`
`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
`
`______________________
`
`DECLARATION OF CHARLES P. O’BRIEN, M.D., Ph.D.
`
`
`
`
`
`
`
`
`
`
`
`
`
`ALKERMES EXHIBIT 2056
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`Page 1 of 76
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`

`

`TABLE OF CONTENTS
`
`Page
`
`Contents
`INTRODUCTION ..................................................................................................... 1
`
`MY BACKGROUNDS AND QUALIFICATIONS ................................................. 1
`
`OPINIONS ................................................................................................................. 4
`
`A.
`
`Introduction ........................................................................................... 7
`
`B.
`
`C.
`
`Comer Does Not Teach Treating .......................................................... 9
`
`Vivitrol Satisfied a Long-Felt but Unmet Need for a Single-Injection
`Depot Formulation of Naltrexone ....................................................... 11
`
`1. Overview of Medications ............................................................... 11
`
`2. Vivitrol Offers Benefits Over Other Naltrexone Formulations ..... 13
`
`D. Vivitrol Faced Skepticism in the Industry .......................................... 15
`
`E.
`
`Vivitrol Has Received Industry Praise ................................................ 17
`
`CONCLUSION ........................................................................................................ 19
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`
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`I, Charles P. O’Brien, M.D., Ph.D., declare:
`
`INTRODUCTION
`
`1.
`
`2.
`
`I am of legal age and am competent to make this Declaration.
`
`I understand that the Patent Trial and Appeal Board has granted
`
`Amneal Pharmaceuticals LLC’s (“Amneal”) Petition for Inter Partes Review of
`
`claims 1–13 of U.S. Patent No. 7,919,499 (“the ’499 patent”).
`
`3.
`
`I understand the ’499 patent to be directed to Vivitrol, which was
`
`formerly known as “Vivitrex.”
`
`MY BACKGROUNDS AND QUALIFICATIONS
`
`4. My qualifications, professional experience, education, and
`
`publications are set forth in my curriculum vitae, attached as Appendix A. Below
`
`is a brief summary.
`
`5.
`
`I am a professor emeritus and have been a faculty member for the
`
`Department of Psychiatry at the University of Pennsylvania since 1971. I also
`
`recently served as its Vice-Chairman, a position I began in 1986. I first started
`
`teaching at the University of Pennsylvania in 1969 as an Instructor.
`
`6.
`
`I received my B.S. from Tulane University in 1960 and my M.D. from
`
`Tulane Medical School in 1964. In 1964 I also received a M.S. in Physiology
`
`(Neurophysiology) from The Graduate School at Tulane University and then in
`
`1966 I received a Ph.D. in Physiology (Neurophysiology) from The Graduate
`
`1
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`School at Tulane University. I completed residencies at multiple hospitals,
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`including the Massachusetts General Hospital in Boston and the National Hospital
`
`for Nervous Diseases in London.
`
`7.
`
`After completing my education I served in the Navy from 1969-1971.
`
`I was a Lieutenant Commander at the Philadelphia Naval Hospital and worked at
`
`the Long Term Neuropsychiatric Unit.
`
`8.
`
`I have held multiple positions at hospitals, including most recently the
`
`Director of Research, MIRECC at the VA Medical Center in Philadelphia, PA.
`
`Before this, I was the Chief of Psychiatry at the Philadelphia VA and I was
`
`responsible for over 9,000 psychiatric patients. I am also the Founding Director of
`
`the Center for Studies of Addiction at the University of Pennsylvania.
`
`9.
`
`I have received numerous awards, honors, and membership
`
`opportunities in honorary societies for my work. Some of these include the 2003
`
`Edward A. Strecker, M.D. Award for outstanding contributions to the field of
`
`Clinical Psychiatry, Pennsylvania Hospital and the Hospital of the University of
`
`Pennsylvania, the 2010 Gold Medal Award – Society of Biological Psychiatry, the
`
`2012 Special Dean’s Award for outstanding achievements in medical education –
`
`University of Pennsylvania. I have also received an Honorary Doctorate from the
`
`University of Bordeaux, France for research collaborations with French scientists.
`
`2
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`In addition, the National Institute on Drug Abuse presented me the 2015 Lifetime
`
`Science Award.
`
`10. More recently, I accepted an award from the Clinical Research Forum
`
`for an article titled, Extended-Release Naltrexone to Prevent Opioid Relapse in
`
`Criminal Justice Offenders, of which I was the senior author and principal
`
`investigator. This article was published in the New England Journal of Medicine.
