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
`CORY J. BERKLAND, Ph.D.
`
`ALKERMES EXHIBIT 2055
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
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`Page 1 of 62
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`(B) 
`
`Contents
`INTRODUCTION .................................................................................................... 3 
`MY QUALIFICATIONS .......................................................................................... 3 
`LEGAL STANDARDS ............................................................................................ 5 
`OPINIONS ................................................................................................................ 8 
`Claim Construction ....................................................................................... 12 
`“the serum AUC of naltrexone . . . achieved by 50
`(A) 
`mg/day oral administration” .................................................... 12 
`“the step of parenterally administering a long acting
`formulation comprising about 310 mg to about 480 mg of
`naltrexone” ............................................................................... 14 
`“initial oral dose of naltrexone” ............................................... 18 
`(C) 
`Comer Does Not Anticipate the Claims (Amneal’s Ground 1) ................... 20 
`(A)  Comer Does Not Disclose “the step of parenterally
`administering a long acting formulation comprising about
`310 mg to about 480 mg of naltrexone” .................................. 22 
`(B)  Comer Does Not Disclose the Claimed AUC Differential ...... 22 
`(C)  Comer Does Not Disclose Treating ......................................... 27 
`(D)  At a Minimum, Certain Dependent Claims Are Not
`Anticipated ............................................................................... 27 
`Nuwayser Does Not Anticipate the Claims (Amneal’s Ground 2) .............. 29 
`(A)  Nuwayser Does Not Disclose “the step of parenterally
`administering a long acting formulation comprising about
`310 mg to about 480 mg of naltrexone” .................................. 29 
`(B)  Nuwayser Does Not Disclose the Claimed AUC
`Differential ............................................................................... 30 
`(C)  Nuwayser Does Not Disclose the Claimed Dose .................... 30 
`(D)  At Minimum, Claim 11 is Not Anticipated ............................. 31 
`The Asserted Combinations Do Not Render the Claims Obvious ............... 31 
`Comer, Nuwayser, Rubio, and Wright Do Not Render the Claims
`Obvious (Amneal’s Grounds 3 & 4) .................................................. 32 
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`(A)  The Asserted Combination Does Not Disclose Key Claim
`Limitations ............................................................................... 32 
`(B)  A POSA Would Not Have Been Motivated or Had a
`Reasonable Expectation of Success in Combining the
`Asserted References ................................................................. 33 
`(C)  At a Minimum, Certain Dependent Claims Are Not
`Obvious .................................................................................... 34 
`Nuwayser, Kranzler, Rubio, and Wright Do Not Render the Claims
`Obvious (Amneal’s Ground 5) ........................................................... 37 
`(A)  The Asserted Combination Does Not Disclose Key Claim
`Limitations ............................................................................... 37 
`(B)  A POSA Would Not Have Been Motivated or Had a
`Reasonable Expectation of Success in Combining the
`Asserted References ................................................................. 38 
`(C)  At a Minimum, Certain Dependent Claims Are Not
`Obvious .................................................................................... 40 
`Alkermes 10-K, Vivitrex Specimen, Rubio, and Wright Do Not
`Render the Claims Obvious (Amneal’s Ground 6) ............................ 40 
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`I, Cory J. Berkland, Ph.D., declare:
`
`INTRODUCTION
`I am of legal age and am competent to make this Declaration.
`
`I understand that the Patent Trial and Appeal Board has granted
`
`1.
`
`2.
`
`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”).
`
`MY QUALIFICATIONS
`3. My qualifications, professional experience, education, and
`
`publications are set forth in my curriculum vitae, attached as Appendix A. I
`
`provide a brief summary below.
`
`4.
`
`I completed my undergraduate training in Chemical Engineering from
`
`Iowa State University, Ames, IA in 1998. I completed my post-graduate training
`
`from the University of Illinois, Urbana, IL and received my M.S. (in Chemical
`
`Engineering) and my Ph.D. (in Chemical and Bimolecular Engineering) in 2001
`
`and 2003, respectively.
`
`5.
`
`I am currently the Solon E. Summerfield Distinguished Professor at
`
`The University of Kansas. I am appointed as a Distinguished Professor in the
`
`Department of Pharmaceutical Chemistry in the School of Pharmacy and in the
`
`Department of Chemical & Petroleum Engineering in the School of Engineering.
