`Case IPR2018-00943
`Patent No. 7,919,499
`Declaration of Kinam Park, Ph.D.
`Attorney Docket No. AMNEAL 7.1R-005
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________________
`
`AMNEAL PHARMACEUTICALS LLC,
`Petitioner,
`
`v.
`
`ALKERMES PHARMA IRELAND LIMITED,
`
`Patent Owner.
`
`Patent No. 7,919,499 to Elliot Ehrich
`Issue Date: May 19, 2015
`Title: NALTREXONE LONG ACTING
`FORMULATIONS AND METHODS OF USE
`____________________________
`Inter Partes Review No. IPR2018-00943
`__________________________________________________________________
`
`(Exhibit 1030)
`
`DECLARATION OF KINAM PARK, Ph.D. IN SUPPORT
`OF INTER PARTES REVIEW OF U.S. PATENT NO. 7,919,499
`
`
`
`
`
`
`5412401_1.docx
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`AMN1030
`IPR of Patent No. 7,919,499
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`ALKERMES EXHIBIT 2009
`Apotex Inc. v. Alkermes Pharma Ireland Limited
`IPR2025-00514
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`Case IPR2018-00943 (Patent No. 7,919,499)
`Declaration of Kinam Park, Ph.D.
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`TABLE OF CONTENTS
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`Page
`
`INTRODUCTION ........................................................................................... 3
`
`I.
`
`II. MY BACKGROUND AND QUALIFICATIONS ......................................... 3
`
`III. THE ’499 PATENT ......................................................................................... 7
`
`IV. PERTINENT PROSECUTION
`HISTORY OF THE ’499 PATENT ..............................................................11
`
`V. A PERSON OF ORDINARY SKILL IN THE ART ....................................13
`
`VI. CLAIM CONSTRUCTION ..........................................................................16
`
`A. “a long acting formulation” ....................................................................16
`
`B. “the serum AUC of naltrexone … than that
`achieved by 50 mg/day oral administration” ..........................................17
`
`C. “about three” ...........................................................................................20
`
`D. “five or more days” .................................................................................21
`
`E. “initial oral dose” ....................................................................................22
`
`F. “about 35% by weight” ...........................................................................22
`
`VII. TECHNICAL BACKGROUND AND STATE OF THE ART ....................23
`
`A. The Area Under The Curve (AUC) ........................................................25
`
`B. AUC Does Not Meaningfully Impact Efficacy ......................................28
`
`C. A POSA Would Find The Claimed Comparison Inapt ..........................30
`
`D. The Claimed AUC Differential Is
`Known Or Would Be Apparent ..............................................................33
`
`1. The AUC Of Comer .........................................................................33
`
`2. The AUC Of Nuwayser ...................................................................39
`
`3. The AUC Of Vivitrex ......................................................................41
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`Case IPR2018-00943 (Patent No. 7,919,499)
`Declaration of Kinam Park, Ph.D.
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`E. AUC Differential Varies With The Data Used .......................................44
`
`VIII. THE CHALLENGED CLAIMS WERE
`TAUGHT BY COMER AND NUWAYSER................................................46
`
`A. Comer Discloses The Subject Matter
`Of Claims 1, 3-5, And 10-12 ..................................................................46
`
`B. Nuwayser Discloses The Subject Matter
`Of Claims 1, 3-5, And 11-12 ..................................................................50
`
`IX. THE CHALLENGED CLAIMS WERE
`READILY APPARENT TO A POSA ..........................................................52
`
`A. Comer In View Of Nuwayser And/Or Nuwayser In
`View Of Comer And Either In View Of Wright And Rubio .................52
`
`B. Nuwayser In View Of Kranzler, Wright, And Rubio .............................59
`
`C. Alkermes’ 10-K In View Of The
`Vivitrex Specimen, Wright, And Rubio .................................................65
`
`1. Alkermes’ 10-K ................................................................................66
`
`2. Vivitrex Specimen ............................................................................67
`
`3. Wright ..............................................................................................67
`
`X.
`
`CONCLUSION ..............................................................................................76
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`
`
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`2
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`Case IPR2018-00943 (Patent No. 7,919,499)
`Declaration of Kinam Park, Ph.D.
