UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`APOTEX INC.
`Petitioner
`
`v.
`
`ALKERMES PHARMA IRELAND LIMITED
`Patent Owner
`__________________
`
`Case No. IPR2025-00514
`Patent 7,919,499
`__________________
`
`DECLARATION OF JASON SCHIFFMAN, M.D. IN SUPPORT OF
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 7,919,499
`
`APOTEX EXHIBIT 1048
`Apotex v. Alkermes
`IPR2025-00514
`
`

`

`Declaration of Jason Schiffman
`
`TABLE OF CONTENTS
`
`
`
`
`
`
`
`
`Page
`INTRODUCTION ........................................................................................... 1
`BACKGROUND AND QUALIFICATIONS ................................................. 1
` THE ’499 PATENT ......................................................................................... 2
` PERTINENT PROSECUTION HISTORY OF THE ’499 PATENT ............. 6
` A PERSON OF ORDINARY SKILL IN THE ART ...................................... 8
` CLAIM CONSTRUCTION ............................................................................ 9
`“the step of parenterally administering a long acting
`formulation comprising about 310 mg to about 480 mg of
`naltrexone” ............................................................................................ 9
`“the serum AUC of naltrexone … than that achieved by 50
`mg/day oral administration” ................................................................ 10
`“about three” ........................................................................................ 13
`“five or more days” ............................................................................. 14
`“initial oral dose” ................................................................................. 14
`“about 35% by weight” ....................................................................... 15
`
` TECHNICAL BACKGROUND AND STATE OF THE ART .................... 15
` SUMMARY OF THE PRIOR ART .............................................................. 18
`A.
`Comer (EX1004) ....................................................................... 18
`B.
`Nuwayser (EX1005) ................................................................. 21
`C.
`Rubio (EX1006) ........................................................................ 22
`D. Wright (EX1007) ...................................................................... 23
` THE CHALLENGED CLAIMS WERE READILY APPARENT TO A
`POSITA ......................................................................................................... 24
`
`
`
`
`
`
`
`
`
`i
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`Declaration of Jason Schiffman
`
` A Single Injection Would be Obvious Based on Comer in View
`of Nuwayser and/or Nuwayser in view of Comer and Either in
`View of Wright and Rubio .................................................................. 24
`CONCLUSION .............................................................................................. 28
`
`
`
`
`
`
`
`
`ii
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`Declaration of Jason Schiffman
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`
`
`EXHIBIT LIST
`
`EXHIBIT DESCRIPTION
`
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`U.S. Patent No. 7,919,499, issued on April 5, 2011 to E. Ehrich
`(“the ’499 Patent”)
`
`File History of U.S. Patent Application No. 11/083,167, filed on
`March 17, 2005 (“the ’167 Application)
`
`U.S. Provisional Application No. 60/564,542, filed on April 22,
`2004
`
`Sandra D. Comer et al., Depot naltrexone: long-lasting
`antagonism of the effects of heroin in humans, 159(4)
`Psychopharmacology (Feb. 2002), at 351-360
`
`U.S. Patent No. 7,157,102, issued on January 2, 2007 to E.
`Nuwayser (“the ’102 Patent” or “Nuwayser”)
`
`G. Rubio et al., Naltrexone Versus Acamprosate: One Year
`Follow-Up of Alcohol Dependence Treatment, 36(5) Alcohol &
`Alcoholism (2001), at 419-425
`
`U.S. Patent No. 6,264,987, issued on July 24, 2001 to S. Wright
`et al. (“the ’987 Patent” or “Wright”)
`
`Henry R. Kranzler et al., Sustained-Release Naltrexone for
`Alcoholism Treatment: A Preliminary Study, 22(5) Alcoholism:
`Clinical and Experimental Research (Aug. 1998), at 1074-79
`
`U.S. Patent No. 6,306,425, issued on October 23, 2001 to T.
`Tice et al. (“Tice”)
`
`C.N. Chiang et al., Clinical Evaluation of A Naltrexone
`Sustained-Release Preparation, 16 Drug & Alcohol Dependence
`(1985), at 1-8
`
`iii
`
`

