Inter Partes Review 2014-00360
`
`US. Patent No. 8,329,216
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`AMNEAL PHARMACEUTICALS, LLC,
`
`Petitioner,
`
`V.
`
`Patent of ENDO PHARMACEUTICALS INC.,
`Patent Owner
`
`Case 2014-00360
`
`US. Patent No. 8,329,216
`
`DECLARATION OF PROF. DIANE J. BURGESS, PH.D.
`
`Mail Stop PATENT BOARD
`Patent Trial and Appeal Board
`United States Patent and Trademark Office
`
`PO. Box 1450
`
`Alexandria, VA 22313-1450
`
`Dated: October 27, 2014
`
`Filed by:
`
`Joseph A. Mahoney (Lead Counsel)
`Registration No. 38,956
`MAYER BROWN LLP
`
`71 South Wacker Drive
`
`Chicago, IL 60606
`Telephone: (312) 701-8979
`Facsimile:
`(312) 706-8530
`
`711136759
`
`— Amnea'v-Em
`|PR2014-00360
`
`ENDO - Ex. 2070
`
`AstraZeneca Exhibit 2167 p. 1
`InnoPharma Licensing LLC V. AstraZeneca AB IPR2017-00904
`Fresenius-Kabi USA LLC V. AstraZeneca AB IPR2017-01910
`
`

`

`Email: jmahoney@mayerbrown.com
`
`Erick J. Palmer (Back-Up Counsel)
`Registration No. 64,456
`MAYER BROWN LLP
`
`71 South Wacker Drive
`
`Chicago, IL 60606
`Telephone:
`(312) 701-8352
`Facsimile:
`(312) 706-9316
`Email: ejpalmer@mayerbrown.com
`
`Counsel for Patent Owner, Endo
`Pharmaceuticals Inc.
`
`711136759
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`AstraZeneca Exhibit 2167 p. 2
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`

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`TABLE OF CONTENTS
`
`I.
`
`SUMMARY OF MY OPINIONS ................................................................... 1
`
`II. MATERIALS CONSIDERED ........................................................................ 3
`
`III.
`
`IV.
`
`EXPERIENCE AND QUALIFICATIONS ..................................................... 4
`
`SU1VIMARY OF THE ’216 PATENT ............................................................. 8
`
`V.
`
`THE LEVEL OF ORDINARY SKILL IN THE ART .................................. 11
`
`VI. MULTIPLE PEAKS IN THE OXYMORPHONE PLASMA
`
`CONCENTRATION IS NOT AN INHERENT PROPERTY OF ALL
`
`OXYMORPHONE COMPOSITIONS ......................................................... 11
`
`A. Multiple Plasma Concentration Peaks Within 12 Hours of
`Administration Is Not an Inherent Property of All Oxymorphone
`Compositions ......................................................................................... 12
`
`I . StudyA ........................................................................................... 14
`
`2. Study B ........................................................................................... 17
`
`B. Any Differences in the Protocols of These Clinical Studies Do Not
`Account for Differences in the Peak Plasma Properties ....................... 19
`
`I . Naltrexone has no eflect on the pharmacokinetics of
`oxymorphone ................................................................................. 2O
`
`2. Administering Oxymorphone Under Fasted Conditions
`Would Not Aflect the General Shape of the Mean Plasma
`Concentration Profile .................................................................... 23
`
`C.
`
`The Peak Limitations of Claim 70 Are Not Inherent to All
`
`Oxymorphone Compositions ................................................................ 24
`
`VII. THE COMBINATION OF OSHLACK AND THE HANDBOOK OF
`
`DISSOLUTION TESTING DOES NOT RENDER OBVIOUS ANY OF
`
`THE CHALLENGED CLAIMS ................................................................... 25
`
`A.
`
`B.