`
`This award was for the Top Ten Clinical Research Achievement Awards
`
`Ceremony and recognizes major research advances. I also had the honor of giving
`
`the keynote address at the National Academy of Medicine’s Public Workshop of
`
`the Committee on Medication — Assisted Treatment for Opioid Use Disorder.
`
`11.
`
`I am also involved in numerous professional and scientific societies,
`
`including national societies such as the American College of
`
`Neuropsychopharmacology (President, 2001), the American Psychiatric
`
`Association, and the American Society of Clinical Psychopharmacology. I have
`
`also held editorial positions on journals such as Science, Journal of Pharmacology
`
`& Experimental Therapeutics, New England Journal of Medicine, Drug & Alcohol
`
`Dependence, Neuropsychopharmacology, Neuroscience, Life Science, American
`
`Journal of the Addictions, Biological Psychiatry, and others.
`
`12.
`
`I have authored or co-authored over 500 peer-reviewed articles, many
`
`of these on the treatment of addiction, including many on the topic of naltrexone
`
`3
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`use. I have also authored the addiction chapters of the Goodman & Gilman’s
`
`textbook, The Pharmacological Basis of Therapeutics.
`
`13.
`
`I am being compensated at my standard expert witness rate of $600
`
`per hour. My compensation in no way affects the statements in this declaration.
`
`Nor is my compensation dependent on the outcome of this IPR.
`
`OPINIONS
`
`14.
`
`I have been asked to provide opinions on Comer (Ex. 1010) and
`
`Vivitrol. In forming my opinions, I have reviewed the ’499 patent (Ex. 1001) and
`
`particularly the following exhibits:
`
`Exhibit #
`1001
`
`1010
`
`1011
`
`1012
`
`1013
`
`1015
`1019
`
`Description
`Elliot Ehrich, U.S. Patent No. 7,919,499 (issued Apr. 5, 2011) (“the
`’499 Patent”)
`Sandra D. Comer et al., Depot naltrexone: long-lasting antagonism of
`the effects of heroin in humans, 159(4) Psychopharmacology (Feb.
`2002)
`Henry R. Kranzler et al., Sustained-Release Naltrexone for
`Alcoholism Treatment: A Preliminary Study, 22(5) Alcoholism:
`Clinical and Experimental Research (Aug. 1998)
`C.N. Chiang et al., Clinical Evaluation of A Naltrexone Sustained-
`Release Preparation, 16 Drug & Alcohol Dependence (1985)
`T.N. Alim et al., Tolerability Study of A Depot Form of Naltrexone
`Substance Abusers, Problems of Drug Dependence, 1994:
`Proceedings of the 56th Annual Scientific Meeting, The College on
`Problems of Drug Dependence, Inc., Vol. II: Abstracts, National
`Institute on Drug Abuse Research Monograph 153 (1995)
`U.S. Patent No. 6,306,425 (“Tice”)
`S.J. Heishman et al., Safety And Pharmacokinetics of a New
`Formulation of Depot Naltrexone, Problems of Drug Dependence,
`1993: Proceedings of the 55th Annual Scientific Meeting, The
`College on Problems of Drug Dependence, Inc., Volume II: Abstracts,
`National Institute on Drug Abuse Research Monograph 141 (1994)
`
`4
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`
`
`1023
`1025
`
`1030
`
`1050
`
`2003
`
`2006
`
`2007
`
`2008
`
`2010
`
`2011
`
`2016
`
`ReVia, Physicians’ Desk Reference 936-938 (53rd ed. 1999)
`Chiang et al., Kinetics of a naltrexone sustained-release preparation,
`36(5) Clin. Pharmacol. Ther. (Nov. 1984), at 704-08 “Kinetic of a
`naltrexone sustained-release preparation.”
`Declaration of Kinam Park Ph.D in Support of Inter Partes Review of
`U.S. Patent No. 7,919,499
`B.A. Johnson, Naltrexone long-acting formulation in the treatment of
`alcohol dependence, 3(5) Ther. Clin. Risk Manag., 741-749 (2007), at
`742.
