`“reducing the total dose [down from 206 mg] in each injection” in order to “reduce
`
`adverse effects.” (Ex. 1011 at 1078.)
`
`Similarly misguided is Amneal’s attempt to cobble together the claimed
`
`AUC differential via its expert’s hindsight-fueled foray through references that, for
`
`good reason, say nothing of AUC and do not support a reasoned calculation of it.
`
`(See, e.g., Pet. at 24, 26.) Amneal, no doubt aware of the weaknesses in its AUC
`
`analysis, eventually posits that “this limitation should be given little weight.” (Pet.
`
`at 31.) The Petition’s slew of missteps do not stop there—its six grounds showcase
`
`an assortment of errors: missing claim limitations; failures of proof on motivation
`
`to combine and reasonable expectation of success; lack of public accessibility for
`
`asserted references, and more. Amneal also ignores compelling objective indicia of
`
`nonobviousness of these claims, such as commercial success, skepticism, and
`
`industry praise and recognition.
`
`For these reasons and those discussed below, and as further supported by the
`
`declarations of Drs. Berkland (Ex. 2055) and O’Brien (Ex. 2056), Amneal has not
`
`carried its burden with respect to Grounds 1–6, and the claims should be
`
`confirmed.
`
`3
`
`

`

`
`
`II. Claim Construction3
`
`
`
`Case IPR2018-00943
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`The ’499 patent’s claims should be given their “broadest reasonable
`
`construction in light of the specification of the patent in which it appears.”
`
`37 C.F.R. § 42.100(b) (2016). Under this standard, a term “generally is given its
`
`ordinary and customary meaning,” which is the meaning that the term would have
`
`to a POSA4 at the time of the invention. Gen. Elec. Co. v. United Tech. Corp.,
`
`IPR2016-00534, Paper 9 at 6–7 (Aug. 12, 2016). Amneal proposes the construction
`
`of several claim terms (Pet. at 16–21), without explaining why they require
`
`construction, why the Board should depart from their ordinary and customary
`
`meaning, or why the proposed constructions are relevant to the alleged grounds for
`
`unpatentability.5
`
`
`3 These claim construction arguments are not concessions on the proper scope of
`
`any claim term in any future litigation or other patent proceeding.
`
`4 A person of ordinary skill in the art would have either a Master’s degree with at
`
`least two or three years’ experience, or have a Ph.D. or M.D. degree with at least
`
`one or two years’ experience. (Ex. 2055 ¶ 28.)
`
`5 Alkermes does not necessarily agree with any of Amneal’s proposed
`
`constructions, and it addresses only those that are relevant to the arguments set
`
`forth herein.
`
`4
`
`

`

`
`
`
`A.
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`
`
`Case IPR2018-00943
`
`“the step of parenterally administering a long acting formulation
`comprising about 310 mg to about 480 mg of naltrexone”
`
`Claim 1 recites a method for treating that comprises “the step of parenterally
`
`administering a long acting formulation comprising about 310 mg to about 480 mg
`
`of naltrexone.” (Ex. 1001 at 21:3–5.) The broadest reasonable construction of this
`
`term, in the context of the ’499 patent, is “a single injection of a long acting
`
`formulation comprising about 310 mg to about 480 mg of naltrexone.” (Ex. 2055
`
`¶ 36.)
`
`This construction is consistent with the words of the claim term, which refer
`
`to “the step” and “a long acting formulation” in singular form. It is also consistent
`
`with the ’499 patent’s specification. Example 1 concerns manufacture and does not
`
`mention administration (Ex. 1001 at 5:37–8:2), but all of the specification’s other
`
`working examples disclose single-injection regimens:
`
` Example 2 mentions “all 6 injections” (Ex. 1001 at 10 (flow chart))
`
`given over a “6-month treatment period” (id. at 14:35). “Patients
`
`received an injection of study medication at 4-week intervals over 24
`
`weeks, alternating between the left and right [buttocks].” (Id. at 8:41–
`
`45.) Injections, occurring at 4-week intervals, were either a single
`
`injection of 380 mg long-acting naltrexone, a single injection of
`
`190 mg long-acting naltrexone, or a single placebo injection. (Id.
`
`at 8:32–44.)
`
`5
`
`

`

`
`
`
`
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`Case IPR2018-00943
`
` Example 3 compares meta-analyses on oral naltrexone to the 380 mg
`
`dose of the clinical study of Example 2. (Id. at 18:40–56.)
`
` Examples 4 and 5 each refer to “6 monthly injections of LA-NTX
`
`[long-acting naltrexone] 380 mg” over a “24-week” period, which a
`
`POSA would have understood to disclose a single injection per month
`
`for six months. (Id. at 19:43–49, 20:8–31.)
`
`In addition, when describing the invention’s unexpected nature, the specification
`
`refers to “a single IM administration of Vivitrex®” (Id. at 2:34–37). See Luxshare
`
`Precision Indus. Co., Ltd. v. Bing Xu Precision Co., Ltd., IPR2017-01404, Paper
`
`51 at 30 (Jan. 10, 2019) (relying on Toro Co. v. White Consol. Indus., Inc., 199
`
`F.3d 1295, 1301–02 (Fed. Cir. 1999), which adopted a claim scope that was
`
`consistent with the specification that disclosed a single embodiment and described
`
`it as important to the invention).
`
`Moreover, this construction is consistent with the ’499 patent’s prosecution
`
`history, where the Ehrich Declaration was relied on by the Examiner in allowing
`
`the ’499 patent. (Paper 8 at 10–11.) In particular, the Ehrich Declaration states:
`
`“The present invention is directed to the unexpected discovery that a sin