`

`Declaration of Jason Schiffman
`
`EXHIBIT DESCRIPTION
`
`1011
`
`1012
`
`1013
`
`1014
`
`1016
`
`1017
`
`1018
`
`1019
`
`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), at 253
`
`U.S. Securities and Exchange Commission, FORM 10-K, Annual
`Report Pursuant to Section 13 or 15(d) of the Securities
`Exchange Act of 1934 for the fiscal year ended March 31, 2002.
`Alkermes, Inc. (July 2002)
`
`U.S. Trademark Application Serial Number 76/271,990,
`Allegation of Use of a Mark & specimen of the mark as used in
`commerce, Aug. 15, 2002 (“Vivitrex Specimen” or “Specimen”)
`
`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)
`
`Stewart B. Leavitt, PhD, ed., Evidence for the Efficacy of
`Naltrexone in the Treatment of Alcohol Dependence
`(Alcoholism), Addition Treatment Forum Naltrexone Clinical
`Update (2002 Clinco Communications, Inc.), at 1-8
`
`ReVia, Physicians’ Desk Reference 936-938 (53rd ed. 1999)
`(“PDR”)
`
`U.S. Patent No. 4,882,335, issued on November 21, 1989 to J.
`Sinclair (“Sinclair”)
`
`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.”
`
`iv
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`

`Declaration of Jason Schiffman
`
`EXHIBIT DESCRIPTION
`
`1020
`
`1025
`
`1029
`
`1031
`
`1042
`
`1046
`
`1049
`
`1055
`
`1056
`
`1058
`
`1060
`
`1061
`
`Reuning et al., Pharmacokinetic Quantitation of Naltrexone
`Release From Several Sustained-Release Delivery Systems,
`Naltrexone: Research Monograph 28 (R. E. Willette and G.
`Barnett, eds. National Institute on Drug Abuse 1980)
`
`Orange Book: Approved Drug Products with Therapeutic
`Equivalence Evaluations, Product Details for NDA 018932,
`REVIA (NALTREXONE HYDROCHLORIDE) 50MG
`
`TREXAN™, Physicians’ Desk Reference 936-938 (46 ed. 1992)
`(“PDR”), at 937-939
`
`Orange Book: Approved Drug Products with Therapeutic
`Equivalence Evaluations, NALTREXONE (VIVITROL) FOR
`SUSPENSION, EXTENDED RELEASE 380MG/VIAL
`
`U.S. Patent No. 3,332,950, issued on July 25, 1997 to H.
`Blumberg
`
`Declaration of Thomas Dowling
`
`Curriculum Vitae of Jason Schiffman
`
`Declaration Under 37 C.F.R. §1.132 of Elliot Ehrich filed in
`Application No. Serial No. 11/083,167
`
`S. Hamilton et al., Pharmacokinetics and Pharmacodynamics of
`Hyaluronan Infused Healthy Human Volunteers, 3 The Open
`Drug Metabolism Journal 43-55 (2009)
`
`Institution Decision entered November 7, 2018 (Paper 8) in
`IPR2018-00943
`
`Patent Owner’s Response, filed February 7, 2019 (Paper 14) in
`IPR2018-00943
`
`U.S. Patent No. 5,210,083, issued on May 11, 1993 to R.
`Pfirrmann
`
`v
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`

`

`Declaration of Jason Schiffman
`
`EXHIBIT DESCRIPTION
`
`1062
`
`1063
`
`U.S. Patent No. 5,234,906, issued on August 10, 1993 to A.
`Young and G. Cooper
`
`U.S. Patent No. 6,677,320, issued on January 13, 2004 to A.
`Diederich et al.
`
`
`
`
`vi
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`

