Paper No. ______
`Filed: August 9, 2018
`
`
`
`
`
`
`
`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 Preliminary Response
`to Petition for Inter Partes Review
`of U.S. Patent No. 7,919,499
`
`
`
`

`

`TABLE OF CONTENTS
`
`
`I.
`
`II.
`
`Page
`INTRODUCTION ......................................................................................... 1
`
`BACKGROUND ............................................................................................ 2
`
`A. Naltrexone Is Unlike Other Treatments for Substance Use
`Disorder ................................................................................................ 3
`
`B.
`
`The Need for a Better Alternative Lasted Decades .......................... 5
`
`C. Vivitrol Is the Only FDA-Approved Depot Injection Product that
`Solves the Problems Associated With Oral Naltrexone ................... 9
`
`III. AMNEAL’S ALLEGED INVALIDITY GROUNDS ...............................12
`
`A.
`
`B.
`
`The ’499 Patent Claims Methods of Treating with Novel
`Formulations of Naltrexone That Are Capable of Achieving an
`Unexpected AUC Profile ...................................................................12
`
`The Prior Art Fails to Teach Naltrexone Formulations Having the
`Claimed Dose and AUC Profile .......................................................13
`
`C. Grounds 1 and 2: Disguised as Anticipation Grounds, Amneal’s
`Arguments Are Improper, Unsupported, and Lack Requisite
`Disclosures of Key Elements .............................................................15
`
`1.
`
`Amneal’s Anticipation Arguments Are Flawed Because
`They Rely on Multiple References ........................................16
`
`2.
`
`Ground 1: The Comer Ground Is Flawed ...........................17
`
`a.
`
`b.
`
`c.
`
`Comer Fails to Teach Treating a Patient in Need of
`Naltrexone .....................................................................18
`
`Comer Fails to Teach the Claimed Serum AUC
`Profile .............................................................................19
`
`Comer’s Reference to Depotrex is Insufficient to
`Teach the Claimed Formulation .................................26
`
`3.
`
`Ground 2: The Nuwayser Ground Is Flawed ......................30
`
`- i -
`
`

`

`
`
`TABLE OF CONTENTS
`(continued)
`
`a.
`
`b.
`
`Amneal’s Ground 2 Suffers from the Same
`Deficiencies as Ground 1 ..............................................30
`
`Page
`
`Nuwayser Fails to Teach the Claimed Dose and AUC
`Profile .............................................................................31
`
`4.
`
`Amneal’s Argument Regarding Use of a Secondary
`Reference Contravenes the Law on Anticipation ................32
`
`5.
`
`Conclusion ................................................................................33
`
`D. Grounds 3 and 4: As the Obviousness-Equivalents of Grounds 1
`and 2, Amneal’s Arguments Incorrectly Rely on Hindsight and
`Lack Support .....................................................................................33
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`Even Combined, Comer and Nuwayser Still Suffer from
`Striking Deficiencies ...............................................................34
`
`There Is No Motivation or Reasonable Expectation of
`Success ......................................................................................35
`
`Amneal’s Arguments Rely on Hindsight ..............................38
`
`Comer Teaches Away from the Claimed Invention ............40
`
`Amneal Has Not Shown that the Dependent Claims Are
`Obvious ....................................................................................42
`
`6.
`
`Conclusion ................................................................................44
`
`E. Ground 5: Amneal’s Arguments Rely on Questionable Analysis
`and Ignore Key Results that Teach Away from the Claimed
`Invention .............................................................................................44
`
`F. Ground 6: Amneal’s Arguments Are Flawed Because They Are
`Hindsight Driven and Not Based on References Shown to be
`Printed Publications ..........................................................................47
`
`- ii -
`
`