`
`Since 2009, I have been a tenured professor in both the Department of
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`Pharmaceutical Chemistry and the Department of Chemical & Petroleum
`
`Engineering at The University of Kansas.
`
`6.
`
`I have received numerous awards for my work in the field of
`
`nanoparticles and drug delivery, including recently being inducted into the
`
`American Institute for Medical and Biological Engineering (AIMBE) based, in
`
`part, for my work in controlled release drug delivery systems. I was also elected to
`
`the National Academy of Inventors as a result of my work in the pharmaceutical
`
`sciences.
`
`7.
`
`I have been a thesis advisor and postgraduate-scholar sponsor for
`
`numerous students in the fields of Pharmaceutical Chemistry, Bioengineering,
`
`Chemistry, and Chemical Engineering.
`
`8.
`
`I have taught a variety of classes on both the undergraduate and
`
`graduate level including classes titled, Emerging Trends in Pharmaceutical
`
`Chemistry, Drug Delivery, and Biopharmaceutics and Drug Delivery.
`
`9.
`
`I have received recognition for my teaching including being awarded
`
`the W.T. Kemper Fellowship for Teaching Excellence (2010) and a Teaching
`
`Achievement Award (2007).
`
`10.
`
`I am currently on, or have served on, multiple advisory boards for
`
`journals, including the Journal of Pharmaceutical Sciences, the Journal of
`
`Pharmaceutical Innovation, and the Journal of Therapeutic Delivery.
`
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`11.
`
`I have approximately 150 peer-reviewed publications and I am a co-
`
`author on multiple book chapters, including a chapter titled, “Modified Release
`
`Delivery Systems” in Biodrug Delivery Systems, Vol. 194, in which Dr. Park is an
`
`editor.
`
`12.
`
`I have also been involved in the development of several products in
`
`the pharmaceutical industry. I am a named inventor on numerous patents and I am
`
`a co-founder of four companies, one of which is Orbis Biosciences, Inc., a
`
`company that develops controlled-release delivery systems, including long acting
`
`injectable formulations.
`
`13. My research has been particularly focused on the development of drug
`
`delivery systems including long-acting microsphere formulations to improve the
`
`performance of therapeutic agents.
`
`14.
`
`I am being compensated at my standard rate of $ 500/hr. My
`
`compensation in no way affects the statements in this declaration and not in any
`
`way based on the outcome of this inter partes review.
`
`LEGAL STANDARDS
`15. Counsel has informed me that Amneal has the burden of proving the
`
`alleged unpatentability of the ’499 patent in this IPR proceeding.
`
`16. Counsel has informed me that the construction of a patent claim
`
`applied during this proceeding may differ from that in a district court proceeding.
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`Specifically, I have been advised that in inter partes review proceedings before the
`
`U.S. Patent & Trademark Office, a patent claim receives the broadest reasonable
`
`interpretation in light of the specification of the patent in which it appears, as well
`
`as in the prosecution history of that patent. I have also been advised that, at the
`
`same time, claims are given their ordinary and customary meaning as would be
`
`understood by one of ordinary skill in the art.
`
`17. Counsel has informed me that a patent claim may be unpatentable if it
`
`is either anticipated by a single prior art reference, or obvious over one or more
`
`prior art references.
`
`18. Counsel has informed me that, for Amneal to prevail in showing that a
`
`claim is anticipated, Amneal must show that a single, allegedly anticipatory prior
`
`art document discloses each and every element recited in the patent claim. This
`
`disclosure must be either express or inherent.
`
`19. Counsel has informed me that, for Amneal to prove that an allegedly
`
`anticipatory prior art document discloses a claim element inherently (as opposed to
`
`expressly), Amneal must show that the missing element is necessarily present in
`
`the allegedly anticipatory prior art reference. A mere possibility or probability is
`
`not enough.
`
`20. Counsel has also informed me that the question of whether an alleged
`
`prior art document anticipates a patent claim is to be analyzed through the lens of a
`
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`person of ordinary skill in the art (“POSA”) at the time of the priority date of the
`
`’499 patent, and that to anticipate a claim, the alleged prior art document must
`
`provide sufficient information to enable a POSA to practice the claimed invention.
`
`21. Counsel has informed me that, for Amneal to prevail in showing that a
`
`patent claim is obvious, Amneal must show that the claim as a whole would have
`
`been obvious to a POSA at the time of its invention,1 without the benefit of
`
`hindsight (i.e., bias based on present knowledge). I have been told that it is
`
`improper to use hindsight knowledge of the invention to limit the field of prior art.