`

`Declaration of Jason Schiffman
`
`I, Jason Schiffman, declare and state as follows
`
`
`
`INTRODUCTION
`1.
`I am a U.S. citizen and a resident of the State of California.
`
`2.
`
`I have been retained by Buchanan Ingersoll & Rooney PC (“counsel”)
`
`to provide my opinions in the field of pharmaceutical formulation for purposes of
`
`supporting a petition for Inter Partes Review (“IPR”). I have read and understand
`
`U.S. Patent No. 7,919,499 (“the ’499 Patent”) (EX1001) as well as all other
`
`references discussed in this declaration. I am being compensated for my time in an
`
`amount consistent with my customary consulting fee, and my compensation is not
`
`contingent on my opinion or the outcome of this proceeding.
`
` BACKGROUND AND QUALIFICATIONS
`3.
`I am the founder of Camden Center, an internationally recognized
`
`center of excellence for the treatment of psychiatric, addictive, and eating disorders.
`
`A copy of my CV is attached as EX1049. It contains a description of my education,
`
`academic appointments, professional activities, and publications.
`
`4.
`
`I am a Diplomate of the National Board of Psychiatry and Neurology
`
`and am certified in Addiction Medicine by the American Board of Preventive
`
`Medicine. I am also the founder and Medical Director of the UCLA Dual Diagnosis
`
`Program and have written extensively on the subjects of addiction, trauma, anxiety,
`
`and depression in both the academic and popular press.
`
`1
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`

`Declaration of Jason Schiffman
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`5.
`
`I completed my residency in psychiatry at the UCLA Semel Institute
`
`for Neuroscience and Human Behavior.
`
`6.
`
`I am a graduate of the MD/MBA program at the University of Southern
`
`California and received a Master of Arts degree in Linguistics from UCLA where I
`
`specialized in syntax and semantics.
`
`7.
`
`I have extensive research experience in psychopharmacology and
`
`molecular biology and am the author of numerous scientific publications in these
`
`fields.
`
`8.
`
`In my practice, I am familiar with various controlled release
`
`pharmaceuticals and their uses in patients. I am also aware of and have experience
`
`in administering controlled release pharmaceuticals to patients and have done so for
`
`14 years.
`
`9.
`
`In my clinical and research experience, I have worked on teams that
`
`include, in addition to other clinicians, research scientists experienced with
`
`pharmacokinetics as well as pharmaceutical formulations that have controlled
`
`release characteristics.
`
` THE ’499 PATENT
`10.
`I understand from the face of the ’499 Patent (EX1001) that it issued
`
`on April 5, 2011, from U.S. Application Serial No. 11/083,167 (“the ’167
`
`Application”), which was filed on March 17, 2005. The ’499 Patent states on its face
`
`2
`
`

`

`Declaration of Jason Schiffman
`
`that it claims the benefit of U.S. Provisional Application No. 60/564,542, filed April
`
`22, 2004 (“the Provisional Application”) (EX1003). I have been advised by counsel
`
`to assume that the earliest possible effective filing date for the ’499 Patent is April
`
`22, 2004.
`
`11. The ’499 Patent alleges that the “inventions described herein arose from
`
`unexpected discoveries made during clinical trials with a long acting formulation of
`
`naltrexone.” EX1001, Abstract, 1:31-33. The allegedly unexpected discovery was
`
`that the AUC from the depot formulation tested was at least three times that observed
`
`from 50 mg/day oral dosing. I note that the specification does not provide any data
`
`allowing one to review or calculate the claimed differential (“differential”) between
`
`any claimed formulation and 50 mg/day oral dosing.
`
`12. The specification discusses the need for improving naltrexone therapies
`
`by improving patient compliance. EX1001, 1:13-26. It is my understanding that
`
`Alkermes never equated its discovered difference in a pharmacokinetic property to
`
`any meaningful therapeutic difference. I believe it is worth noting that the ‘499
`
`Patent did not suggest that it provided a cure to alcohol use disorder or any other
`
`substance use disorder. I understand that using its own data, while the claimed
`
`injection tested against a placebo did reduce the rate at which patients relapsed—11
`
`out of 28 patients still relapsed during the 12-week test period. EX1001, 18:48-52.
`
`I understand it acknowledged that based on semi-quantitative comparisons of three
`
`3
`
`