`
`The USP Paddle Method at 50 rpm and Basket Method at 100 rpm Are
`Useful Not Because They Provide Equivalent Dissolution, But Because
`They Provide a Reproducible, Discriminatory Quality-Control Test...27
`
`There Is No Evidence Demonstrating That the USP Paddle Method at
`50 rpm and Basket Method at 100 rpm Are “Roughly Equivalent” for
`Any Oxymorphone Composition .......................................................... 32
`
`I . The Paddle Method at 50 rpm and the Basket Method at 100 rpm
`generate diflerent hydrodynamics in the dissolution vessel ......... 36
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`AstraZeneca Exhibit 2167 p. 3
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`a)
`
`b)
`
`The type ofstirrer and agitation level will change the
`hydrodynamics of the dissolution vessel .............................. 36
`
`The Paddle Method at 50 rpm creates a ”dead zone ” of
`fluidflow where the dissolvingformulation is located........ 39
`
`2. Due to factors unique to each formulation, hydrodynamics often
`cause dijferent dissolution profiles for the two methods .............. 41
`
`3. The scientific literature confirms that the statement in the
`Handbook ofDissolution Testing is not generally applicable ...... 45
`
`a)
`
`b)
`
`c)
`
`Exhibit 2030 i Ozkan, et al. (Acetaminophen) .................... 46
`
`Exhibit 2031 i DeHaan (Theophylline) ............................... 49
`
`Exhibit 2033 i Cappola (ranitidine) .................................... 51
`
`4. The Statement in the Handbook ofDissolution Testing Is Not
`Generally Applicable to Controlled Release Formulations ......... 53
`
`5. The skilled artisan could not have reasonably predicted what
`Oshlack ’s dissolution rates would have been using the Paddle
`Method at 50 rpm .......................................................................... 56
`
`VIII. THE PRIOR ART TEACHES AWAY FROM A CONTROLLED
`
`RELEASE OXYMORPHONE COMPOSITION ......................................... 59
`
`A.
`
`The Prior Art Taught Away From Using Low Bioavailable Drugs
`in Controlled Release Formulations ...................................................... 61
`
`B. Dr. Palmieri’s Testimony Regarding the Relevance of First-Pass
`Metabolism Associated With Oxymorphone Is Wrong ........................ 71
`
`C.
`
`The Prior Art Taught Away From Using Oxymorphone in
`Controlled Release Formulations .......................................................... 72
`
`D. Nothing in Maloney Overcomes This Teaching Away ........................ 74
`
`E. Oshlack Actually Teaches That Bioavailability Is a Critical
`Consideration in Pharmaceutical Development and Therefore
`Discourages the Skilled Artisan From Attempting the Claimed
`Invention ............................................................................................... 75
`
`F.
`
`Dr. Palmieri’s Opinions Are Underrnined by His Deposition Testimony
`............................................................................................................... 81
`
`IX.
`
`THERE IS NO EVIDENCE SHOWING THAT THE CLAIlVIED FOOD
`
`EFFECTS ARE INHERENT IN THE FORMULATIONS DISCLOSED
`
`IN OSHLACK ............................................................................................... 85
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`AstraZeneca Exhibit 2167 p. 4
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`A.
`
`B.
`
`C.
`
`The Claimed Food Effects Should Be Determined Using a Ratio
`of Least-Squares Means of Natural Log-Transformed Data ................ 86
`
`The Evidence Unmistakably Shows That the Claimed Food
`Effects Are Not Inherent Properties of Oxymorphone Itself................ 97
`
`1.
`
`2.
`
`Increase in AUC(0_l-nfl of ”about 18% ” and ”less than 20% ” ....... 97
`
`Increase in Cmax of “at least 50% ” and ”about 58% ” ................. 99
`
`There Is No Evidence Showing That All Controlled Release
`Oxymorphone Compositions Necessarily Exhibit the Claimed
`Food Effects ........................................................................................ 103
`
`X.
`
`SECONDARY CONSIDERATIONS OF NONOBVIOUSNESS ............. 104
`
`A.
`
`The Commercial Success of Opana® ER Flows from Novel Aspects of
`the Claims ............................................................................................ 104
`
`1. Opana® ER Is Covered by the Claims of the ’216 Patent .......... 104
`
`2. The Commercial Success Is Connected to Novel Aspects
`of the Claims of the ’216 Patent .................................................. 105
`
`B.
`
`The Claimed Invention of the ’216 Patent Addressed a
`
`Long-Felt But Unmet Need ................................................................ 107
`
`XI.
`
`PROPOSED AMENDED CLAIMS 83 AND 84 ARE PATENTABLE
`
`OVER THE PRIOR ART ............................................................................ 110
`
`A.
`
`B.
`
`C.
`
`D.
`
`The Proposed Amended Claims Are Narrower in Scope Than the
`Original Claims ................................................................................... 1 1 1
`
`The Proposed Amended Claims Are Supported by the Written
`Description .......................................................................................... 1 12
`
`The Proposed Amendments Obviate the Grounds on Which Institution
`Was Granted ........................................................................................ 1 17
`
`The Proposed Amended Claims Are Patentable Over the Closest
`Prior Art of Which I Am Aware ......................................................... 120
`
`XII. CERTIFICATION OF EXHIBITS .............................................................. 121
`
`XIII. CONCLUSIONS ......................................................................................... 121
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`AstraZeneca Exhibit 2167 p. 5
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`1, Diane J. Burgess, Ph.D., hereby declare:
`
`I.