`
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`I, KINAM PARK, declare and state as follows:
`
`I.
`
`INTRODUCTION
`I am a U.S. citizen and a resident of the State of Indiana.
`1.
`
`2.
`
`I have been retained by Lerner, David, Littenberg, Krumholz &
`
`Mentlik, LLP (“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”)
`
`(Ex. 1001) 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.
`
`II. MY BACKGROUND AND QUALIFICATIONS
`I am
`the Showalter Distinguished Professor of Biomedical
`3.
`
`Engineering, as well as a full Professor of Pharmaceutics at Purdue University. A
`
`copy of my CV is attached as Exhibit 1031. It contains a description of my
`
`education, academic appointments, professional activities, service on the editorial
`
`board of professional journals, books, referenced articles in scholarly journals,
`
`journal
`
`cover
`
`stories, patents, presentations, book
`
`reviews,
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`teaching
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`responsibilities, and thesis supervision.
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`3
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`Case IPR2018-00943 (Patent No. 7,919,499)
`Declaration of Kinam Park, Ph.D.
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`4.
`
`I obtained my Ph.D. in Pharmaceutics from the University of
`
`Wisconsin in 1983, and completed a postdoctoral training in Chemical Engineering
`
`from the University of Wisconsin in 1985. I joined Purdue University as an
`
`Assistant Professor in 1986, and since 1994, I have been a Professor in the
`
`Department of Pharmaceutics at Purdue University. I also have been a Professor in
`
`the Department of Biomedical Engineering since 1998, and became the Showalter
`
`Distinguished Professor of Biomedical Engineering at Purdue University in 2006.
`
`5.
`
`Since about 1986, I have been involved in the research, development,
`
`and manufacture of pharmaceutical
`
`formulations,
`
`and
`
`in particular
`
`controlled/sustained release drug delivery systems. I have conducted numerous
`
`research activities at Purdue University related to drug delivery technologies
`
`utilizing various polymers.
`
`6.
`
`Since about 1994, one of my research interest has been developing
`
`long-acting microparticle formulations for oral administration. Since 2000, my
`
`research focused on
`
`injectable
`
`long-acting depot formulations based on
`
`biodegradable poly(lactide-co-glycolide) (PLGA), also known as poly(lactic-co-
`
`glycolic
`
`acid), using different manufacturing
`
`technologies,
`
`such
`
`as
`
`microenvironment-controlled encapsulation process, solvent exchange method,
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`microfabrication, and double emulsion methods.
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`4
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`Case IPR2018-00943 (Patent No. 7,919,499)
`Declaration of Kinam Park, Ph.D.
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`7.
`
`I have published 283 papers in peer reviewed journal articles, 100
`
`book chapters, 98 conference proceedings, 22 patents, 191 journal cover stories,
`
`and 12 books, and given 294 invited lectures. Many of my publications relate
`
`directly to research, development, and design of sustained release formulations.
`
`8.
`
`Over the years, I have received numerous honors and awards,
`
`including the Research Achievement Award (Pharmaceutics and Drug Delivery
`
`Section) (2001), the Clemson Award (basic research category) of Society for
`
`Biomaterials (2001), the Controlled Release Society Founders Award (2004), the
`
`Louis W. Busse Lectureship of School of Pharmacy at University of Wisconsin
`
`(2008), the Sigma Xi Research Award (Purdue University Chapter) (2009),
`
`Thomson Reuters’ list of “The World’s Most Influential Scientific Minds: 2014
`
`(2014), Korean-American Society in Biotech and Pharmaceuticals-Daewoong
`
`Award (2014), and Controlled Release Society Distinguished Service Award
`
`(2015), Special Government Employee at FDA CDER (2016), and The University
`
`of Auckland Distinguished Visitor Award (2017).
`
`9.
`
`I have also been on the Board of Governors of the Controlled Release
`
`Society (1993-1996), a Fellow at the American Association for Pharmaceutical
`
`Scientists (AAPS) (1993), the President of the Korean-American Pharmaceutical
`
`Scientists Association (1995-1997), a Fellow at the American Institute for Medical
`
`and Biological Engineering (1996), a Fellow at the Biomaterials Science and
`
`5
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`Case IPR2018-00943 (Patent No. 7,919,499)
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`Engineering of the Society for Biomaterials (2000), the President of the Controlled
`
`Release Society (2001-2002), and a Fellow of Controlled Release Society (2010).