`Vivitrol® Prescribing Information, revised 12/2015
`(https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021897s
`029lbl.pdf)
`“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)
`“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)
`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)
`December 23, 2005 Division Director Approvable Memo for NDA
`No. 21897 (https://www.accessdata.fda.gov/drugsatfda_docs/
`nda/2006/021897_toc_Vivitrol.cfm)
`
`5
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`
`2020
`
`2023
`
`2037
`
`2038
`
`2039
`
`2040
`
`2041
`
`2042
`
`2043
`
`2045
`
`2046
`
`
`
`“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)
`Yun et al., “Controlled Drug Delivery: Historical perspective for the
`next generation,” Journal of Controlled Release, 219 2–7 (2015)
`“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)
`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/MATopioidUseDisord
`er/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)
`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)
`
`6
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`15. The bases for my opinions also include my education and decades of
`
`experience as a clinician and researcher in the field of addiction.1
`
`A.
`
`Introduction
`
`16. Progress in the development of effective, non-addictive, treatments for
`
`alcohol and opioid addiction has been hindered by the difficulties of maintaining
`
`
`1 I am aware of the definitions of a “Person of Ordinary Skill in the Art” set forth
`
`by Drs. Berkland and Park:
`
` Berkland: (“[A] POSA . . . is experienced in the field of controlled-release
`
`formulations. This field often requires collaborative teamwork among
`
`individuals with relevant experience, including pharmaceutical scientists,
`
`clinicians, and formulation scientists. Here, a POSA 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.”)
`
` Park: (“[O]ne of ordinary skill in the art would have a Pharm.D. or Ph.D.
`
`degree in pharmaceutics (also known as pharmaceutical chemistry or
`
`pharmaceutical science), chemistry, chemical engineering, or biomedical
`
`engineering with two or more years of experience in in the field of
`
`controlled-release formulations, or a Master's degree in said field with five
`
`or more years of experience in the field of controlled-release
`
`formulations.”).
`
`I agree with Dr. Berkland’s definition and have applied it here, but my opinions
`
`remain the same under either definition.
`
`7
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`patient compliance. (Ex. 2006 at Page 26 of 40.) For example, oral naltrexone, a
`
`product that was first approved by the FDA in 1984, has been shown to reduce
`
`craving for alcohol and opioids. (Ex. 2008 at Page 42 of 126; Ex. 2006 at Pages
`
`26–27 of 40.) While oral naltrexone may reduce cravings, individuals frequently
`
`do not comply with the daily dosing as is required for oral naltrexone to be
`
`effective. (Ex. 1023 at 936; Ex. 2006 at Page 26 of 40.) This problem with patient
`
`compliance resulted in oral naltrexone having limited success in treating addicts.
`
`(Ex. 2006 at Page 26 of 40.)
`
`17. To address this problem of patient compliance, researchers, as early as
`
`1980s, were actively pursuing approaches to overcome the patient compliance
`
`shortcomings. (Ex. 2006 at 26 of 40 (noting that “[n]altrexone has been available
`
`for more than 2 decades”); Ex. 1015.) While multiple attempts were made to
`
`develop a long-lasting naltrexone formulation (e.g., Ex. 1015 at Abstract
`
`(disclosing an “injectable slow-release naltrexone formulation” that had “use in the
`
`treatment of heroin addicts and alcoholics to reduce consumption of the abused
`
`substances”); Ex. 1010; Ex. 1050), Vivitrol was the first (and is the only) non-
`
`narcotic, non-addictive depot injection to be approved by the FDA for the
`
`treatment of alcohol dependence and for the prevention of relapse to opioid
`
`dependence following opioid detoxification. (Ex. 2020 at Page 2 of 8; Ex. 2003;
`
`Ex. 2011 at Page 2 of 19.) In other words, Vivitrol is the only FDA approved
`
`8
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`naltrexone formulation that helps address the patient compliance shortcomings
`
`associated with oral naltrexone.
`
`18. This single injection, once-monthly, naltrexone formulation
`
`breakthrough has received praise for its ability to treat individuals in need of
`
`naltrexone for 28-days at a time. (E.g., Ex. 2007 at Page 34 of 43 (noting Vivitrol’s
`
`“[c]onsistent product performance over 28 days is pivotal for [its] safety and
`
`efficacy”).) Vivitrol, through its ability to address the patient compliance
`
`shortcomings that oral naltrexone faced, “represents a significant advancement in
`
`addiction treatment.” (Ex. 2037.)
`
`B. Comer Does Not Teach Treating
`
`19. Comer does not teach treating individuals in need of naltrexone.