`
`SUMMARY OF MY OPINIONS
`
`1.
`
`In my opinion, claims 1, 2, 6, and 12 are patentable over Maloney
`
`(Exhibit 1006). First, the multiple peaks limitations of claims 1, 2, 6, and 12 of
`
`US. Patent No. 8,329,216 (the “’216 patent”) are not inherent properties of any
`
`oxymorphone composition, regardless of formulation. The clinical evidence I have
`
`considered demonstrates that some oxymorphone compositions, including an oral
`
`oxymorphone solution and immediate release oxymorphone tablets, do not exhibit
`
`multiple plasma concentration peaks of oxymorphone within about 12 hours of
`
`administration. Second, the prior art teaches away from the claimed controlled
`
`release oxymorphone formulations, and a person of ordinary skill in the art would
`
`not have had a reasonable expectation of achieving a controlled release
`
`oxymorphone formulation having a therapeutic effect over a period of at least 12
`
`hours from the teachings of Maloney.
`
`2.
`
`In my opinion, claims 1, 2, 6, and 12 are also patentable over the
`
`combination of Oshlack (Exhibit 1007) and the Handbook of Dissolution Testing
`
`(Exhibit 1008) for the very same reasons.
`
`3.
`
`In my opinion, claims 13, 14, 17, 21-43, 45-51, and 54-71 are
`
`patentable over the combination of Oshlack and the Handbook of Dissolution
`
`Testing. First, neither of these prior art references teaches the claimed dissolution
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`ranges. A person of ordinary skill in the art would have understood that there is no
`
`general correlation between the dissolution profile obtained using Paddle Method
`
`at 50 rpm, as recited in the claims of the ’216 patent, and one obtained using the
`
`Basket Method at 100 rpm, as disclosed in Oshlack. A person of ordinary skill in
`
`the art would have also understood that the Handbook of Dissolution Testing’s
`
`statement to the contrary is wrong and is contradicted by numerous scientific
`
`publications available at the time of the invention. Second, the prior art teaches
`
`away from the claimed controlled release oxymorphone formulations, and a skilled
`
`artisan would not have reasonably expected to achieve a controlled release
`
`oxymorphone composition having a therapeutic efficacy over a period of at least
`
`12 hours from the combined teachings of Oshlack and the Handbook of
`
`Dissolution testing. Oxymorphone is known to undergo substantial first-pass
`
`metabolism in the liver and is converted primarily to a metabolite that is inactive
`
`toward treating pain. However,
`
`the prior art teaches away from formulating
`
`extended release compositions containing drugs that are substantially metabolized
`
`before systemic circulation.
`
`4.
`
`In my opinion, claims 31, 32, 35, 36, 38-41, 49-51, and 56 are
`
`patentable for an additional reason. The food effect limitations of these claims are
`
`not
`
`inherent properties of any oxymorphone
`
`composition,
`
`regardless of
`
`formulation. The evidence I have considered demonstrates that when immediate
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`711136759
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`AstraZeneca Exhibit 2167 p. 7
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`release oxymorphone compositions are administered with food, the claimed effects
`
`on Cmax and AUC(0-jnf) are not achieved.
`
`5.
`
`In my opinion, certain secondary considerations,
`
`including the
`
`commercial success of Patent Owner’s Opana® ER covered by the ’216 patent,
`
`unexpected results, and the satisfaction of a long-felt but unmet need, support the
`
`nonobviousness of the challenged claims.
`
`II. MATERIALS CONSIDERED
`
`6.
`
`In forming my opinions in this declaration, I considered the following
`
`documents:
`
`0
`
`0
`
`o
`
`0
`
`Amneal’ s Petition and Exhibits 1001-1024
`
`The ’216 patent and it prosecution history,
`
`including the
`
`various declarations submitted to the PTO during prosecution
`
`of the ’216 patent
`
`The deposition testimony of both Dr. Palmieri and Ms. Gray in
`
`this proceeding
`
`The exhibits I specifically reference in this declaration
`
`7.
`
`Additionally,
`
`I
`
`reviewed general
`
`texts and publications in the
`
`scientific and regulatory literature commonly used by pharmaceutical scientists as
`
`resources for information and considered the common knowledge that would have
`
`been available to a person of ordinary skill in the art at the time of the invention.