`

`TABLE OF CONTENTS
`(continued)
`
`
`
`1.
`
`Page
`Amneal Has Not Established that the Alkermes 10-K and
`the Vivitrex Specimen Qualify as Printed Publications
`Under 35 U.S.C. § 311(b) ........................................................47
`
`a.
`
`b.
`
`Amneal Has Failed to Establish that the Alkermes
`10-K Is a Printed Publication ......................................48
`
`Amneal Has Failed to Establish that the Vivitrex
`Specimen Is a Printed Publication ..............................51
`
`Amneal Has Not Established that a POSA Would Have
`Combined the Alkermes 10-K, the Vivitrex Specimen, and
`Wright ......................................................................................53
`
`The Asserted Combination of References Does Not Teach or
`Suggest All Claim Features ....................................................54
`
`2.
`
`3.
`
`IV. SECONDARY INDICIA OF NONOBVIOUSNESS................................55
`
`A.
`
`The Claimed Invention Provided Unexpected Results ..................56
`
`B. Others Failed and There Was a Long-Felt, But Unsolved, Need .58
`
`C.
`
`There Was Skepticism in the Industry ............................................59
`
`D. Commercial Success ..........................................................................60
`
`V.
`
`THE BOARD SHOULD EXERCISE ITS DISCRETION TO DENY
`THE PETITION UNDER 35 U.S.C. § 325(D) ..........................................61
`
`VI. AMNEAL’S CLAIM CONSTRUCTIONS ARE UNNECESSARY OR
`INCORRECT ...............................................................................................62
`
`VII. CONCLUSION ............................................................................................63
`
`
`
`
`
`- iii -
`
`

`

`TABLE OF AUTHORITIES
`
`
`Cases
`
`A.R.M., Inc. v. Cottingham Agencies Ltd.,
`IPR2014-00671, Paper 10 (Oct. 3, 2014) ........................................................... 48
`
`Page(s)
`
`Actavis, Inc. v. Research Corp. Techs., Inc.,
`IPR2014-01126, Paper 21 (Jan. 9, 2015) ............................................................ 48
`
`Apple Inc. v. ITC,
`725 F.3d 1356 (Fed. Cir. 2013) .......................................................................... 55
`
`Arendi S.A.R.L. v. Apple Inc.,
`832 F.3d 1355 (Fed. Cir. 2016) .......................................................................... 46
`
`Ashland Oil, Inc. v. Delta Resins & Refractories, Inc.,
`776 F.2d 281 (Fed. Cir. 1985) ............................................................................ 23
`
`In re Baxter Travenol Labs.,
`952 F.2d 388 (Fed. Cir. 1991) ............................................................................ 32
`
`Brown & Williamson Tobacco Corp. v. Philip Morris Inc.,
`229 F.3d 1120 (Fed. Cir. 2000) .......................................................................... 60
`
`Celltrion, Inc. v. Biogen, Inc.,
`IPR2017-01095, Paper 12 (Oct. 6, 2017) ........................................................... 50
`
`Cheese Sys., Inc. v. Tetra Pak Cheese & Powder Sys., Inc.,
`725 F.3d 1342 (Fed. Cir. 2013) .......................................................................... 33
`
`Coal. For Affordable Drugs III LLC v. Jazz Pharms., Inc.,
`IPR2015-01018, Paper 17 (Oct. 15, 2015) ......................................................... 48
`
`Coal. For Affordable Drugs IV LLC v. Pharmacyclics, Inc.,
`IPR2015-01076, Paper 33 (Oct. 19, 2015) ......................................................... 48
`
`Coal. For Affordable Drugs XI LLC v. Insys Pharma, Inc.,
`IPR2015-01797, Paper 9 (Mar. 10, 2016) ...................................................... 2, 21
`
`Coal. For Affordable Drugs XI LLC v. Insys Pharma, Inc.,
`IPR2015-01799, Paper 9 (Mar. 10, 2016) ................................................ 2, 21, 23
`
`- iv -
`
`