`

`Declaration of Jason Schiffman
`
`meta-analyses, “the efficacy of Vivitrex suspension compares favorably with oral
`
`naltrexone.” Id., 19:30-34. I understand it did not, however, argue superior efficacy.
`
`I believe that a POSITA would read the phrase “compares favorably” in this context
`
`as no better than oral naltrexone. I understand what is meant by that is that there is
`
`no evidence of efficacy improvement and that there was no argument of superior
`
`efficacy and no “meaningful” evidence in the patent or raised during prosecution
`
`that would allow a POSITA to draw a conclusion of improved efficacy or
`
`superiority. I understand that a POSITA would note Alkermes’ acknowledgement
`
`that there were no direct studies comparing these two dosing protocols. I understand
`
`that they would know that to make any valid claim of improved efficacy would
`
`require a properly structured clinical study such as a randomized, or crossover,
`
`double-blind trial. I understand that meta-analysis alone offers uncertain weight to a
`
`POSITA, which is perhaps reflected by the fact that, during prosecution, Alkermes
`
`did not make more of any alleged efficacy improvements. I understand that
`
`Alkermes never explained why any argued improvement in efficacy over oral dosing
`
`was not completely attributable to compliance improvements which were known to
`
`result from using a long acting injection over oral dosing. I also understand that
`
`Alkermes never linked any efficacy difference to a difference in AUC.
`
`13. From my review, I understand that naltrexone is combined with well-
`
`known polymers, such as PLGA, to “entrap or encapsulate” the naltrexone to form
`
`4
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`

`

`Declaration of Jason Schiffman
`
`long acting formulations. EX1001, 3:14-15. I saw that the specification describes its
`
`formulations as releasing naltrexone over a period of at least one week. Id., 4:42-44.
`
`It then describes “Vivitrex” as a monthly administration that releases naltrexone for
`
`four weeks and states that the therapy can be maintained for 24 weeks or more. Id.,
`
`4:55-64.
`
`14. The specification further includes five examples, three of which were
`
`not present in the original provisional application to which the ’499 Patent claims
`
`priority. EX1001; EX1003. Example 1 describes how to manufacture the Vivitrex
`
`formulations. The microparticles manufacturing procedure portion of this example
`
`is virtually identical to the preparation described by Example 3 of Wright. Compare
`
`EX1001, 3:3-33, 5:35-8:2 and EX1007, 7:48-8:60; see ¶133, infra.
`
`15.
`
`I saw that the remaining examples describe various aspects of a clinical
`
`trial, none of which provide any data for AUC or the claimed AUC differential. For
`
`example, Example 2 describes screening, eligibility, and adverse events. EX1001,
`
`8:5-18:2. Example 3 compares the “efficacy” of oral verse injectable naltrexone, but
`
`clearly states that “a direct head-to-head comparison of efficacy has not been
`
`studied” and thus “a definitive comparison of efficacy between Vivitrex and oral
`
`naltrexone cannot be made.” Id., 18:8-12. Instead, as noted above, the specification
`
`admits to using data from three non-related studies for a “semi- quantitative
`
`comparison.” Id., 18:12-29, 19:30-33. Examples 4 and 5 were directed to “quality of
`
`5
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`

`

`Declaration of Jason Schiffman
`
`life” and “durability of effect and tolerability” of long acting naltrexone
`
`formulations. Again, none of the examples provided any data regarding AUC.
`
`16. The ’499 Patent then claims a method of treating an individual in need
`
`of naltrexone by parenterally administering a long acting formulation that includes
`
`310-480 mg of naltrexone and a biocompatible polylactide-co-glycolide (“PLGA”)
`
`polymer to the individual, where the serum AUC of naltrexone is about three times
`
`greater than what is achieved by administration of 50 mg/day oral administration.
`
`EX1001, 21:2-8, 22:15-22. The amount of naltrexone in the formulations claimed
`
`varies from a range of between 190 mg to 240 mg (claim 14) and 310 mg to about
`
`480 mg of naltrexone (claim 1).
`
` PERTINENT PROSECUTION HISTORY OF THE ’499 PATENT
`17. While I have been an inventor on a patent application, I do not have
`
`extensive experience in patent law. Therefore, when I review the ’499 Patent
`
`prosecution history, I do so as a technical expert.
`
`18.
`
`I understand and have been informed by counsel that the ’499 Patent
`
`was filed under 37 C.F.R. §1.102(e) on March 17, 2005, as the ’167 Application. I
`
`understand that a non-final rejection was mailed on May 5, 2009 (EX1002, at 333-
`
`342), which rejected the claims as allegedly being anticipated by Tice (EX1009) and,
`
`in the alternative, as being obvious over the combination of Tice and Chandrashekar.
`
`I understand that Alkermes responded on October 5, 2009 (EX1002, at 291-299)
`
`6
`
`