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`AstraZeneca Exhibit 2167 p. 8
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`In forming my opinions in this declaration, I also conducted searches of the
`
`scientific literature.
`
`III. EXPERIENCE AND UALIFICATIONS
`
`8.
`
`A copy of my current curriculum vitae is attached at Exhibit 2011. A
`
`summary of my relevant experience and qualifications are provided below.
`
`9.
`
`In 1979, I received a Bachelors of Science degree in Pharmacy from
`
`the University of Strathclyde, Glasgow, UK.
`
`In 1984, I received a doctorate in
`
`Pharmaceutics from the University of London, UK.
`
`I joined the faculty at the
`
`University of Connecticut
`
`in 1993 and was promoted to Full Professor of
`
`Pharmaceutics in 1999.
`
`I am currently a Distinguished Professor at the University
`
`of Connecticut (appointed in 2009) and hold positions as the Pharmaceutics
`
`Discipline Coordinator, and the Chair of the School of Pharmacy Study Abroad
`
`Committee.
`
`10.
`
`I have served as an executive of several professional organizations
`
`focused on the field of pharmaceutics and drug development. For example, I was
`
`the 2002 President of the American Association of Pharmaceutical Scientists
`
`(“AAPS”), which is the largest professional organization globally representing
`
`scientists in pharmaceutics, biopharrnaceutics, and related disciplines. From 2009
`
`until 2010, I was president of the Controlled Release Society (“CRS”), which is a
`
`711136759
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`AstraZeneca Exhibit 2167 p. 9
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`professional organization focused on developments
`
`in controlled release
`
`technologies.
`
`11.
`
`I have served on the Editorial Advisory Boards of nine international
`
`journals.
`
`I
`
`currently
`
`serve
`
`on
`
`the board of THE AAPS JOURNAL,
`
`AAPSPHARMSCITECH, THE INTERNATIONAL JOURNAL OF PHARMACEUTICS,
`
`the
`
`JOURNAL OF MICROENCAPSULATION,
`
`THE
`
`JOURNAL OF
`
`PHARMACY AND
`
`PHARMACOLOGY,
`
`CURRENT DRUG DISCOVERY,
`
`CRITICAL REVIEWERS
`
`IN
`
`THERAPEUTIC DRUG CARRIER SYSTEMS, THE JOURNAL OF DRUG DELIVERY &
`
`TRANSFORMATIONAL RESEARCH, and the JOURNAL OF DIABETES SCIENCE &
`
`TECHNOLOGY.
`
`12.
`
`I am also currently an editor of THE INTERNATIONAL JOURNAL OF
`
`PHARMACEUTICS. From 2003 until 2012, I was an editor for the JOURNAL OF DRUG
`
`DELIVERY SCIENCE AND TECHNOLOGY. From 1999 until 2004, I was an editor for
`
`the AMERICAN ASSOCIATION OF PHARMACEUTICAL SCIENCE JOURNAL.
`
`I also serve
`
`as referee for 19 journals,
`
`including the JOURNAL OF CONTROLLED RELEASE,
`
`CRITICAL REVIEWERS IN THERAPEUTIC DRUG CARRIER SYSTEMS, PHARMACEUTICAL
`
`RESEARCH, NATURE,
`
`INTERNATIONAL JOURNAL OF PHARMACEUTICS, and the
`
`JOURNAL OF PHARMACY AND PHARMACOLOGY, to name a few.
`
`In my roles as
`
`editor and referee,
`
`I
`
`routinely analyze the scientific methodologies, data,
`
`descriptions, and analyses provided in submissions
`
`to confirm that
`
`such
`
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`AstraZeneca Exhibit 2167 p. 10
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`methodologies, data, descriptions, and analyses are scientifically rigorous and
`
`correctly support any conclusions and hypotheses drawn there from.
`
`In cases
`
`where the data does not conclusively support a proposition set forth in the article, I
`
`may suggest additional experiments for the author(s) to conduct to confirm such
`
`proposition or may suggest rejection of the manuscript from publication.
`
`13. My research group has studied controlled release formulations for
`
`more than thirty years.
`
`I have authored or co-authored 178 refereed scientific
`
`articles, most of which have been published in high-impact scientific journals.
`
`I
`
`have also authored two pharmaceutical books relating to drug delivery and
`
`authored chapters related to drug delivery and drug release in 34 other books.