`

`TABLE OF AUTHORITIES
`(continued)
`
`Eisai Co., Ltd. v. Teva Pharm. USA, Inc.,
`
`No. 03-cv-9223 (GEL), 2006 WL 2872615 (S.D.N.Y. Oct. 6,
`2006) ................................................................................................................... 38
`
`Page(s)
`
`Excelsior Med. Corp. v. Lake,
`IPR2013-00494, Paper 10 (Feb. 6, 2014) ........................................................... 62
`
`Glaxo Inc. v. Novopharm Ltd.,
`52 F.3d 1043 (Fed. Cir. 1995) ............................................................................ 16
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) ................................................................................................ 38
`
`In re Hall,
`781 F.2d 897 (Fed. Cir. 1986) ............................................................................ 49
`
`Hulu LLC v. Intertainer, Inc.,
`IPR2014-01456, Paper 8 (Mar. 6, 2015) ............................................................ 62
`
`Intri-Plex Techs., Inc. v. Saint-Gobain Performance Plastics Rencol
`Ltd.,
`IPR2014-00309, Paper 83 (Mar. 23, 2015) ........................................................ 56
`
`In re Klopfenstein,
`380 F.3d 1345 (Fed. Cir. 2004) .................................................................... 47, 52
`
`L-3 Comm. Holdings v. Power Survey, LLC,
`IPR2014-00832, Paper 9 (Nov. 14, 2014) .......................................................... 48
`
`Liberty Mut. Ins. Co. v. Progressive Cas. Ins. Co.,
`CBM2013-00009, Paper 68 (Feb. 11, 2014) ...................................................... 49
`
`In re Lister,
`583 F.3d 1307 (Fed. Cir. 2009) .......................................................................... 49
`
`Millennium Pharm., Inc. v. Sandoz Inc.,
`862 F.3d 1356 (Fed. Cir. 2017) .......................................................................... 58
`
`Monarch Knitting Mach. Corp. v. Sulzer Moral GmbH,
`139 F.3d 877 (Fed. Cir. 1998) ............................................................................ 59
`
`- v -
`
`

`

`TABLE OF AUTHORITIES
`(continued)
`
`Net MoneyIN, Inc. v. VeriSign, Inc.,
`
`545 F.3d 1359 (Fed. Cir. 2008) .................................................................... 16, 32
`
`Page(s)
`
`Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) .......................................................................... 56
`
`Polaris Indus., Inc. v. Arctic Cat, Inc.,
`882 F.3d 1056 (Fed. Cir. 2018) .......................................................................... 41
`
`Prism Pharma Co. v. Choogwae Pharma Corp.,
`IPR2014-00315, Paper 14 (July 8, 2014) ........................................................... 62
`
`Rambus Inc. v. Rea,
`731 F.3d 1248 (Fed. Cir. 2013) .......................................................................... 60
`
`SAS Institute Inc. v. Iancu,
`138 S. Ct. 1348 (2018) ........................................................................................ 61
`
`Scherk v. Alberto-Culver Co.,
`417 U.S. 506 (1974) ............................................................................................ 53
`
`SRI Int’l, Inc. v. Internet Sec. Sys., Inc.,
`511 F.3d 1186 (Fed. Cir. 2008) .......................................................................... 49
`
`Star Sci., Inc. v. R.J. Reynolds Tobacco Co.,
`655 F.3d 1364 (Fed. Cir. 2011) .......................................................................... 56
`
`Teleflex, Inc. v. Ficosa N. Am. Corp.,
`299 F.3d 1313 (Fed. Cir. 2002) .................................................................... 16, 32
`
`Unigene Labs., Inc. v. Apotex, Inc.,
`655 F.3d. 1352 (Fed. Cir. 2011) ......................................................................... 38
`
`In re Zletz,
`893 F.2d 319 (Fed. Cir. 1989) ............................................................................ 63
`
`Statutes
`
`35 U.S.C. § 311(b) ............................................................................................. 47, 53
`
`35 U.S.C. § 313 .......................................................................................................... 1
`
`- vi -
`
`

`

`TABLE OF AUTHORITIES
`(continued)
`
`Page(s)
`35 U.S.C. § 314(a) ................................................................................................... 61
`
`35 U.S.C. § 325(d) ................................................................................................... 61
`
`Other Authorities
`
`37 C.F.R. § 41.100(b) .............................................................................................. 63
`
`37 C.F.R. § 42.6(a)(3) .............................................................................................. 21
`
`37 C.F.R. § 42.65(a) ................................................................................................. 23
`
`37 C.F.R. § 42.107 ..................................................................................................... 1
`
`77 Fed. Reg. 48756, 48732 (Aug. 14, 2012) ........................................................... 23
`
`- vii -
`
`

`

`Case IPR2018-00943
`
`LIST OF EXHIBITS
`
`Ex. 2001. April 13, 2006 Vivitrol® Approval Letter for NDA No. 21897
`(https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021897_t
`oc_Vivitrol.cfm)
`
`Ex. 2002. 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)
`
`Ex. 2003. Vivitrol® Prescribing Information, revised 12/2015
`(https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021897s
`029lbl.pdf)
`
`Ex. 2004.
`
`“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))
`
`Ex. 2005.
`
`“Overdose Death Rates,” published by the National Institute on Drug
`Abuse (https://www.drugabuse.gov/related-topics/trends-
`statistics/overdose-death-rates)
`
`Ex. 2006.
`
`“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)
`
`Ex. 2007. 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)
`
`Ex. 2008.
`
`“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)
`
`Ex. 2009. Leavitt, S.B., “Evidence for the Efficacy of Naltrexone in the
`Treatment of Alcohol Dependence (Alcoholism),” published by
`
`- viii -
`
`