`
`10.
`
`I have been a member of numerous Advisory Boards, including the
`
`Advisory Panel on Polymeric Excipients, USP (1995-2005); the ACS Books
`
`Advisory Board (1997-2000); the Scientific Advisory Board, International
`
`Symposium on Recent Advances in Drug Delivery Systems (2000-2001);
`
`International Nanomedicine and Drug Delivery Symposium (2005); Board of
`
`Directors & Chairman of Fellowship Committee, CRS Foundation (2008-2013);
`
`Scientific Advisory Board, the International Conference on Biomaterials Science
`
`in Tokyo (2016), External Advisor for Internal Projects at Korea Institute of
`
`Science and Technology (KIST) (2017), and International Organizing/Advisory
`
`Committee, 5th Symposium on Innovative Polymers for Controlled Delivery,
`
`Suzhou, China (2018).
`
`11.
`
`I am currently on editorial boards of 20 journals, including for the
`
`Journal of Biomaterials Science – Polymer Edition; the Journal of Bioactive and
`
`Compatible Polymers; Colloids and Surfaces B: Biointerfaces; Archives of
`
`Pharmacal Research; Advanced Drug Delivery Reviews; Biomaterials Research;
`
`the Journal of Pharmacy and Pharmacology; the Journal of Drug Delivery Science
`
`and Technology; Nano Reviews; Frontiers in Drug Delivery Biotechnology; and
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`Regenerative Engineering and Translational Medicine.
`
`6
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`Case IPR2018-00943 (Patent No. 7,919,499)
`Declaration of Kinam Park, Ph.D.
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`12.
`
`I currently am the Editor-in-Chief for the Journal of Controlled
`
`Release. I previously have been a journal editor for several publications, including
`
`Pharmaceutical Research (Associate Editor); Pharmaceutical Research (Book
`
`Review Editor); Advanced Drug Delivery Reviews (Guest Editor); and Journal of
`
`Controlled Release (Editor, Americas).
`
`13. Accordingly, I believe I am an expert in the field of pharmaceutical
`
`formulations,
`
`including
`
`controlled-release
`
`polymer-based
`
`pharmaceutical
`
`formulations, and I have been an expert in this field since prior to April 22, 2004.
`
`Additional details of my education, experience, and credentials are set forth in my
`
`aforementioned curriculum vitae. (Ex. 1031.) I also believe that, because of my
`
`education, experience, and interactions with students at all levels (undergraduate,
`
`Master, Pharm.D., and Ph.D.) and scientists, researchers, and administrators at all
`
`levels in this field, both in academia and industry, I understand who a person of
`
`ordinary skill in the art was as of April 22, 2004, and what such a person would
`
`have known. I also believe that I understand who a person of ordinary skill in the
`
`art was as of April 22, 2004, and what such a person would know from, my review
`
`of the literature in connection with my consideration of the ’499 Patent.
`
`III. THE ’499 PATENT
`I understand from the face of the ’499 Patent (Ex. 1001) that it issued
`14.
`
`on April 5, 2011,
`
`from U.S. Application Serial No. 11/083,167
`
`(“the
`
`7
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`’167 Application”), which was filed on March 17, 2005. The ’499 Patent states on
`
`its face that it claims the benefit of U.S. Provisional Application No. 60/564,542,
`
`filed April 22, 2004 (“the Provisional Application”) (Ex. 1032). I have been
`
`advised by counsel to assume that the earliest possible effective filing date for the
`
`’499 Patent is April 22, 2004.
`
`15. The ’499 Patent alleges that the “inventions described herein arose
`
`from unexpected discoveries made during clinical trials with a long acting
`
`formulation of naltrexone.” (Exs. 1001 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
`
`16. The specification discusses the need for improving naltrexone
`
`therapies by improving patient compliance. (Ex. 1001, 1:13-26.) Alkermes never
`
`equated its discovered difference in a pharmacokinetic property to any meaningful
`
`therapeutic difference. It is worth noting that the ‘499 Patent did not suggest that it
`
`provided a cure to alcoholism or drug abuse. Indeed, 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.