`

`Declaration of Jason Schiffman
`
`with claim amendments and a declaration under 37 CFR §1.132 by Elliot Ehrich (the
`
`“Ehrich Declaration”) (EX1002, at 300-304; EX1055), the inventor of the ’499
`
`Patent.
`
`19.
`
`I understand that the Examiner issued a second non-final office action
`
`on January 6, 2010 (EX1002, at 276-286), which withdrew the anticipation and
`
`obviousness rejections over Tice in view of the Ehrich Declaration but nevertheless
`
`finally rejected the claims based on lack of enablement. Alkermes responded on
`
`April 5, 2010, by amending the claims to require a biocompatible polymer. EX1002,
`
`at 177-188. A final rejection was mailed on July 20, 2010 (EX1002, at 130-143.),
`
`maintaining the enablement rejection. Alkermes filed a response after final on
`
`October 20, 2010 (EX1002, at 121-126), amending the claims to require that the
`
`biocompatible polymer be PLGA. I note that the Ehrich Declaration did not argue
`
`that either oral dosing or Tice’s depot injection was clinically ineffective or even
`
`somehow less therapeutically effective, had fewer side effects, or was in any way an
`
`inferior treatment. The inventor did not even allege that the observed difference in
`
`AUC was somehow advantageous— just different. Nothing in the ’499 Patent or its
`
`prosecution history is more enlightening on this point. All three protocols (i.e., oral
`
`naltrexone, PLA/naltrexone microspheres of Tice, and the PLGA/naltrexone
`
`microspheres of Comer and the ’499 Patent) resulted in plasma levels of 1 ng/ml or
`
`above, which had already been established as the therapeutic threshold.
`
`7
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`

`

`Declaration of Jason Schiffman
`
`20. A notice of allowance was mailed on December 1, 2010, which, I
`
`understand, acknowledged a telephone interview of November 19, 2010 where the
`
`examiner allegedly proposed to insert certain language into the claims, e.g., “about
`
`310 mg to about 480 mg” into claim 1. EX1002, at 105-114. I understand the
`
`Examiner also included a reason for allowance, which stated that “[t]here is no prior
`
`art disclosing the applicants’ [sic] composition and effect, particularly an AUC about
`
`three times greater than that achieved by 50 mg/day oral administration.” Id. at 4.
`
`According to the Examiner, Tice was the closest prior art and reported that its
`
`injectable formulation was comparable to taking 50 mg tablets orally. Id. I disagree.
`
` A PERSON OF ORDINARY SKILL IN THE ART
`21.
`It is my opinion that a POSITA, with respect to the technology at issue
`
`in this inter partes review, 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 POSITA 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.
`
`22. Based on the technical and clinical nature of the subject matter of the
`
`’499 Patent, I understand who a person of ordinary skill in the art was as of April
`
`22, 2004, and what such a person would know.
`
`8
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`