`
`In
`
`addition, my research has been presented 487 times at major international scientific
`
`meetings, and I have been invited to present on more than 240 occasions, including
`
`giving 20 keynote and plenary addresses.
`
`14. At the University of Connecticut, I direct an active research group of
`
`assistant research professors, post-doctoral fellows, graduate students, professional
`
`students, and undergraduate students. My research interests relate to microsphere,
`
`liposome, emulsion and hydrogel preparation and characterization for application
`
`as targeted and controlled release delivery systems for drugs, genes, vaccines and
`
`other systems, including fundamental colloid and surface chemistry, investigation
`
`of mechanisms of formation, formulation, development of novel technologies,
`
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`AstraZeneca Exhibit 2167 p. 11
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`stability assessment and prediction,
`
`transport and mathematical modeling of
`
`transport, IVIVC testing of drug release, surface and interfacial phenomena related
`
`to biological systems and drug delivery, and interfacial rheology and tension. As
`
`part of our research, my research group routinely performs dissolution testing of
`
`various pharmaceutical formulations. Indeed, in 2009, the Board of Trustees of the
`
`University of Connecticut renamed one of my laboratories as the SOTAX
`
`Dissolution and Release Testing Laboratory (SOTAX is a manufacturer of
`
`apparatus uses for the dissolution testing of pharmaceuticals).
`
`15. My research is funded by extramural grants from companies and
`
`funding agencies. More than 22 graduate students working under my direction
`
`have obtained their doctorate. Also, as part of my academic career, I have taught
`
`courses
`
`in Controlled Drug Delivery, Foundations of Pharmaceutics, Drug
`
`Discovery and Development, Advanced Biopharrnaceutics, and Interfacial and
`
`Colloid Chemistry.
`
`16.
`
`I have received various honors and awards throughout my career.
`
`In
`
`2014,
`
`I am the recipient of the AAPS Research Achievement Award in
`
`Formulation Design and Development, the AAPS Outstanding Educator Award,
`
`and the CRS’s Distinguished Service Award.
`
`In 2013, I was awarded the AAPS
`
`IPEC Ralph Shangraw Memorial Award for outstanding research in the area of
`
`pharmaceutical excipients.
`
`In 2011, I received the APSTJ Nagai International
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`AstraZeneca Exhibit 2167 p. 12
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`Woman Scientist Award from the Japanese Pharmaceutical Science Association.
`
`I
`
`was the first recipient of the CRSI Fellowship for outstanding contributions in the
`
`area of drug delivery in 2010.
`
`In 2007, I received the Outstanding Manuscript
`
`Award from the AAPS Journal.
`
`I was elected Pharmacy School Teacher of the
`
`Year in 2005. And in 1991, I was awarded the Outstanding Teacher of the Year
`
`Award.
`
`17.
`
`I am a named inventor of two issued US. patents and three US.
`
`patent applications, none of which are at issue in this proceeding.
`
`18.
`
`Based on my academic credentials and research over the past thirty
`
`plus years, I am an expert in pharmaceutical drug development, controlled release
`
`technologies, dissolution testing of pharmaceutical formulations, and assessment of
`
`in vivo clinical data, to name a few.
`
`19.
`
`I am being compensated at my standard rate of $600 for providing my
`
`opinions and analysis in this proceeding. My compensation is not contingent in
`
`any way on the substance of my opinions.
`
`IV.
`
`SUMMARY OF THE ’216 PATENT
`
`20.
`
`Severe pain is one of the most
`
`frequently treated complaints
`
`confronting today’s clinicians.
`
`It is a well-known fact that pain is both under-
`
`treated and inappropriately managed. One paramount goal of pain management
`
`involves providing continuous relief of chronic pain, which can be recurring or
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`otherwise last for an extended duration.
`
`(Ex. 1001 at 1:39-42). Patients suffering
`
`from this level of pain typically include those with advanced-stage cancer, back
`
`problems, and other serious diseases. A class of compounds called opioids is
`
`frequently used for analgesia. Opioids that have been used for pain include
`
`oxycodone, fentanyl, hydromorphone, hydrocodone, and oxymorphone.
`
`21.
`
`These compounds have traditionally been available as immediate
`
`release (“IR”) formulations, which means that
`
`the entire dose of the active
`
`ingredient is released quickly. As such, IR opioid formulations have multiple
`
`drawbacks. Opioids that rapidly metabolize (like oxymorphone as discussed
`
`below) require frequent dosing because of the short duration during which
`
`analgesia is achieved.