`
`Indeed, Comer expressly excluded individuals “if they were seeking drug
`
`treatment” (Ex. 1010 at 352), and only “during the last week of [Comer’s] study”
`
`were its participants finally “offered referrals for treatment” (Ex. 1010 at 353.)
`
`Notably, Comer consistently refers to individuals receiving naltrexone as
`
`“participants” undergoing “test[s],” and not as “patients” receiving “treatment.”
`
`(See, e.g., Ex. 1010 at 354 (“the low dose of Depotrex was tested in the first six
`
`participants, and the high dose of Depotrex was tested in the next six
`
`participants”).) Though its study participants are “heroin-dependent,” Comer gives
`
`them a range of heroin doses going from low to high. (Ex. 1010 at 351 (Abstract).)
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`This is not treatment. One does not treat heroin addicts by giving them ascending
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`doses of heroin.
`
`20. To the extent that Comer discusses “effective[ness],” that term is
`
`directed to pharmacological effect (i.e., “antagonism of the effects of heroin” (see,
`
`e.g., Ex. 1010 at 351 (Abstract)), and not a therapeutic one. That effect certainly is
`
`not sufficient for treatment. Indeed, Comer identified exploring potential
`
`“treatment implications” as a goal for “future studies.” (Ex. 1010 at 359.)
`
`21. Comer does not teach treatment simply because of the mean plasma
`
`levels depicted in Figure 1, as Dr. Park suggests. (See, e.g., Ex. 1030 ¶ 60
`
`(“naltrexone provides effective treatment as long as its blood concentration is
`
`maintained at or above 1 ng/ml”).) There is no one-size-fits-all plasma level of
`
`naltrexone to obtain a therapeutic effect. For example, there is scientific literature
`
`from August 2003 that refers to 2 ng/mL as the “minimum therapeutic range” that
`
`is required “to develop an acceptable and effective sustained-release formulation of
`
`naltrexone.” (Ex. 2010 at 1980 (citing Ex. 2038 at 156 (“in therapy . . . plasma
`
`levels of 2.0 ng/ml or greater should be maintained”) (emphases added).)
`
`22. Nor does Comer teach treatment of alcohol-dependent individuals in
`
`particular. This is because, among other things, Comer expressly excluded
`
`participants “if they were . . . dependent on alcohol.” (Ex. 1010 at 352.) To the
`
`extent that Comer mentions Kranzler’s results, it says nothing of whether they
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`could translate to much higher doses and not be offset by negative side effects.
`
`(Ex. 1010 at 352.) Indeed, Kranzler recommended decreasing its 206 mg dose in
`
`order to reduce adverse effects, even if doing so would require more frequent
`
`injections. (Ex. 1011 at 1078.) In contrast, the lowest dose recited in the contested
`
`claims of the ’499 patent is “about 310 mg” (Ex. 1001 at 21:4), which is around
`
`150% of the dose that Kranzler suggests lowering (Ex. 1011 at 1078).
`
`C. Vivitrol Satisfied a Long-Felt but Unmet Need for a Single-
`Injection Depot Formulation of Naltrexone
`
`1. Overview of Medications
`
`23. Besides naltrexone products, the FDA has only approved a limited
`
`number of drugs to treat drug addiction and drug dependence. Some of the drugs
`
`that the FDA has approved for long-term opiate abuse include methadone and
`
`buprenorphine. (Ex. 2006 at Page 26 of 40.) For alcohol abuse, the FDA has
`
`approved drugs such as acamprosate and disulfiram. (Ex. 2006 at Page 26 of 40.)
`
`While these drugs have had many positive impacts in the treatment of addiction,
`
`they also have flaws.
`
`24. For example, methadone is an opioid agonist and buprenorphine is a
`
`partial opioid agonist, whereas Vivitrol is an opioid antagonist (Ex. 2020 at Page 2
`
`of 8.) As agonists, methadone and buprenorphine have abuse potential and
`
`individuals remain physically dependent on opioids. (Ex. 2020 at Page 2 of 8;
`
`Ex. 2039 at 23–24.) If a dose is delayed or missed, the individual may suffer
`
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`withdrawal symptoms. (Ex. 2039 at 23.) In addition, some physicians are reluctant
`
`to treat opioid dependence with agonists, which tend to face a stigma in
`
`“traditional treatment settings.” (Ex. 2020 at Page 2 of 8; Ex. 2039 at 24.)