`Declaration of Jason Schiffman
`
` CLAIM CONSTRUCTION
`23.
`I have been informed that during an inter partes review proceeding,
`
`claims are to be construed in light of the specification as would be read by a person
`
`of ordinary skill in the relevant art at the time the application was filed. I have been
`
`informed that claim terms are given their ordinary and customary meaning as would
`
`be understood by a person of ordinary skill in the relevant art in the context of the
`
`entire disclosure. A claim term, however, will not receive its ordinary meaning if the
`
`patentee acted as his own lexicographer and clearly set forth a definition of the claim
`
`term in the specification. In that case, the claim term will receive the definition set
`
`forth in the patent.
`
`
`
`24.
`
` “the step of parenterally administering a long acting formulation
`comprising about 310 mg to about 480 mg of naltrexone”
`In the ’943 IPR, Patent Owner asserted that the phrase “the step of
`
`parenterally administering a long acting formulation comprising about 310 mg to
`
`about 480 mg of naltrexone” should be construed as “a single injection of a long
`
`acting formulation comprising about 310 mg to about 480 mg of naltrexone.”
`
`EX1060, 5-7 (emphasis added). The “single injection” language appears nowhere in
`
`the claims or specification, and nothing supports so limiting the claims.
`
`25. Patent Owner pointed to the use of “the step” and “a long acting
`
`formulation” in the claims as meaning “singular.” The ’499 Patent does focus on the
`
`difference between an injectable formulation given once every 28 days and once-a-
`
`9
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`

`

`Declaration of Jason Schiffman
`
`day oral dosing for 28 days. In this context, clearly the ’499 Patent is claiming the
`
`number of doses used during the claimed period rather than how many shots, or how
`
`many pills, were needed to administer the claimed dose.
`
`26. Further, Patent Owner’s construction requiring a “single injection”
`
`cannot be correct given that “parenteral” administration is not limited to injection
`
`but also encompasses infusion. See, e.g., EX1061, claim 1 (“composition for
`
`parenteral infusion or injection”), EX1062, 12:18-20 (“parenteral compositions for
`
`injection or infusion”), EX1063, 7:55-62 (“the parenteral route comprises
`
`subcutaneous, intramuscular and intravenous injection or infusion”). This is further
`
`apparent from claim 12 which depends from claim 1 and recites “naltrexone is
`
`administered by injection”.
`
`27.
`
`In view of the foregoing and in view of my analysis of the specification,
`
`it is my opinion that the term “the step of parenterally administering a long acting
`
`formulation comprising about 310 mg to about 480 mg of naltrexone” should be
`
`given its plain meaning which does not exclude multiple injections for the reasons
`
`explained above.
`
`
`
`“the serum AUC of naltrexone … than that achieved by 50 mg/day
`oral administration”
`28. The ’499 Patent does not define “the serum AUC of naltrexone … than
`
`that achieved by 50 mg/day oral administration.”
`
`10
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`

`Declaration of Jason Schiffman
`
`29. The claims require a “serum AUC” but “serum AUC” is not defined by
`
`the specification. A POSITA would appreciate that this refers to serum “area under
`
`the curve.” AUC is merely the area under a curve created by plotting plasma drug
`
`concentration versus time. In other words, the area under the curve is a plot of plasma
`
`concentration of a drug versus time after dosage and gives insight into the extent of
`
`exposure to a drug and its clearance rate from the body. The area under the curve or
`
`AUC has a long history of use in pharmacology and pharmacokinetics, As Dr.
`
`Dowling explains in his declaration, a POSITA would clearly know the meaning of
`
`AUC and how it is determined. EX1046, ¶¶98-99.
`
`30.
`
`I am also aware that in IPR2018-00943, the Board also confirmed that
`
`“AUC is a well-known pharmacokinetic parameter referring to area under the
`
`curve.” EX1058, 9. The Board determined that “serum AUC is represented by a
`
`plasma concentration-time curve.” Id. The Board also determined that “[b]y its
`
`plain terms, claim 1 requires that the serum AUC achieved by parenterally
`
`administering the long-acting formulation of naltrexone (i.e., a long-acting
`
`formulation comprising about 310 mg to about 480 mg naltrexone and a polylactide-
`
`co-glycolide polymer as a biocompatible polymer) is about three times the serum
`
`AUC achieved by administration of a 50 mg/day oral naltrexone formulation.”
`
`EX1001, 21:3–9. I have adopted this understanding of the term “the serum AUC”
`
`11
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`