`
`(Ex. 1001 at 1:50-54). If frequent dosing is not maintained,
`
`the patient may experience recurring pain as the drug loses effect in the body,
`
`leaving the patient without relief.
`
`In order to maintain continuous relief, IR
`
`opioids must therefore be taken according to a rigid schedule to provide effective
`
`management of chronic pain. Typically, patients take the IR medications every 4
`
`to 6 hours in order to maintain pain relief.
`
`(1d,).
`
`22.
`
`Opioid-containing controlled release (“CR”) formulations, also called
`
`extended release (“ER”) formulations, can have a profound effect on the quality of
`
`life of the patient and directly affect the success of the treatment regimen. ER
`
`dosage forms have been shown to provide therapeutic benefits beyond simply
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`reducing the number of daily doses required. The inventors were the first to
`
`discover an in vitro dissolution profile that achieved a safe and effective treatment
`
`for relieving pain over a 12 hour period.
`
`(EX. 1001 at Figures 1-4). The ’216
`
`patent pertains to methods of relieving pain over a period of 12 to 24 hours by
`
`administering controlled release oxymorphone tablets.
`
`23.
`
`Oxymorphone is a semisynthetic opioid agonist with a significantly
`
`higher
`
`parenteral
`
`analgesic
`
`potency
`
`compared
`
`to
`
`parenteral morphine.
`
`Oxymorphone was first approved by the Food and Drug Administration (“FDA”)
`
`(NDA No. 11-737) in 1959 and marketed in June of that year.
`
`Immediate release
`
`oral oxymorphone was originally marketed in the early 1960s, but was voluntarily
`
`removed from the market for commercial reasons. 2 mg and 5 mg tablets were
`
`commercially available for about 7 years, and 10 mg tablets were commercially
`
`available for about 11 years.
`
`24.
`
`The ’216 patent pertains to a method of relieving pain over a period of
`
`at least 12 hours by administering a controlled release oxymorphone tablet. The
`
`inventors were the first to discover an in vitro dissolution profile that unexpectedly
`
`achieved therapeutic efficacy for the treatment of pain over at least a 12 hour
`
`period.
`
`(EX. 1001 at Figures 1-4).
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`AstraZeneca Exhibit 2167 p. 15
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`V.
`
`THE LEVEL OF ORDINARY SKILL IN THE ART
`
`25.
`
`In my opinion, a person of ordinary skill in the art at the time of the
`
`claimed invention would possess at
`
`least a Master’s degree in the field of
`
`pharmaceutical
`
`sciences or a related discipline and have several years of
`
`experience in formulation of various dosage forms, including immediate release
`
`and extended release, and the testing of such dosage forms for regulatory
`
`approval. A person of ordinary skill in the art could be a person with a lower level
`
`of formal education if such a person has a higher degree of experience.
`
`I have
`
`considered this level of ordinary skill in the art in forming my opinions in this
`
`declaration.
`
`26.
`
`I not only met but exceeded these qualifications in the relevant 2001
`
`timeframe.
`
`VI. MULTIPLE
`
`PEAKS
`
`IN THE OXYMORPHONE
`
`PLASMA
`
`CONCENTRATION IS NOT AN INHERENT PROPERTY OF ALL
`
`OXYMORPHONE COMPOSITIONS
`
`27.
`
`I have been asked to provide my opinion on whether Amneal’s
`
`Petition sufficiently demonstrates by a preponderance of the evidence (116., more
`
`likely than not) that the claimed multiple peaks feature of the oxymorphone plasma
`
`concentration in claims 1, 2, 6, and 12 is an inherent property of any oxymorphone
`
`composition, regardless of formulation.
`
`In my opinion, Amneal’s Petition does
`
`not.
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`AstraZeneca Exhibit 2167 p. 16
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`28.
`
`In forming my opinions,
`
`I considered the following statements
`
`regarding the legal standard for determining a claimed feature is an inherent
`
`property of a prior art composition:
`
`0
`
`0
`
`o
`
`Inherency requires that the feature be “necessarily present” in
`
`the prior art reference.
`
`Inherency may not be
`
`established by probabilities
`
`or
`
`possibilities.
`
`A claimed feature is inherent in a prior art reference if it is the
`
`natural
`
`result
`
`flowing from the explicit disclosure of the
`
`reference.
`
`A. Multiple Plasma Concentration Peaks Within 12 Hours of
`Administration Is Not an Inherent Property of All Oxymorphone
`Compositions
`
`29.