`
`22. Counsel has informed me that it is improper to assume obviousness by
`
`following the path taken by the inventor, rather than casting one’s mind back prior
`
`to the date of invention without the benefit of hindsight.
`
`23. Counsel has informed me that, in determining whether Amneal has
`
`met its burden to show that a patent claim is unpatentable for obviousness, the
`
`following factors may be considered: (a) the full scope and content of the prior art;
`
`(b) the differences between the claims at issue and the prior art; (c) the level of
`
`ordinary skill in the pertinent art; and (d) the presence of objective indicia of
`
`nonobviousness.
`
`1 Counsel has asked me to assume that the date of invention for the ’499 patent is
`
`April 22, 2004.
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`24. Counsel has informed me that objective indicia that tend to show
`
`nonobviousness can include, for example, (a) evidence that the invention satisfied
`
`a long-felt but unmet need that existed at the time of the invention; (b) commercial
`
`success of products embodying the invention; (c) industry praise and recognition of
`
`the claimed invention; (d) the failure of others; and (e) the unexpected results of
`
`the claimed invention.
`
`25. Counsel has informed me that a patent claim is not obvious over
`
`alleged prior art if a POSA, without the benefit of hindsight, (a) would have had no
`
`motivation to combine the alleged prior art references to achieve the claimed
`
`invention, or (b) would not have a reasonable expectation of success in doing so.
`
`OPINIONS
`I have been asked to respond to certain opinions by Dr. Park. My
`
`26.
`
`opinions are set forth below. In forming my opinions, I have reviewed U.S. Patent
`
`No. 7,919,499 to Elliot Ehrich (Ex. 1001), its prosecution history, and particularly
`
`the following exhibits:
`
`Exhibit
`1001
`
`1003
`
`1010
`
`Description
`Elliot Ehrich, U.S. Patent No. 7,919,499 (issued Apr. 5, 2011) (“the
`’499 Patent”)
`Serial No. 11/083,167, Declaration Under 37 C.F.R. § 1.132 of Elliot
`Ehrich (undated)
`Sandra D. Comer et al., Depot naltrexone: long-lasting antagonism of
`the effects of heroin in humans, 159(4) Psychopharmacology (Feb.
`2002)
`
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`1013
`
`1011 Henry R. Kranzler et al., Sustained-Release Naltrexone for Alcoholism
`Treatment: A Preliminary Study, 22(5) Alcoholism: Clinical and
`Experimental Research (Aug. 1998)
`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)
`1014 U.S. Patent No. 7,157,102 (“Nuwayser”)
`1015 U.S. Patent No. 6,306,425 (“Tice”)
`1018 U.S. Patent No. 6,264,987 (“Wright”)
`1019
`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)
`1027 Appeal Brief, Application No. 13/871,534, Oct. 19, 2015
`1028 G. Rubio et al., Naltrexone Versus Acamprosate: One Year Follow-Up
`of Alcohol Dependence Treatment, 36(5) Alcohol& Alcoholism (2001)
`1030 Declaration of Kinam Park Ph.D in Support of Inter Partes Review of
`U.S. Patent No. 7,919,499
`1037 Bioequivalence, Center for Drug Evaluation and Research, Application
`Number: 75-434, Naltrexone Hydrochloride Tablets, Eon Labs
`Manufacturing, Inc.,
`Synopsis, Naltrexone HCl, ALZA Corporation (Nov. 3, 2003)
`In-hwan Baek et al., Evaluation of the Bioequivalence of Two Brands of
`Naltrexone 50 mg Tablet in Healthy Volunteers, 16(1) Kor. J. Clin.
`Pharm. (2006)
`1044 Bertil Abrahamsson and Anna-Lena Ungell, Biopharmaceutical support
`in formulation development: A Practical Guide from Candidate Drug
`Selection to Commercial Dosage Form, Pharmaceutical Preformulation
`and Formulation (Mark Gibson ed., Interpharm/CRC) (2004),
`1045 Guidance for Industry. Bioavailability and Bioequivalence Studies for
`Orally Administered Products—General Considerations. FDA CDER
`(March 2003)
`2024 Kleber et al., “Nontolerance to the Opioid Antagonism of Naltrexone,”
`Biological Psychiatry, 20:66–72 (1985)
`2025
`Transcription of January 23, 2019 Deposition of Kinam Park, Ph.D.