`

`Case IPR2018-00943
`
`LIST OF EXHIBITS
`(continued)
`
`Addiction Treatment Forum, March 2002,
`(https://www.samhsa.gov/medication-assisted-treatment/
`treatment/naltrexone)
`
`Ex. 2010. 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)
`
`Ex. 2011.
`
`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)
`
`Ex. 2012. U.S. Patent No. 7,919,499
`
`Ex. 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)
`
`Ex. 2014. Orange Book: Approved Drug Products with Therapeutic
`Equivalence Evaluations, Patent Listing for Vivitrol®
`(https://www.accessdata.fda.gov/scripts/cder/ob/patent_info.cfm?Prod
`uct_No=001&Appl_No=021897&Appl_type=N)
`
`Ex. 2015.
`
`“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)
`
`Ex. 2016. December 23, 2005 Division Director Approvable Memo for NDA
`No. 21897 (https://www.accessdata.fda.gov/drugsatfda_docs/
`nda/2006/021897_toc_Vivitrol.cfm)
`
`- ix -
`
`

`

`Case IPR2018-00943
`
`LIST OF EXHIBITS
`(continued)
`
`Ex. 2017. Vereby et al., “Naltrexone: disposition, metabolism, and effects after
`acute and chronic dosing,” Clinical Pharmacology & Therapeutics,
`20:315-329 (1976)
`
`Ex. 2018.
`
`“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)
`
`Ex. 2019. American Psychiatric Association, “DSM-5 Frequently Asked
`Questions,” (https://www.psychiatry.org/psychiatrists/practice/
`dsm/feedback-and-questions/frequently-asked-questions)
`
`Ex. 2020.
`
`“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)
`
`Ex. 2021. 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=UGFyZW50SUQ9NjkzNjEzfENoaWxkSU
`Q9NDA0ODMwfFR5cGU9MQ==&t=1)
`
`
`
`- x -
`
`

`

`Case IPR2018-00943
`
`
`
`I.
`
`INTRODUCTION
`
`Vivitrol® is an extended-release injectable formulation of naltrexone
`
`developed by Alkermes Pharma Ireland Limited (“Patent Owner” or “Alkermes”).
`
`The FDA approved it 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.) This groundbreaking, once-a-month injectable
`
`suspension flouted decades of focus on oral naltrexone administration, providing
`
`healthcare professionals and their patients with a novel approach to combating
`
`problems associated with medication noncompliance and fluctuating drug plasma
`
`levels.
`
`Vivitrol is covered by several patents, including U.S. Patent No. 7,919,499
`
`(“the ’499 patent”) at issue in this proceeding. This Preliminary Response,
`
`submitted in accordance with 35 U.S.C. § 313 and 37 C.F.R. § 42.107, explains the
`
`many reasons why the Patent Trial and Appeal Board (“the Board”) should not
`
`institute a trial. As demonstrated herein, the Petition by Amneal Pharmaceuticals
`
`LLC (“Petitioner” or “Amneal”) sets forth flawed grounds rooted in declaration
`
`testimony that is brimming with unsupported conclusions and questionable
`
`analysis. Among other deficiencies, the Petition’s anticipation grounds each rely
`
`on more than one reference. Its obviousness grounds are tainted by hindsight, fail
`
`to address every claim feature, and the references that form the basis of the
`
`- 1 -
`
`