`
`Claim 1 is an independent claim. One of its limitations is that “the
`
`blood plasma levels of oxymorphone exhibit two or three peaks within about 12
`
`hours after administration. .
`
`.
`
`.” Claims 2, 6, and 12 all depend from claim 1 and
`
`therefore also contain this limitation.
`
`30.
`
`I understand that Dr. Palmieri believes that multiple peaks in the
`
`plasma concentration of oxymorphone within 12 hours of administration “is an
`
`inherent property of all oxymorphone compositions.” (Palmieri Decl., Ex. 1003 at
`
`1] 95). Dr. Palmieri’s opinion is based on Figures 6 and 7 of the ’216 patent. (Id).
`
`Figure 6 plots the plasma concentration of oxymorphone as a function of time for
`
`Treatments 2A (controlled release oxymorphone tablet), 2B (controlled release
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`711136759
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`12
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`AstraZeneca Exhibit 2167 p. 17
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`oxymorphone tablet), and 2C (oral solution of oxymorphone).
`
`(’216 patent, Ex.
`
`1001 at 13:58-14:56). Figure 7 plots the plasma concentration of oxymorphone as
`
`a function of time for Treatments 3A (controlled release oxymorphone tablet under
`
`fasted conditions), 3B (controlled release oxymorphone tablet under
`
`fed
`
`conditions), 3C (oral solution of oxymorphone under fasted conditions), and 3D
`
`(oral solution of oxymorphone under fed conditions).
`
`(Id. at 15:42-16:35). Dr.
`
`Palmieri relies on the small shoulders at around 12 hours in the oral solutions to
`
`conclude that all oxymorphone compositions necessarily exhibit multiple peaks
`
`after administration.
`
`31. However, Dr. Palmieri’s deposition testimony confirmed that
`
`the
`
`claimed multiple peaks
`
`are not
`
`inherent properties of all oxymorphone
`
`compositions.
`
`I understand that Dr. Palmieri was asked whether he considered any
`
`scientific publications outside of the ’216 patent
`
`to determine whether those
`
`formulations exhibited multiple peaks within 12 hours of administration. (Palmieri
`
`Tr., Ex. 2012 at 170:16-20). Dr. Palmieri responded that some oxymorphone
`
`compositions exhibit multiple peaks while others do not:
`
`A
`
`Do I recall reading the documents that
`
`I cite?
`
`Sometimes they’re there, and sometimes they
`
`weren’t there. But again, you have to wonder
`
`about the validity of the data. With clinical studies
`
`there's always variation.
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`711136759
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`AstraZeneca Exhibit 2167 p. 18
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`(Id. at 170:21-171:3 (emphasis added)).1
`
`32.
`
`I agree with Dr. Palmieri on this point:
`
`some oxymorphone
`
`compositions exhibit multiple peaks in the plasma concentration of oxymorphone
`
`within about 12 hours of administration, and some oxymorphone compositions do
`
`not.
`
`In reaching my conclusion,
`
`I have considered two clinical studies not
`
`disclosed in the ’216 patent. The first is a clinical study—
`
`—. nne see n n ennnen
`
`study in which immediate release oxymorphone tablets were administered to
`
`subjects. Based on my reView of the clinical results of these studies, it is my
`
`opinion that multiple peaks in the oxymorphone plasma concentration within about
`
`12 hours of administration are not inherent to all oxymorphone compositions
`
`because sometimes the unclaimed oral solution and immediate release tablets
`
`clearly do not exhibit multiple peaks.
`
`1.
`
`Study A
`
`33.
`
`1 I understand that Dr. Palmieri later testified that multiple peaks are exhibited by
`all oxymorphone compositions.
`(Palmieri Tr., Ex. 2012 at 205 :9-206:1).
`However, this testimony came only after Dr. Palmieri conferred with Amneal’s
`counsel.
`(Id. at 210:19-212:1).
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`711136759
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`AstraZeneca Exhibit 2167 p. 19
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`U) .">
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`711136759
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`1—1 Lh
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`AstraZeneca Exhibit 2167 p. 20
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`711136759
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`1—1 Ch
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`AstraZeneca Exhibit 2167 p. 21
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`36.
`
`It is therefore my opinion that multiple plasma concentration peaks of
`
`oxymorphone are not necessarily exhibited by all oxymorphone compositions,
`
`regardless of formulation, and there is no evidence that they naturally flow from
`
`the compositions disclosed in Maloney or Oshlack.
`
`2.
`
`Study B
`
`37.