`
`25. Methadone and buprenorphine also require daily dosing (Ex. 2020
`
`at Page 3 of 8), which tends to create difficulties in ensuring patient compliance
`
`(i.e., Ex. 1010 at 352 (discussing short comings of oral naltrexone)). In addition,
`
`the ability for a physician to prescribe buprenorphine requires special training and
`
`a DEA prescribing waiver. (Ex. 2020 at Page 3 of 8.) Methadone is also strictly
`
`controlled, and can be purchased only at a certified methadone treatment program
`
`or in certain hospitals. (Ex. 2020 at Page 3 of 8.)
`
`26. FDA-approved drugs for treating alcohol abuse also have their
`
`shortcomings. For example, acamprosate must be taken three times per day.
`
`(Ex. 2008 at Page 29 of 126.) As such, there are challenges in maintaining patient
`
`adherence which have resulted in health care providers trying to establish creative
`
`ways to ensure the individual remembers to take the three daily pills. (Ex. 2008
`
`at Page 29 of 126.)
`
`27. Disulfiram was approved by the FDA in the 1950s without a positive
`
`clinical trial and has resulted in “severe reactions” when alcohol is consumed after
`
`disulfiram has been administered. (Ex. 2008 at Page 31 of 126.) As a result, the
`
`“therapeutic emphasis [has] shift[ed] from using disulfiram for aversion
`
`12
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`conditioning to using it to support abstinence.” (Ex. 2008 at Page 31 of 126.) In
`
`addition, since disulfiram disrupts the metabolism of alcohol, relapsing disulfiram
`
`takers may experience adverse reactions that can be moderate (i.e., nausea) or
`
`severe (i.e., death). (Ex. 2008 at Pages 31–32 of 126.) Its potential for severe
`
`adverse effects has led to a black-box warning from the FDA. (Ex. 2008 at Page 34
`
`of 126.)
`
`28. As a result of the limited medications available in the field of
`
`addiction, I have been a major proponent of Vivitrol. Unlike the above mentioned
`
`drugs, Vivitrol does not have the same level of concerns regarding overdose risk,
`
`negative stigma, or severe adverse side effects associated with it. (Ex. 2039 at 23–
`
`24; Ex. 2020.)
`
`2.
`
`Vivitrol Offers Benefits Over Other Naltrexone
`Formulations
`
`29. Before the application for the ’499 patent (in April 2004), patient
`
`compliance and fluctuating plasma concentration levels were recognized as
`
`significant barriers to clinical utility of naltrexone as a maintenance therapy for
`
`addiction. (Ex. 1010 at 351; Ex. 2010 at 1974.).) Indeed, the possibility that
`
`sustained-release forms of naltrexone could increase compliance and ultimately
`
`improve treatment effectiveness had been researched for decades. (See, e.g.,
`
`Ex. 1010 at 352.)
`
`13
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`30. Development of a satisfactory, long-acting formulation of naltrexone
`
`was difficult for many reasons. One of the challenges was ensuring that effective
`
`levels of drug were maintained, but without reaching any hazardous level.
`
`(Ex. 1015 at 2:8-25.) Developers also had to consider the potential influence of
`
`naltrexone’s metabolites (including, for example, its active metabolite) and ensure
`
`that they remain at acceptable levels. (Ex. 1015 at 2:8-25.) Patient compliance was
`
`also a central concern. (Ex. 1030 ¶ 54.) The “difficulty associated with developing
`
`parenteral depot formulations” is apparent from, among other things, the fact that
`
`there are many more oral sustained release formulations than depot formulations.
`
`(Ex. 2023 at 5.)
`
`31. Before Vivitrol, which was the first (and only) FDA-approved form of
`
`sustained-release naltrexone (Ex. 2011 at Page 2 of 19), naltrexone depot
`
`formulations failed to show “clear evidence of clinical success, for reasons
`
`including initial and sustained release rates, . . . inadequate duration of release,
`
`suboptimal physical characteristics (dose size/volume, naltrexone loading), and
`
`local site reactions.” (Ex. 2010 at 1979-80.) There was no consensus on target
`
`dose, and research teams were investigating a wide range of doses. (See, e.g., Ex.
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`1010 (192 and 384 mg); Ex. 1011 (206 mg); Ex. 1012 (63 mg); Ex. 1013 (103 and
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`206 mg); Ex. 1015 (150-300 mg); Ex. 1019 (52 mg); Ex. 1025 (63 mg).)