`

`
`
`obviousness grounds teach away from the claimed invention. To make matters
`
`Case IPR2018-00943
`
`worse, the Petition heavily relies on the Park Declaration, which is entitled to little
`
`or no weight. Indeed, Dr. Park’s testimony has been criticized by this Board in
`
`other IPRs as “conclusory and unpersuasive because it is not keyed to objective
`
`proof” (Coal. For Affordable Drugs XI LLC v. Insys Pharma, Inc., IPR2015-01797
`
`(“CFAD I”), Paper 9, at 9 (Mar. 10, 2016) (denying institution)) and as “sweeping,
`
`but unsupported” (Coal. For Affordable Drugs XI LLC v. Insys Pharma, Inc.,
`
`IPR2015-01799 (“CFAD II”), Paper 9 at 12 (Mar. 10, 2016) (denying institution)).
`
`In sum, Amneal simply has not shown that there is a reasonable likelihood it will
`
`prevail with respect to any claim and cannot prove unpatentability by a
`
`preponderance of the evidence. Therefore, Patent Owner respectfully submits that
`
`the Board should decline to institute a trial.
`
`II. BACKGROUND
`
`Addiction is a widespread and complex disease characterized by compulsive
`
`behavior and drug use, resulting in harmful consequences (including death) and
`
`permanent changes in the brain. (Ex. 2004, at 1.) The National Institute on Drug
`
`Abuse estimates that there were over 30,000 opioid-related overdose deaths in the
`
`United States in 2015, with a 2.8-fold increase in the annual deaths between 2002
`
`and 2015. (Ex. 2005, at 3.) Alcohol use disorder (“AUD”) is also a major public
`
`health problem in the United States, with an estimated 18.0 million people afflicted
`
`- 2 -
`
`

`

`
`with AUD1 in the United States in 2013. (Ex. 2018, at 1.) Altogether, substance
`
`Case IPR2018-00943
`
`abuse reportedly costs American society billions of dollars, including costs
`
`associated with drug- and alcohol-related crime. (Ex. 2006, at 26; Ex. 2015, at 3.)
`
`Treatment of substance abuse is cost effective and brings about related savings in
`
`health care. (Ex. 2006, at 27.) It has also consistently been shown to reduce the
`
`costs associated with lost productivity, crime and incarceration. (Id.) Yet many
`
`substance abusers remain untreated. (Ex. 2015, at 4.)
`
`A. Naltrexone Is Unlike Other Treatments
`for Substance Use Disorder
`
`Naltrexone is a competitive opioid-receptor antagonist. (E.g., Ex. 2007, at 2;
`
`Ex. 2003, at 22.) Therefore its effectiveness for treating opioid-related disorders is
`
`based on blocking opioid receptors from binding exogenous opioids (e.g., heroin),
`
`
`1 The American Psychiatric Association published the fifth edition of the
`
`Diagnostic and Statistical Manual of Mental Disorders (“DSM-5”) in May 2013.
`
`(Ex. 2018, at 1.) The DSM-5 is used by health care professionals in the United
`
`States and much of the world as the authoritative guide to the diagnosis of mental
`
`disorders, and contains descriptions, symptoms, and other criteria for diagnosing
`
`mental disorders. (Ex. 2019, at 1.) DSM-5 defines AUD as a combination of
`
`alcohol abuse and alcohol dependence that is diagnosable using 11 criteria. (Ex.
`
`2018, at 1.)
`
`- 3 -
`
`

`

`
`
`which largely stops them from triggering the physiological and psychological
`
`Case IPR2018-00943
`
`effects associated with drug use. Unlike other treatments for opioid use disorders,
`
`such as methadone and buprenorphine, naltrexone is non-narcotic and non-
`
`addictive.2 (Ex. 2011, at 2 of 19; Ex. 2020, at 2 (“Naltrexone has no abuse
`
`potential, whereas methadone and buprenorphine do.”))
`
`Naltrexone’s effectiveness at treating alcohol use disorder, however, is not
`
`completely understood. Preclinical data suggest that naltrexone’s effectiveness
`
`relates to the endogenous opioid system. For example, naltrexone may block
`
`neurotransmission in the brain’s natural reward pathways, thereby reducing
`
`alcohol’s reinforcing properties. (Ex. 2007, at 2; Ex. 2018, at 15; Ex. 1028,
`
`at 423.) Other pharmacotherapies for AUD, such as disulfiram and acamprosate,
`
`have completely different effects: disulfiram induces vomiting and other aversive
`
`reactions in those who drink alcohol while taking it (Ex. 1022, at 1), and
`
`acamprosate lessens the intensity of withdrawal symptoms (Ex. 1028, at 423).
`
`
`2 Methadone is an opioid receptor agonist, and buprenorphine is a partial agonist.
`
`(Ex. 2020, at 2.) As opposed to an antagonist like naltrexone, these agonists
`
`activate opioid receptors, binding to them and producing a narcotic effect. (Id.)
`
`- 4 -
`
`