`
`1038
`1039
`
`
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`2026 Guidance for Industry. Bioequivalence Studies with Pharmacokinetic
`Endpoints for Drugs Submitted Under an ANDA. FDA CDER
`(December 2013)
`2028 Meyer et al., “Bioequivalence, Dose-Proportionality, and
`Pharmacokinetics of Naltrexone after Oral Administration,” Journal of
`Clinical Psychiatry, 45:9 (Sept. 1984)
`Hamilton et al., “Pharmacokinetics and Pharmacodynamics of
`Hyaluronan Infused into Healthy Human Volunteers,” Open Drug
`Metabolism J. 3 43–55 (2009)
`2031 Dale et al., “Bioavailability of Rectal and Oral Methadone in Healthy
`Subjects” British J. Clin. Pharmac., 58(2):156–162 (Aug. 2004)
`Saghir & Schultz, Low-Dose Pharmacokinetics and Oral Bioavailability
`of Dichloroacetate in Naïve and GSTζ-Depleted Rats, Environmental
`Health Perspectives, 110(8) 757–763 (Aug. 2002)
`Swanson et al., Development of a New Once-a-Day Formulation of
`Methylphenidate for the Treatment of Attention-deficit/Hyperactivity
`Disorder, Arch Gen Psychiatry, 60 204–211 (Feb. 2003)
`2034 Remington: The Science and Practice of Pharmacy (2000)
`2035 Berkland et al., “Precise control of PLG microsphere size provides
`enhanced control of drug release rate,” J. Controlled Release 82 137–
`138 (2002)
`2054 Merriam-Webster’s Collegiate Dictionary, Eleventh Edition (2003)
`(excerpt)
`2056 Declaration of Charles P. O’Brien, M.D., Ph.D.
`
`2032
`
`2033
`
`2030
`
`
`
`27. The bases for my opinion also include my education and experience
`
`as a researcher and in the field of therapeutic particles and biomaterials technology.
`
`28.
`
`It is my opinion that a POSA, 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
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`with relevant experience, including pharmaceutical scientists, clinicians, and
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`formulation scientists.2 Here, a POSA would have either a Master’s degree with at
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`least two or three years’ experience, or have a Ph.D. or M.D. degree with at least
`
`one or two years’ experience.
`
`29. My definition of a POSA is based on my review of the ’499 patent,
`
`the technology, the educational level and experience of active workers in the field,
`
`the types of problems faced by workers in the field, the solutions found to those
`
`problems, the sophistication of the technology in the field, and drawing from my
`
`own experience. For instance it is based on my interactions with individuals who I
`
`know through many years of research and teaching experience in the
`
`pharmaceutical sciences. It is also based on my interaction with formulation
`
`research teams in the pharmaceutical industry.
`
`30. Furthermore, my definition of a POSA is largely consistent with the
`
`definition provided by Dr. Park in his declaration (Ex. 1030 ¶ 28), and my opinions
`
`would not change if Dr. Park’s definition were applied to this case.
`
`
`2 For example, I note Dr. Park’s understanding “that a POSA may be a composite
`
`of different types of individuals.” (Ex. 1030 ¶ 27.)
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`Claim Construction
`(A) “the serum AUC of naltrexone . . . achieved by 50 mg/day
`oral administration”
`31. Claim 1 refers to administering a long acting formulation “wherein the
`
`serum AUC of naltrexone is about three times greater than that achieved by
`
`50 mg/day oral administration.” (Ex. 1001 at 21:6–7.)
`
`
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`32. Serum AUC values for the claimed long acting formulation and
`
`50 mg/day oral naltrexone were disclosed during prosecution, via the Ehrich
`
`Declaration. (Ex. 1003.)
`
`33. The Ehrich Declaration discloses two average daily AUC values for
`
`50 mg/day oral naltrexone, which it describes as “similar.” (Ex. 1003 at 4.) One is
`
`27.8 ug h/L, as reported by Tice. (Ex. 1015.) The other is 30.5 ug h/L, as reported
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`by an Alkermes study report. (Ex. 1003 at 3, 6–13.)
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`34.
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`I agree with Dr. Park that a POSA seeking information on claim scope
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`would be able to “look at the Ehrich Declaration.”3 (Ex. 1030 ¶ 72.) A POSA
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`would have understood that the given average daily AUC values for 50 mg/day
`
`oral naltrexone provide an objective baseline for interpreting the claims. Thus, a
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`POSA would have understood the claim term “the serum AUC of naltrexone . . .