`

`Declaration of Jason Schiffman
`
`for purposes of this proceeding, and I believe it to be an accurate understanding
`
`based upon my knowledge and experience.
`
`31. The ’499 Patent does not define or specify the AUC of the claimed
`
`formulation or oral dosing. However, during prosecution of the ’499 Patent, Patent
`
`Owner filed a Declaration under 37 C.F.R. §1.132 (“the Ehrlich Declaration”)
`
`purporting to show unexpected results for the serum AUC of the claimed long-acting
`
`naltrexone formulation over that of a 50 mg/day oral formulation (i.e., an unexpected
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`serum AUC differential). EX1055, 1–18.
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`32. The Ehrich Declaration provides two data sets (Cohort A and Cohort
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`B) for the serum AUCs of the claimed long-acting naltrexone formulation and the
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`50 mg/day oral naltrexone. See id. at 6 (Table 8). For Cohort A, the serum AUC of
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`the 380 mg dose of the claimed long-acting naltrexone formulation is 4.307,2 which
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`is 3.37 times the serum AUC value of 1.278 for the 50 mg oral naltrexone dose. Id.
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`at 2. Similarly, for Cohort B, the serum AUC of the 380 mg dose of the claimed
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`long-acting naltrexone formulation is 4.921, which is 3.35 times the 1.468 serum
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`AUC value for the 50 mg oral naltrexone dose. Id.
`
`33.
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`In the Examiner’s Statement of Reasons for Allowance, the Examiner
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`referenced this data as showing “an AUC about three times greater than that achieved
`
`by 50 mg/day oral administration,” and explained that “no prior art disclos[es]” this
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`effect. EX1055, 4. Because these serum AUC data points were presented during
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`Declaration of Jason Schiffman
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`prosecution and were relied on by the Examiner in allowing the application issuing
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`as the ’499 Patent, a POSITA would understand that the serum AUC achieved by 50
`
`mg/day oral administration encompasses these data points. Accordingly, I agree
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`with the Board’s determination in IPR2018-00943 that “the reference to a ‘50
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`mg/day’ AUC in ‘than that achieved by 50 mg/day oral administration’ as
`
`encompassing at least serum AUCs of 1.278 ngꞏday/ml and 1.468 ngꞏday/ml.”
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`EX1058, 11-12.
`
`
`“about three”
`34. The ’499 Patent does not define “about three.” However, Claim 5
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`(which depends from claim 1) specifies an AUC of about 3.3 times greater than oral
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`dosing. Thus, “about three” necessarily encompasses at least 3.3. A POSITA would
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`thus appreciate that “about three” also encompasses at least “about 2.7.” As
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`explained by Dr. Dowling, this term could encompass a wider range. (EX1046,
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`¶102.) I agree with the Board’s determination in IPR2018-00943 that “about three
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`necessarily encompasses at least 3.3” and “at least about 2.7.” EX1058, 13. During
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`prosecution, Patent Owner submitted the Ehrlich Declaration which provides data of
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`a serum AUC for long-acting naltrexone formulation that is 3.3 times greater than
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`that achieved by oral dosing. EX1055, 2. Additionally, Dr. Dowling testifies, and
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`supports with evidence, that the term “about” as used in the art encompasses “a
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`quantity within 10%.” EX1046, ¶¶102-103.
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`Declaration of Jason Schiffman
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`“five or more days”
`35. Claim 2 requires that the individual not use oral naltrexone within five
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`or more days before administration of the formulation. This was not the original
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`language of the claim, as filed. The original language mirrors the language used in
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`the specification, namely “has not used oral naltrexone within five days, such as
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`within ten days, before said administration.” EX1001, 2:1-2. Putting aside the fact
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`that within five days entails within 10 days, the claim can either be read to
`
`encompass no prior oral naltrexone administration within five days or simply no