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`32. For example, Kranzler (Ex. 1011) reports on one of the naltrexone
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`depot formulations being tested prior to Vivitrol. The Biotek-produced formulation
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`used by Kranzler never received FDA approval and was eventually abandoned,
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`perhaps because of the prevalence of indurations that occurred (Ex. 1011 at 1074.).
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`As another example, DrugAbuse Sciences also attempted to develop a naltrexone
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`depot formulation called Naltrel. (Ex. 1050 at 742.) Further, Southern Research
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`Institute attempted to develop a depot formulation of naltrexone (Ex. 1015
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`at Abstract.) These companies abandoned their efforts as well.
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`33. Vivitrol, however, received FDA approvals in 2006 and 2010, making
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`it the first (and only) non-addictive depot injection product to be approved by the
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`FDA for treating alcohol dependence and for the prevention of relapse to opioid
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`dependence following opioid detoxification. (Ex. 2011 at Pages 2, 4, 17 of 19;
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`Ex. 2003.)
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`D. Vivitrol Faced Skepticism in the Industry
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`34. Prior to its launch, there was much industry skepticism about Vivitrol
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`and its potential therapeutic effectiveness. For instance, Vivitrol requires a single
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`injection of 380 mg naltrexone. (Ex. 2003 at Pages 1, 8, 26 of 39.) Kranzler tested
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`much less than that (i.e., 206 mg) and reported indurations in 73% of treated
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`subjects. (Ex. 1011 at 1076.) Indurations are a problem because they lead to patient
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`discomfort and infections, which lessens patient retention and compliance.
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`(Ex. 2040 at 123.) To reduce such adverse effects, Kranzler suggests decreasing
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`the total dose per injection, directing researchers away from the much higher dose
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`ultimately used by Vivitrol. (Ex. 1011 at 1078.)
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`35. There has been concern that relapsing addicts might attempt to
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`override naltrexone’s pharmacological blockade (in other words, they might
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`simply take more heroin to surmount the blockade and achieve a “high”).
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`(Ex. 2041 at 9.) This concern was first seen in animal studies. (Ex. 2042 at
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`Abstract.) Some studies found evidence that an addict would not override the
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`blockade, but the possibility of accidental overdose was a major concern in the
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`industry and is one that researchers and regulators continue to monitor. (E.g.,
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`Ex. 2041 at 9; Ex. 2043 at 1238; Ex. 2020 at Pages 2–3 of 8.)
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`36. Similarly concerning is the possibility that a relapsing addict, no
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`longer feeling the euphoria associated with opioids because of the naltrexone-
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`caused blockade, may turn to other, non-opioid drugs to achieve a “high.”
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`(Ex. 2041 at 9.) This concern remained for years after the launch of Vivitrol and
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`led me to explore the issue in my 2016 article titled, Extended-Release Naltrexone
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`to Prevent Opioid Relapse in Criminal Justice Offenders. (Ex. 2043.) There, my
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`colleagues and I were finally able to show that extended-release naltrexone did not
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`lead to increased use of other, non-opioid drugs, such as cocaine and alcohol.
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`(Ex. 2043 at Abstract.)
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`E. Vivitrol Has Received Industry Praise
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`37. Vivitrol has received praise since its launch and, from my experience,
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`is becoming increasingly prevalent for the treatment of addiction.
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`38.
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`Indeed, Vivitrol received “priority review” designation from the FDA.
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`(Ex. 2016 at Page 1 of 9.) The FDA awards that designation “[o]n a case-by-case
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`basis,” based on “whether the proposed drug would be a significant improvement
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`in the safety or effectiveness of the treatment, prevention, or diagnosis of a serious
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`condition.” (Ex. 2046 at 24 (emphasis in original).) The FDA observed that the
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`exposure of naltrexone resulting from Vivitrol is several fold greater than that of
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`Revia (50 mg oral naltrexone) yet requires less than a third of the amount of
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`naltrexone to be administered to an individual (i.e., for 28 days of oral naltrexone
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`an individual would require the administration 1400 mgs of naltrexone whereas for
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`Vivitrol only a single, 380 mg dose is required.) (Ex. 2007 at Page 22 of 43;
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`Ex. 2016 at Page 1 of 9.)
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`39.