`
`8
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`(Ex. 1001, 18:48-52.) In fact, it acknowledged that based on semi-quantitative
`
`comparisons of three meta-analyses, “the efficacy of Vivitex suspension compares
`
`favorably with oral naltrexone.” (Id. 19:30-34.) It did not, however, argue superior
`
`efficacy. I believe that a POSA would read the phrased “compares favorably” in
`
`this context as no better than oral naltrexone. What I mean by that, and what I
`
`mean when I state that there is no evidence of efficacy improvement, that there was
`
`no argument of superior efficacy, or other words to the effect, is that there is no
`
`“meaningful” evidence in the patent or raised during prosecution that would allow
`
`a POSA to draw a conclusion of improved efficacy or superiority. A POSA would
`
`note Alkermes’ acknowledgement that there were no direct studies comparing
`
`these two dosing protocols. They would know that to make any valid claim to
`
`improve efficacy would require a properly structured clinical study such as a
`
`randomized, or crossover, double-blind trial. Meta-analysis alone is of dubious
`
`weight to a POSA which is, perhaps reflected by the fact that during prosecution,
`
`Alkermes did not make more of any alleged efficacy improvements. Particularly
`
`important here is the fact 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. And Alkermes never linked any efficacy difference to a
`
`difference in AUC.
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`17.
`
`In some embodiments, naltrexone is combined with well-known
`
`polymers, such as PLGA, to “entrap or encapsulate” the naltrexone to form long
`
`acting formulations. (Exs. 1001, 3:14-15.) 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 that the therapy can be maintained for 24 weeks or
`
`more. (Id. 4:55-64.)
`
`18. The specification also includes five examples, three of which were not
`
`present in the original provisional application to which the ’499 Patent claims
`
`priority. (Exs. 1001; 1032.) 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 Exs. 1001, 3:3-33, 5:35-8:2 and 1018, 7:48-8:60; see ¶ 133, infra.)
`
`19. 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. (Ex. 1001,
`
`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
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`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 life” and “durability of effect and tolerability” of long acting
`
`naltrexone formulations. Again, none of the examples provided any data regarding
`
`AUC.
`
`20. The ’499 Patent 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.
`
`(Id. 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).
`
`IV. PERTINENT PROSECUTION HISTORY OF THE ’499 PATENT
`I am an inventor and have been involved in patent prosecution and
`21.
`
`litigation and therefore I have a general understanding of the patent prosecution
`
`process. However, when I review a prosecution history, I do so as a technical
`
`expert.
`
`22.
`
`I understand from 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
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`non-final rejection was mailed on May 5, 2009 (Ex. 1002), which rejected the
`
`claims as allegedly being anticipated by Tice (Ex. 1015) and, in the alternative, as
`
`being obvious over the combination of Tice and Chandrashekar. I understand that
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`Alkermes responded on October 5, 2009 (Ex. 1004) with claim amendments and a
`
`declaration under 37 CFR § 1.132 by Elliot Ehrich (the “Ehrich Declaration”)
`
`(Ex. 1003), the inventor of the ’499 Patent.
`
`23.
`
`I understand that the Examiner issued a second non-final office action
`
`on January 6, 2010 (Ex. 1005), 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. (Ex. 1006.) A
`
`final rejection was mailed on July 20, 2010 (Ex. 1007), maintaining the enablement
`
`rejection. Alkermes filed a response after final on October 20, 2010 (Ex. 1008),
`
`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
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`(i.e., oral naltrexone,
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`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.
`
`24. 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. (Ex. 1009.) I understand the Examiner also
`
`included a reasons 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.
`
`V. A PERSON OF ORDINARY SKILL IN THE ART
`I understand from my own experiences and from counsel that patents
`25.
`
`are read by, and are to be read in light of the knowledge of, a person of ordinary
`
`skill in the art (“POSA”) as of the earliest effective filing date of the patent. I have
`
`been told by counsel to assume that the earliest effective filing date is April 22,
`
`2004, for purposes of this declaration. All of the prior art relied on in my
`
`declaration was filed or published more than a year before the earliest effective
`
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`filing date or was filed in the United States before the earliest effective filing date
`
`of the ’499 Patent.