`

`
`
`B.
`
`The Need for a Better Alternative Lasted Decades
`
`Oral naltrexone was first approved by the FDA to block the pharmacologic
`
`effects of opioids in 1984 and marketed under the brand name “Trexan®.” (Ex.
`
`Case IPR2018-00943
`
`2008, at 27.) A decade later, Trexan was approved by the FDA for the treatment of
`
`AUD and the tablets were rebranded under the name “Revia®.” (Id., at 28.) Revia
`
`was only the second drug to be approved by the FDA to treat AUD. (Ex. 2009, at
`
`1.)
`
`Oral naltrexone treatments are well known to be associated with compliance
`
`issues.3 For example, the patient is faced with the daily decision to either take the
`
`medication or instead take the abused substance to which he is addicted.
`
`Moreover, in patients experiencing drug-induced effects (or withdrawal
`
`therefrom), perception, motivation, cognition, memory, and decision-making may
`
`be impaired, posing further challenges to disciplined compliance with daily oral
`
`dosing regimens. (See Ex. 2004, at 1.)
`
`
`3 According to the Trexan and Revia labels, there were no data demonstrating a
`
`beneficial effect of Trexan and Revia on rates of recidivism among detoxified,
`
`formerly opioid-dependent individuals.” (Ex. 1023, at 936; Ex. 1040, at 937.) The
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`Revia label notes further that “[t]he failure of the drug in this setting appears to be
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`due to poor medication compliance.” (Ex. 1023, at 936.)
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`In addition, the susceptibility of oral naltrexone to high first-pass
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`Case IPR2018-00943
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`metabolism causes “widely fluctuating plasma levels that occur with daily dosing.”
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`(Ex. 2010, at 1974.) With each daily oral dose, high initial plasma levels of
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`naltrexone may precipitate withdrawal and cause side effects such as nausea,
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`vomiting, and dysphoria. (Id., at 1974, 1979; Ex. 1049, at 352; Ex. 1023, at 937.)
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`And, as shown by the below plot of oral naltrexone plasma levels, the dwindling
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`plasma levels at the end of the day may compromise treatment until the next dose
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`is taken. (Id.)
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`(Ex. 2007, at 19 (edited to focus on naltrexone data).)
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`Oral naltrexone’s compliance issues and fluctuating naltrexone plasma
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`concentrations combine to produce a potentially deadly scenario. In this regard,
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`the Trexan and Revia labels note that naltrexone’s antagonist effect is
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`Case IPR2018-00943
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`surmountable and warns that “any attempt by a patient to overcome the antagonism
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`by taking opioids is very dangerous and may lead to a fatal overdose.” (Ex. 1023,
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`at 937; Ex. 1040, at 938.) The labels acknowledge that an accidentally missed
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`dose of oral naltrexone coupled with a relapse to opioid use “may prove
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`dangerous.” (Ex. 1040, at 938 (stating that “lesser amounts of exogenous opioids
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`may prove dangerous if they are taken in a manner (i.e. relatively long after the last
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`dose of naltrexone) and in an amount that will persist in the body longer than the
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`effective concentrations of naltrexone and its metabolites.”); Ex. 1023, at 937
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`(similar).) They note further that “[i]njury may arise because the plasma
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`concentration of exogenous opioids attained immediately following their acute
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`administration may be sufficient to overcome the competitive receptor blockade”
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`and “[a]s a consequence, the patient may be in immediate danger of suffering life
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`endangering opioid intoxication.” (Ex. 1023, at 937; Ex. 1040, at 938.)
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`The use of depot injections to solve the issues with oral dosing was not a
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`novel idea in 2004. Naltrexone depot injections were originally conceived as early
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`as 1984 to solve the patient compliance problem. (Ex. 1025, at 704.) Trexan’s
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`approval in 1984 provided a basis for developing an injectable formulation that
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`could provide similar naltrexone exposure as 50 mg daily oral naltrexone. (Ex.
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`1040, at 937.) After some time, experimental depot injection formulations based
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`on this goal started to appear. For example, one depot formulation patented by the
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`Southern Research Institute in 2001 demonstrated AUC data that showed “fairly
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`Case IPR2018-00943
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`comparable exposure of naltrexone whether taking a 300 mg once monthly
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`injection or 50 mg orally once daily.” (Ex. 1015 (“Tice”), at 15:57-61.) But this
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`and other experimental injectable formulations failed to produce a meaningful
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`effect without serious adverse effects. (Ex. 1011, at 1076.) And a review of the