`
`achieved by 50 mg/day oral administration” to mean a serum AUC of oral
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`naltrexone of about 30 µg h/L.4
`
`
`3 Dr. Park creates needless confusion by attempting to rely on evidence outside of
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`the ’499 patent and the 499 patent’s prosecution history (including non-prior art
`
`Exhibit 1039) for allegedly varying AUC values for 50 mg/day oral naltrexone.
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`(Ex. 1030 at ¶¶ 82–83 (citing Exs. 1037–39).)
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`4 My proposed construction applies the “broadest reasonable interpretation”
`
`standard in the context of this particular IPR. I reserve my right to propose a
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`different construction under other circumstances.
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`(B) “the step of parenterally administering a long acting
`formulation comprising about 310 mg to about 480 mg of
`naltrexone”
`35. Claim 1 also refers to a method for treating that comprises “the step of
`
`parenterally administering a long acting formulation comprising about 310 mg to
`
`about 480 mg of naltrexone.” (Ex. 1001 at 21:3–5.)
`
`
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`36. Given the ’499 patent’s claim language, its specification, and its
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`prosecution history, a POSA would have understood the broadest reasonable
`
`construction of this claim term to be “a single injection of a long acting
`
`formulation comprising about 310 mg to about 480 mg of naltrexone.”
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`37. With respect to the language of independent claim 1 itself (from
`
`which all other claims at issue depend), the claim term “the step of parenterally
`
`administering a long acting formulation comprising about 310 mg to about 480 mg
`
`of naltrexone” uses the singular phrase “the step of,” followed by “a long acting
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`formulation,” which a POSA would understand as limiting the claim to a single
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`injection.
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`38. With respect to the ’499 patent’s specification, there are five working
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`examples, four of which disclose single-injection regimens. The remaining
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`example discusses manufacturing and not administration:
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`39. Example 1 describes methods for manufacturing and does not mention
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`administration. (Ex. 1001 at 5:38–39.)
`
`40. Example 2 (i.e., ALK21-003, a phase III clinical trial) refers to “all
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`6 injections”5 (Ex. 1001 at 10 (flow chart)) over the course of a “6-month treatment
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`period.” (Ex. 1001 at 14:35.) It further indicates that “[p]atients received an
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`injection of study medication at 4-week intervals over 24 weeks, alternating
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`between the left and right gluteus maximus.” (Ex. 1001 at 8:42–45.) Patients were
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`divided into three treatment groups: (i) long-acting injectable naltrexone 380 mg,
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`(ii) long-acting injectable naltrexone 190 mg, or (iii) placebo. (Ex. 1001 at 8:32–
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`37.)
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`5 I understand “all 6 injections” to mean that each patient received six injections. I
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`disagree with Dr. Park’s speculation to the contrary. (See Ex. 2025 (Park
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`Deposition) at 46:11–21 (“I think ‘six injections’ here means six times. So I don't
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`think, in the absence of any indication, that you have to inject in one bolus. I'm not
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`sure whether you have to. . . . One injection, which may mean more than one shot.
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`It can be two shots. Who knows? It doesn't say. It doesn't clarify.”).)
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`41. Example 3 compares Vivitrex to oral naltrexone, not by direct
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`comparison, but instead by discussing three recent meta-analyses and comparing
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`them to ALK21-003, which, as discussed above, used single injections. (Ex. 1001
`
`at 18.)
`
`42. Example 4 refers to “6 monthly injections of LA-NTX [long-acting
`
`naltrexone] 380 mg” over the course of a “24-week” period, which a POSA would
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`understand as disclosing a single injection per month for six months. (Ex. 1001
`
`at 19:43–49.)
`
`43. Example 5, too, refers to “6 monthly injections of LA-NTX [long-
`
`acting naltrexone] 380 mg” over the course of a “24-week” period, which a POSA
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`would understand as disclosing a single injection per month for six months.
`
`(Ex. 1001 at 20:7–31.)
`
`44. The specification’s “Detailed Description of the Invention” section
`
`reports unexpectedly high AUC that resulted from “a single IM [intramuscular]
`
`administration of Vivitrex®” (Ex. 1001 at 2:34–36.)