`
`26.
`
`It was explained to me by counsel that a POSA is a hypothetical
`
`person who is deemed to be aware of all relevant prior art. A POSA is also a
`
`person of ordinary creativity, not an automaton.
`
`27.
`
`I am further told by counsel that factors relevant to determining the
`
`level of skill in the art include: the educational level of the inventor(s), the types of
`
`problems encountered in the art, prior art solutions to those problems, the rapidity
`
`with which innovations are made, the sophistication of the technology, and the
`
`educational level of active workers in the field. I understand from counsel that a
`
`POSA may be a composite of different types of individuals.
`
`28.
`
`In regards to the education levels of the inventor(s) and education
`
`level of active workers in the field, I believe one 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.
`
`29.
`
`I note that Dr. Ehrich, the sole inventor of the ’499 Patent, had a
`
`medical degree. However, the treatment steps of the claimed method are relatively
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`simple and very well known. Moreover, the method was not the central focus of
`
`the discussion of patentability. The central issue was the AUC and how that AUC
`
`compared to other formulations. In my experience, that is the province of a
`
`Pharm.D. or Ph.D. in a related formulation discipline, more than, typically, a
`
`medical doctor.
`
`30. Consistent with my understanding, many of those associated with the
`
`types of solutions to those problems encountered in developing new sustained
`
`release
`
`formulations, and
`
`in particular,
`
`injectable
`
`long-acting PLGA
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`microparticles, have a Ph.D. degree in a relevant formulation discipline. For
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`example, according to their LinkedIn pages, Alkermes’ Dr. Michael Ramstack,
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`who is a co-inventor of Alkermes’ Wright patent (Ex. 1018), has a Ph.D. in
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`Chemical Engineering, and R. H. Reuning, author of Exhibit 1026, has a Ph.D. in
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`Pharmacy (Exs. 1054, 1055).
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`31. The
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`technology
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`tends
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`to be sophisticated, as
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`it requires an
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`interdisciplinary understanding of such diverse topics as PLGA chemistry and
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`degradation properties, drug solubility in water and in polymers, selection of
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`solvents, drug release kinetics, drug dose, PLGA microparticle size, etc. This also
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`suggests that advanced degrees and practical experience are required. Indeed, even
`
`Mr. Steven Wright, first named inventor of Alkermes’ Wright patent (Ex. 1018)
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`has an undergraduate degree in Chemical Engineering and more than 15 years of
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`experience (Ex. 1056).
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`32. As of the relevant date of April 2004, I believe I was a POSA under
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`any plausible definition. Further, I understand who a person of ordinary skill in the
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`art was as of April 22, 2004, and what such a person would know.
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`VI. CLAIM CONSTRUCTION
`I understand that it is often desirable to construe the meaning of claim
`33.
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`terms to eliminate ambiguity when possible. I also understand from counsel that
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`the claims in an IPR are to be given their broadest reasonable interpretation
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`(“BRI”) unless they are specifically defined otherwise. My understanding of
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`broadest reasonable interpretation is that the definition must be consistent with the
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`understanding of a POSA in the field and with the specification and statements
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`made during prosecution. Terms are not necessarily limited to only those examples
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`recited in the specification. Under the BRI standard, terms can be given a more
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`inclusive meaning.
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` “a long acting formulation”
`A.
`34. Claim 1 recites “a long acting formulation.” I believe a POSA would
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`understand this to mean a formulation that provides controlled/sustained/extended
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`release of at least one week. A POSA would appreciate that this is distinct from
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`immediate release. And the specification defines “long acting” as delivering
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`“therapeutically beneficial amounts of naltrexone to a patient for a period of at
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`least one week.” (Ex. 1001, 3:11-13, 3:59-64.) I believe that a POSA would accept
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`that definition.
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`B.
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`“the serum AUC of naltrexone … than that
`achieved by 50 mg/day oral administration”
`35. Claim 1 recites “the serum AUC of naltrexone is about three [or 3.3]
`
`times greater than that achieved by 50 mg/day oral administration.” Interestingly,
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`especially considering the allegedly “unexpected” discovery of this limitation, the
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`’499 Patent does not define this term or provide directly comparative data.