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`prior oral naltrexone administration ever. The use of the phrase “or more” in the
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`claim, and the attempt to define the concept as encompassing ten days, manifests an
`
`intention to cover a range greater than five days. Thus, the term “five or more days”
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`encompasses no prior oral naltrexone administration, ever.
`
`
`“initial oral dose”
`36. Claim 11 requires the individual not receive an “initial oral dose” of
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`naltrexone. The ’499 Patent does not define this term. The only reference to dosing
`
`in the ’499 Patent is to the administration of naltrexone to treat a patient to overcome
`
`his or her addiction. The art, however, makes clear that there are other purposes. For
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`example, Comer teaches the use of naltrexone as part of a detoxification process
`
`prior to treatment. EX1004, at 353. There is a break of two days between
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`administering the detoxification doses and the treatment doses. Id. Similarly, a small
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`Declaration of Jason Schiffman
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`percentage of the patient population can have serious adverse reactions to
`
`naltrexone. Naltrexone has been given orally to test for this prior to giving a depot
`
`injection for treatment. EX1009, 5:65-6:6, 6:13-17; EX1008, 1074. Clearly the art
`
`distinguishes initial treatment doses from prior doses given for other purposes.
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`Accordingly, “initial oral dose” as used in the ’499 Patent is an earlier treatment
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`dose, not a dose provided for other purposes.
`
`
`“about 35% by weight”
`37. Claim 13 requires the long acting formulation be present at a
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`concentration of about 35% by weight. The specification does not specifically define
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`what is meant by “formulation,” but does describe how to produce the
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`microparticles, i.e., 30-75% drug loading. EX1001, 6:52-54. A POSITA would
`
`appreciate that this term refers to the percent by weight of the particle.
`
` TECHNICAL BACKGROUND AND STATE OF THE ART
`38. The challenged claims are directed to treating certain conditions, such
`
`as alcohol use disorder (historically also referred to as “alcohol dependence” and
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`“alcoholism”) and opioid use disorder (historically also referred to as “opioid
`
`dependence” and “opioid addiction”), by parenterally administering about 310-480
`
`mg of naltrexone to a patient via a “long acting” depot injection that includes a
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`biodegradable polymer polylactide-co-glycolide (“PLGA”).
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`39. As noted elsewhere, naltrexone as a treatment for patients suffering
`
`from alcohol use disorder and opioid use disorder dates back to the 1980s. EX1004,
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`at 351-352; EX1008, at 1075; EX1010, Summary; EX1011; EX1005, 19:22-25;
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`EX1012, at 3; EX1016, Abstract; EX1017; EX1018, 1:55-2:50; EX1020, at 173.
`
`Naltrexone was originally developed and patented (EX1042) by Endo Laboratories
`
`in the 1960s. Naltrexone hydrochloride, originally under the tradename Trexan and
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`later known as ReVia, received FDA approval in 1984. EX1031. The formulation
`
`delivered 50 mg/day orally to patients for opioid and alcohol use disorder. EX1017,
`
`936-938; EX1006, at 420; EX1025; EX1029, at 937-939.) A 50 mg daily oral dose
`
`was known to be effective and to provide serum blood levels of at least 1 ng/ml,
`
`which was recognized as necessary for efficacy. EX1004, Abstract; EX1008, at
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`1078; EX1010, at 7; EX1011; EX1009, 6:19-39.
`
`40.
`
`Individuals that may benefit from naltrexone include a wide variety of
`
`people suffering from a number of conditions including, for example, opioid-
`
`induced respiratory failure, anorexia nervosa, bulimia, obesity, self-injury, and
`
`opioid-induced constipation. But, when one speaks of a patient in need of naltrexone,
`
`they are typically referring to a patient with opioid or alcohol use disorder. EX1004,
`
`at 351-352; EX1008, at 1074; EX1009, 1:14-2:60; EX1012, at 3; EX1014; EX1016,
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`Abstract; EX1018, 1:13-2:61.
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`41. One of the most frequently cited problems in treating opioid and alcohol
`
`use disorder is patient compliance. For a variety of reasons, individuals who start
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`treatment for these conditions often discontinue taking medication and/or
`
`participating in other aspects of their care over the many months usually necessary
`
`for recovery. Failure to retain patients in treatment is the primary reason for
`
`treatment failure in substance use disorders. U