`
`45. The “Detailed Description of the Invention” section also suggests that
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`higher doses are to be administered via higher-volume injections to a single
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`buttock, rather than by two injections of identical volume (one to each buttock), as
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`in Comer: “Administration to the buttock in a volume of up to about 4 mL in an
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`injectable diluent was performed in the trials leading up to these inventions.”6
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`(Ex. 1001 at 5:8–13.)
`
`46. Similarly, Example 2 suggests that different volumes were used for
`
`the low- and high-dose injections: “Patients were randomized to one of three
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`treatment groups: long-acting injectable naltrexone 380 mg, long-acting injectable
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`naltrexone 190 mg, or matching volumes of placebo (one-half of the placebo
`
`patients received an injection volume corresponding to 380 mg and the other half
`
`received an injection volume corresponding to 190 mg).” (Ex. 1001 at 8:32–37.)
`
`47. With respect to the ’499 patent’s prosecution history, in the Ehrich
`
`Declaration (Ex. 1030 ¶ 72), the inventor repeatedly confirms that the claims are
`
`limited to a single injection. For example, he states that “[t]he present invention is
`
`directed to the unexpected discovery that a single injection of a naltrexone-
`
`containing long-acting formulation provides systemic exposure to naltrexone
`
`(AUC) which is at least 2 fold higher over a 28 day period than the AUC of an oral
`
`regimen of 50 mg per day over a 28 day period.” (Ex. 1003 at 1.) In particular, he
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`refers to “a single 380 mg injection of naltrexone.” (Ex. 1003 at 4.)
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`6 By way of background, Comer used 2.4 mL for each injection. All study
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`participants received two injections (one per buttock). For low-dose participants,
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`one of those injections was placebo. (Ex. 1010 at 354.)
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`48. For any of these reasons, a POSA would have understood the broadest
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`reasonable construction of this claim term to be “a single injection of a long acting
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`formulation comprising about 310 mg to about 480 mg of naltrexone.”
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`(C) “initial oral dose of naltrexone”
`49. Dependent claim 11 recites “[t]he method of claim 1 wherein the
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`individual does not receive an initial oral dose of naltrexone.” (Ex. 1001 at 22:8–
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`9.)
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`50. As per the dictionary, the ordinary and customary meaning of “initial”
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`is “first.” (Ex. 2054 at 643.) The ’499 patent and its prosecution history give no
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`reason to depart from that meaning.7 Dr. Park seems to agree. (See, e.g., Ex. 2025
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`at 54:3–12 (“Q. Now, you note that the ’499 patent does not define the term ‘initial
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`oral dose,’ correct? A. Yes, that’s what I said in my report, paragraph 49, second
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`sentence, that the ’499 patent does not define this term. Yes, that’s correct. Q. And
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`7 In fact, the ’499 patent’s specification supports this ordinary and customary
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`meaning. For example, the “Detailed Description of the Invention” states that “the
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`inventions also include administering a long acting formulation to individuals who
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`did not receive a prior oral dose of naltrexone, for example, within 3, such as
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`within about 5 days or about 10 days of commencing therapy.” (Ex. 1001 at 2: 49–
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`53.)
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`you don't cite to the prosecution history for any definition of the term in that
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`paragraph, correct? A. I don’t recall seeing prosecution history about this.”).)
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`51.
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`In arguing that Comer discloses individuals who do not receive an
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`“initial oral dose of naltrexone,” Dr. Park suggests construing this claim limitation
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`so that it includes “an earlier treatment dose, but not a dose given for detoxification
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`or to determine tolerance and the like.” (Ex. 1030 ¶ 49 (emphasis added).)
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`Specifically, Dr. Park alleges that Comer discloses “a break between administering
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`the detoxification doses and the treatment doses of two days,” and that “the art
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`distinguishes initial treatment doses from prior doses given for other purposes.”
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`(Ex. 1030 ¶ 49.) Dr. Park’s reasoning however is inconsistent. For instance, Dr.
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`Park’s reliance on Comer to construe “initial oral dose” to exclude prior initial
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`doses for detoxification (Ex. 1030 ¶ 49) is inconsistent with how Dr. Park later
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`provides that Comer discloses an initial oral dose. (Ex. 1030 ¶ 90.)
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`52. Once again, Comer does not teach treating. (See ¶ 69, infra.) While it
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`speculates about “a treatment setting where oral naltrexone may not be given prior
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`to depot naltrexone” (Ex. 1010 at 359 (emphasis added)), Comer makes clear that
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`its data pertain to study participants who did in fact receive depot naltrexone
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`“2 days after the last oral naltrexone dose.” (Ex. 1010 at 353.) Therefore Comer’s
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`study participants undeniably received “an initial oral dose of naltrexone,” and
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`Comer does not teach the limitation recited in claim 11 (i.e., “wherein the
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`individual does not receive an initial oral dose of naltrexone.”).