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`36. Although “serum AUC” is not defined by the specification, a POSA
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`would appreciate that this refers to “area under the curve.” AUC is a
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`pharmacokinetics concept that describes the area under the plasma concentration-
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`time curve. The plasma concentration indicates the drug concentration in the blood,
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`and it is also referred to as the serum concentration or plasma concentration. The
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`pharmacokinetic profile is frequently characterized by the maximum drug
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`concentration (Cmax), the time reaching the Cmax (tmax), the time period that the drug
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`concentration in blood decreases to a half of the initial concentration (t1/2), and the
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`area under the curve (AUC). AUC is simply the total area defined by the plasma
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`concentration-time profile, and thus, its unit is the plasma concentration multiplied
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`by time. Since the plasma concentration plot is often not straight, the AUC is
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`calculated by integrating the drug present in each time interval either manually or
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`using a computer program.
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`37. Moreover, AUC is a function of the drug dose. Alkermes appears to
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`agree. (Ex. 1027, at 7) Integrating the AUC plot therefore allows one to calculate
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`the extent of drug absorption which is related to the dose administered. The
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`information on the bioavailability and clearance of a drug leads to the calculation
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`of the dose administered. More explanation on the AUC is presented below in
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`paragraphs 56-59.
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`38. AUC is not a measure of therapeutic efficacy. So long as the patient
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`consistently has a blood concentration of the drug at or above the level needed for
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`efficacy, the treatment should be effective. But the shape of the blood
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`concentration plot and the AUC does not dictate efficacy. As the ’499 Patent points
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`out, “the most commonly used endpoint for oral naltrexone has been the
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`dichotomous outcome, relapse to heavy drinking (yes/no).” (Ex. 1001, 18:30-32.)
`
`39.
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` The ’499 Patent also lacks a definition of “about three times greater
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`than that achieved by 50 mg/day oral administration.” The problem here is not with
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`the literal wording, but with the fact that no data is provided to establish the AUC
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`of the claimed formulation or the AUC of 50 mg/day oral dosing. Instead, the
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`’499 Patent merely makes unsubstantiated assertions about this relationship.
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`(Ex. 1001, 1:36-40, 2:23-36.) It does discuss comparisons between its formulation
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`and oral formulations, based on “meta-analysis” of the efficacy with oral
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`naltrexone found in the prior art (Id. 18:3-19:33.) But it does not provide the
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`underlying data or provide a differential between the two dosing protocols.
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`40. The ’499 Patent identified a number of references when discussing the
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`differences between the pharmacokinetic profiles of a depot injection and oral
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`dosing. (Id. 17:49-62). But that discussion does not reflect a comparison of the
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`relative AUC of these two dosing protocols. Instead, the ’499 Patent merely
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`discusses peak naltrexone levels and the peaks’ alleged impact on reduced
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`tolerability of oral naltrexone including eliminating daily naltrexone peaks and
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`decreasing the ratio of the drug to a particular metabolite. The ’499 Patent does not
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`suggest that any of these three references contain data that define the AUC of
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`50 mg/day oral dosing. Moreover, the references themselves do not provide AUC
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`data. (See Exs. 1033; 1034; 1035.)
`
`41. As the ’499 Patent does not define the AUC of the claimed
`
`formulation or claimed oral dosing, a POSA must look to the art. They would find,
`
`that there is no single accepted data set for the AUC resulting from administering
`
`50 mg/day orally, in the art or in the specification. Instead, the art reports varying
`
`data sets, none of which match. (See ¶¶ 63-86, infra.) Without knowing this
`
`information, it is not possible to calculate an AUC differential between these two
`
`dosing protocols—the results will vary with the data set used.
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`42. As noted previously, AUC is a function of dose. (Ex. 1027, at 7.)
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`Here, the claim reflects a dosing range of 310 to 480 mg, which is a broad range.
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`So the AUC for each of these doses will necessarily be different. And, since there
`
`is no consistent set of data provided to use for the comparative oral dosing, it is
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`almost impossible to know if the resulting differential is accurate or meaningful.
`
`43.