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`literature, including the references cited by Amneal, fails to show an established
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`dose capable of clinically treating a patient with an injectable naltrexone
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`formulation.4 As late as 2003 it was reported that several attempted formulations
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`failed to show clear evidence of clinical success due to “inconsistent initial and
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`sustained release rates, inadequate duration of release, suboptimal physical
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`characteristics (dose size/volume, naltrexone loading), and local site reactions.”
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`(Ex. 2010, at 1979-80 (citations omitted).)
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`4 See Ex. 1010 (192 mg or 384 mg); Ex. 1011 (206 mg); Ex. 1012 (63 mg) Ex.
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`1013 (103 mg or 206 mg); Ex. 1015 (300 mg); Ex. 1019 (52 mg or 104 mg); Ex.
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`1025 (63 mg).
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`Case IPR2018-00943
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`C. Vivitrol Is the Only FDA-Approved Depot Injection Product that
`Solves the Problems Associated With Oral Naltrexone
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`Alkermes submitted New Drug Application (“NDA”) No. 21897 for
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`Vivitrol5 on March 31, 2005, pursuant to section 505(b)(2), making reference to
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`the FDA’s previous finding of efficacy for the oral naltrexone drug, Revia. (Ex.
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`2001, at 1; Ex. 2007, at 6.) Based on the data submitted, the FDA observed that
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`the 380 mg dose of Vivitrol was a third of one month’s total dose for oral
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`naltrexone (i.e., 1400 mg per month), but provided an approximately 4-fold
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`increase in exposure to naltrexone relative to oral administration. (Ex. 2007, at 18-
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`19.) These data supported Alkermes’s claim of “increased efficacy and safety
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`compared to the available approved products to treat alcohol,” prompting the
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`FDA’s decision to give the application priority review. (Ex. 2016, at 1.)
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`The FDA recognized that “[c]onsistent product performance over 28 days is
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`pivotal for the safety and efficacy of” Vivitrol. (Ex. 2007, at 32.) This product
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`performance, in turn, relied on a precisely manufactured dose of 380 mg of
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`naltrexone, formulated in polylactide-co-glycolide (“PLGA”) microspheres of
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`specific molecular weight and lactide:glycolide (L:G) ratio, and suspended in a
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`precise diluent to provide a specific release profile characterized by three phases:
`
`an initial phase (releasing a quantity of surface-layer naltrexone), a hydration phase
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`5 Vivitrol was previously referred to as Vivitrex.
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`(releasing a quantity of subsurface naltrexone due to diffusion from the swollen
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`microspheres), and a sustained release phase (governing the release of a majority
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`Case IPR2018-00943
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`of the naltrexone due to polymer erosion). (See, e.g., Ex. 2003, at 39; Ex. 2007, at
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`27; Ex. 2011, at 2 of 19; Ex. 2013, at 2.) A plot of Vivitrol’s plasma concentration
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`over time showing the initial phase (which takes place during the first day), the
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`hydration phase (which takes place over the first week), and the sustained release
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`phase (which begins in the second week) is reproduced below:
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`(Ex. 2007, at 3, 19 (edited to show the three phases of release).)
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`The consistent performance of Vivitrol’s precise formulation is complex.
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`Vivitrol’s naltrexone release profile, and the resulting pharmacokinetics, are the
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`result of the precise composition of the microspheres and the molecular weight and
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`Case IPR2018-00943
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`L:G ratio of the polymer, as well as other potential factors such as the
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`“accompanying diluent, manufacturing and product quality, and the dynamic
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`interaction between the microspheres and the conditions at the IM injection and
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`depot site.” (Ex. 2011, at 2 of 19.) For example, the release of naltrexone from the
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`PLGA microspheres is affected by the “molecular weight of the polymer or
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`polymeric matrix material in the final microparticle product.” (Ex. 1018, at 1:25-
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`30 (incorporated by reference in the ’499 patent (Ex. 2012, at, e.g., 2:66-3:2)).)
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`Further, even slight variations in the manufacturing processes can lead to
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`higher amounts of surface naltrexone, which can cause differing initial-phase
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`release kineti