`
`Exhibit 2014 is an article entitled Single- and Multiple-Dose
`
`Pharmacokinetl'c and Dose-Proportionality Study of Oxymorphone Immediate-
`
`Release Tablets, which was published in the scientific journal DRUGS R D in 2005.
`
`This article describes a clinical study examining the pharrnacokinetics and dose
`
`proportionality
`
`of
`
`an
`
`immediate-release
`
`tablet
`
`formulation
`
`containing
`
`oxymorphone following single and multiple-dose administration in healthy
`
`subjects.
`
`(Ex. 2014 at 91). The study included 24 participants (male and female)
`
`and employed a randomized, three-way crossover design.
`
`(Id.). Single doses of 5
`
`mg, 10 mg, and 20 mg of immediate release oxymorphone tablets were co-
`
`administered with the opioid antagonist naltrexone.
`
`(Id.). Subjects were fasted
`
`from 10 pm. the day before and were administered a single dose on Day 1.
`
`(Id. at
`
`93). Subjects were fed four hours after administration of the oxymorphone.
`
`(Id.).
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`711136759
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`AstraZeneca Exhibit 2167 p. 22
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`A 7-day washout period was used prior to administration of the next randomized
`
`oxymorphone formulation. (Id).
`
`38.
`
`The mean single-dose and steady-state plasma concentrations of 5 mg,
`
`10 mg and 20 mg immediate release oxymorphone are shown in Figure 1 of
`
`Exhibit 2014, which is excerpted as follows:
`
`3
`
`Brynn-#1131“: II: 5mg
`
`I lflmmphnrm 5mg dmvgln- tribal
`
`l. Mymphmu Sims; at] untidy 51mm
`
`
`€3me IFI Hing
`I Dmmmfl‘lmm “flung 3511‘:ng (heal
`.I. Gram Tm Mandy 2mm
`
`I: WW I“ 31mg
`
`i flnymclphmm Efllflg Wig 1r: them
`It
`flmymmphmm 243mg Mandy 51mm
`
`6, 5
`
`“:1 .41
`
`16
`
` 3
`
`d}
`
`5
`
`EH 16244$2mdfl
`
`
`
`
`
`
`
`Meanplea-Iramurmur-1mmagpngrL]
`
`(Id. at 97).
`
`711136759
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`TIT-mum
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`18
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`AstraZeneca Exhibit 2167 p. 23
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`39.
`
`The above graphs illustrate that
`
`the mean plasma concentrations
`
`following administration of a single dose of the 5 mg, 10 mg, and 20 mg
`
`immediate-release
`
`oxymorphone
`
`tablets
`
`exhibited
`
`only
`
`a
`
`single
`
`plasma
`
`concentration peak between 0 and 12 hours.2 These results are consistent with the
`
`results of the clinical study described above in Ex. 2013.
`
`40.
`
`This
`
`is
`
`further proof
`
`that not all oxymorphone compositions
`
`necessarily exhibit multiple plasma concentration peaks of oxymorphone within
`
`about 12 hours of administration.
`
`B.
`
`Any Differences in the Protocols of These Clinical Studies Do Not
`Account for Differences in the Peak Plasma Properties
`
`41.
`
`The studies described in Exhibits 2013 and 2014 demonstrate that
`
`some oxymorphone compositions exhibit multiple plasma concentration peaks
`
`within about 12 hours of administration of oxymorphone whereas others do not. In
`
`the studies described in Exhibits 2013 and 2014, a plasma concentration peak at
`
`about 12 hours is absent.
`
`42.
`
`In accounting for
`
`this difference in the observed peak plasma
`
`concentration behavior of the oxymorphone compositions used in the clinical
`
`2 Peak plasma concentrations in the ’216 patent are determined after administration
`of a single dose of oxymorphone.
`(See, e.g., Ex. 1001 at 13:59-62, 15:60-16:9,
`24:20-35). This is consistent with FDA guidances.
`(See Ex. 2015 at 8 (“[T]his
`guidance generally recommends single-dose pharrnacokinetic studies for both
`immediate- and modified-release drug products to demonstrate [bioequivalence]
`because they are generally more sensitive in assessing release of the drug
`substance from the drug product into the systemic circulation. .
`. .”)).
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`711136759
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`19
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`AstraZeneca Exhibit 2167 p. 24
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`

`

`studies described in Exhibits 2013 and 2014 and those in the ’216 patent, I have
`
`considered the clinical study protocols for each study. For example, the clinical
`
`studies in Exhibits 2013 and 2014 administered the oxymorphone form