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`53.
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`In sum, a POSA would have understood the broadest reasonable
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`construction of the claim term “initial oral dose of naltrexone” to be “any oral dose
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`of naltrexone prior to the parenteral administration of a long acting formulation
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`comprising about 310 mg to about 480 mg of naltrexone.” Thus, claim 11 excludes
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`methods involving an initial oral dose of naltrexone given for any reason prior to
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`administration of depot naltrexone.
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`Comer Does Not Anticipate the Claims
`(Amneal’s Ground 1)
`54. Comer is a study “designed to evaluate the time course, safety, and
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`effectiveness of a depot formulation of naltrexone (Depotrex®)” to block the
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`pharmacologic effects of exogenously administered opioids. (Ex. 1010 at 351.) It
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`provides limited information on the formulation administered to study participants,
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`describing it only as “[a] new depot formulation of naltrexone (Depotrex®)” and
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`noting three references that relate to its development: Heishman (Ex. 1019), Alim
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`(Ex. 1013), and Kranzler (Ex. 1011). (Ex. 1010 at 352.) In particular, Comer states
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`that the “same formulation of depot naltrexone used in the present study” was also
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`tested by Kranzler (Ex. 1011). (Ex. 1010 at 359.)
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`55.
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`In Comer, 12 heroin-dependent study participants underwent
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`detoxification for one week, which included the administration of three doses of
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`oral naltrexone—25 mg, 50mg, and 50 mg—over the course of three days.
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`(Ex. 1010 at 353.) Two days later, Comer administered either 384 mg or 192 mg of
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`depot naltrexone. (Ex. 1010 at 353.) Administration involved “one injection per
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`buttock.” (Ex. 1010 at 354.) The higher 384 mg dose was delivered via “two
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`naltrexone injections,” and the lower dose via “one placebo and one naltrexone
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`injection.” (Ex. 1010 at 354.) The investigators then administered “active heroin
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`doses in ascending order” and measured their effects. (Ex. 1010 at 358.)
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`56. Comer states that, “[a]cross the time points measured, the highest
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`naltrexone plasma levels attained after administration of 192 mg and 384 mg of
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`depot naltrexone were 3.8 (±0.2) and 8.9 (±1.4) ng/ml, respectively” (Ex. 1010
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`at 358), which were observed two hours after administration (Ex. 1010 at 354).
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`Comer notes that these maximum concentrations were less than the reported
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`plasma concentrations following daily administration of 50 mg oral naltrexone and
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`“lower than the amount found after a standard dose of naltrexone used clinically
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`for treating heroin dependence (50 mg/day).” (Ex. 1010 at 358.) Comer found that
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`the “formulation of naltrexone produced a long-lasting antagonism of the effects of
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`intravenous heroin,” but concluded that future studies were needed to “evaluate the
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`clinical utility of depot naltrexone in the treatment of heroin dependence.”
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`(Ex. 1010 at 359.)
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`(A) Comer Does Not Disclose “the step of parenterally
`administering a long acting formulation comprising about
`310 mg to about 480 mg of naltrexone”
`57. As discussed above, a POSA would understand that, in the context of
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`the ’499 patent’s claims, specification, and file history, the broadest reasonable
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`construction of this claim term is limited to “a single injection of a long acting
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`formulation comprising about 310 mg to about 480 mg of naltrexone.”
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`58. Comer tests two doses of depot naltrexone: 192 mg and 384 mg. It
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`explains that study participants were administered “one injection per buttock.”
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`(Ex. 1010 at 354.) The high-dose study participants received two naltrexone
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`injections, but the low-dose study participants received one naltrexone injection
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`and one placebo injection. (Ex. 1010 at 354.) Thus, Comer does not teach
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`administration of a dose within the claimed range in a single injection, as the
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`claims require.
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`(B) Comer Does Not Disclose the Claimed AUC Differential
`(1) AUC calculations must begin at time zero
`59. As a POSA would know, quantification of AUC must begin at time
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`zero. (Ex. 1044 at 263 (“[i]t is imperative in single-dose studies . . . to determine
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`the AUC from time zero