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`In addition, my colleagues and I have reported that Vivitrol “offers
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`potential advantages by alleviating the patient burden of daily dosing, and reduced
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`total dosage which may lead to better medication adherence, reduced risk of
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`toxicity and improved outcomes.” (Ex. 2045 at 502.)
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`40. More recently, in a summit hosted by the National Academies of
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`Sciences, Engineering, and Medicine, Dr. Adam Bisaga, from Columbia
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`University and the New York State Psychiatric Institute referred to Vivitrol “as an
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`element of the comprehensive medical response to the opioid epidemic.”2
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`(Ex. 2039 at 1.) Dr. Bisaga noted that Vivitrol, unlike methadone and
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`buprenorphine, has no overdose risk and no potential for misuse. (Ex. 2039 at 24.)
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`41. Further, I co-authored an article in the New England Journal of
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`Medicine that received multiple awards for its reporting on the profound advances
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`and impacts of Vivitrol in treating opioid addiction. (Ex. 2043.) Among other
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`things, the article highlights that Vivitrol “was associated with a rate of opioid
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`relapse that was lower than that with usual treatment.” (Ex. 2043 at 1232, 1240–
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`1241.)
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`2 Dr. Bisaga’s presentation uses the term “XR-naltrexone,” but since Dr. Bisaga is
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`speaking only of “FDA-Approved Medication for [Opioid Use Dependence]”
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`(Ex. 2039 at 2), it is clear that XR-naltrexone refers specifically to Vivitrol (i.e.,
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`the only FDA-approved, extended-release naltrexone product).
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`CONCLUSION
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`42.
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`I declare that all statements made herein of my knowledge are true,
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`and that all statements made on information and belief are believed to be true, and
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`that these statements were made with the knowledge that willful false statements
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`and the like so made are punishable by fine or imprisonment, or both, under
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`Section 1001 of Title 18 of the United States Code.
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`Date: «21512012
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`flfizé fléfi
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`Charles P. O’Brien, M.D., Ph.D.
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`Page 21 of 76
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`Appendix A
`Appendix A
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`Page 22 of 76
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`UNIVERSITY OF PENNSYLVANIA SCHOOL OF MEDICINE
`CURRICULUM VITAE 2018
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`
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`CHARLES PHILLIP O'BRIEN
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`Home Address:
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`Office Address:
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`Phone:
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`Internet:
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`Place of Birth:
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`Marital Status:
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`Education:
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`Residency Training:
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`232 Beech Hill Road
`Wynnewood, Pennsylvania 19096-1110
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`University of Pennsylvania
`Department of Psychiatry
`3535 Market Street
`Philadelphia, Pennsylvania 19104-6178
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`(215) 287 5604
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`obrien@pennmedicine.upenn.edu
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`New Orleans, Louisiana
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`Married, 1960 - Barbara Earnest
`Children: Charles, Evan, and Clinton
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`B.S. 1960
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`M.D. 1964
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`Tulane University
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`Tulane Medical School
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`1964
`M.S.
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`Ph. D. 1966
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`1964-65
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`1965-67
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`1967-68
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`Physiology (Neurophysiology)
`The Graduate School, Tulane University
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`Physiology (Neurophysiology)
`The Graduate School, Tulane University
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`Internal Medicine
`Massachusetts General Hospital
`Harvard Medical School
`Boston, Massachusetts
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`Neurology and Psychiatry
`Tulane University, New Orleans
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`National Hospital for Nervous Diseases
`Queen Square,
`London, England
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`Specialty Certification:
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`Military Service:
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`Faculty Appointments:
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`1968-69
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`Psychiatry
`University of Pennsylvania
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`American Board of Psychiatry and Neurology
` Certificate in Neurology - 1972, No. 12052
` Certificate in Psychiatry - 1973, No. 12796
` Certificate in Addiction Psychiatry 1993, # 314, re-certified 2003
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`1969-71
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`1965-66
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`1966-67
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`1969-71
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`Lieutenant Commander, US Navy
`Philadelphia Naval Hospital
`Chief, Long Term Neuropsychiatric Unit
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`Teaching Assistant in Neurophysiology
`Department of Physiology
`Tulane Medical School
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`Instructor in Physiology (Neurophysiology)
`Tulane Medical School
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`Instructor in Psychiatry
`University of Pennsylvania
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`1971-74
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`Assistant Professor of Psychiatry
`University of Pennsylvania
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`1974-78
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`Associate Professor of Psychiatry
`University