`Case IPR2018-00943
`Patent No. 7,919,499
`Declaration of Sara K. Quinney, Pharm.D., 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 1062)
`
`DECLARATION OF SARA K. QUINNEY, Pharm.D., Ph.D. IN SUPPORT
`OF PETITIONER’S REPLY TO PATENT OWNER’S RESPONSE
`
`
`
`
`
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`AMN1062
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
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`
`
`Case IPR2018-00943 (Patent No. 7,919,499)
`Decl. of Sara K. Quinney, Pharm.D., Ph.D. in Supp. of Pet’s Reply to PO’s Resp.
`
`
`TABLE OF CONTENTS
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`Page
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`INTRODUCTION ........................................................................................... 2
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`I.
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`II.
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`BACKGROUND AND QUALIFICATIONS ................................................. 2
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`III.
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`SUMMARY OF OPINIONS ........................................................................... 8
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`IV. BACKGROUND ON PHARMACOKINETICS ............................................ 9
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`V. A PERSON OF ORDINARY SKILL IN THE ART ....................................15
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`VI. THE ’499 PATENT .......................................................................................16
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`A. The Claimed AUC Differential Is Not Unexpected ...............................17
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`B. The Claimed AUC Differential Is Not Correlated To Improved
`Therapeutic Effects .................................................................................19
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`VII. AUC AND METHODS OF CALCULATION .............................................21
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`A. The Area Under The Curve (AUC) ........................................................21
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`B. Use Of Photoshop To Calculate AUC ....................................................25
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`VIII. AUC AND PK DATA SETS.........................................................................28
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`A. AUC Calculations And Time Zero .........................................................28
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`B. AUC And Plasma Level .........................................................................33
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`C. AUC And Prior Administration ..............................................................40
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`D. A POSA Would Recognize The Data Sets Of Comer And Nuwayser As
`Originating From The Same Study .........................................................47
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`IX. CONCLUSION ..............................................................................................49
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`AMN1062
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
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`
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`Case IPR2018-00943 (Patent No. 7,919,499)
`Decl. of Sara K. Quinney, Pharm.D., Ph.D. in Supp. of Pet’s Reply to PO’s Resp.
`
`
`I, SARA K. QUINNEY, 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 &
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`Mentlik, LLP (“counsel”) to provide my opinions in the field of clinical
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`pharmacology and pharmacokinetics for purposes of this Inter Partes Review
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`(“IPR”). I have read and understand U.S. Patent No. 7,919,499 (“the ’499 Patent”)
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`(Ex. 1001) as well as all other references discussed in this declaration. I am being
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`compensated for my time in an amount consistent with my customary consulting
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`fee, and my compensation is not contingent on my opinion or the outcome of this
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`proceeding.
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`II. BACKGROUND AND QUALIFICATIONS
`I am an expert in pharmacokinetics, which is frequently abbreviated
`3.
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`as “PK.” Pharmacokinetics is the branch of pharmacology that describes and
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`quantifies the movement of a drug within the body of a living organism.
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`Pharmacokinetics provides information on mechanisms of drug absorption,
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`distribution, metabolism, excretion, and transport (ADMET). My background and
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`qualifications are set forth in my curriculum vitae. (Ex. 1063.) It contains a
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`description of my education, academic appointments, professional activities,
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`research grants, presentations, service as a reviewer for professional journals,
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`AMN1062
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`Case IPR2018-00943 (Patent No. 7,919,499)
`Decl. of Sara K. Quinney, Pharm.D., Ph.D. in Supp. of Pet’s Reply to PO’s Resp.
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`published articles in peer reviewed scholarly journals, teaching responsibilities,
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`and thesis supervision.
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`4.
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`I hold a primary appointment as an Assistant Professor of Obstetrics
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`and Gynecology at Indiana University School of Medicine (IUSM). Additionally, I
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`hold adjunct appointments in the Division of Clinical Pharmacology, Department
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`of Medicine in IUSM, the School of Informatics and Computing at Indiana
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`University Purdue University Indianapolis (IUPUI), and the Department of
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`Pharmacy Practice, College of Pharmacy, Purdue University.
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`5.
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`I am the Associate Director of the Indiana Clinical and Translational
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`Sciences Institute (CTSI) Disease and Therapeutic Response Modeling Program.
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`This program provides training in pharmacometrics and quantitative systems
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`pharmacology, including pharmacokinetic/pharmacodynamic (PK/PD) modeling,
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`physiologically based pharmacokinetic (PBPK) modeling, and machine learning. I
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`am also a member of the Center for Computational Biology and Bioinformatics
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`(CCBB) at the Indiana University School of Medicine.
`
`6.
`
`I obtained my Doctorate in Pharmacy from Purdue University in 2000
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`and obtained my Ph.D. in Pharmacy Practice from Purdue University in 2004. I
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`subsequently completed a Postdoctoral Fellowship in Clinical Pharmacology at the
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`Indiana University Division of Clinical Pharmacology in 2007 and completed a
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`Postdoctoral Fellowship in Bioinformatics and Biostatistics at the Indiana
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`AMN1062
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
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`Case IPR2018-00943 (Patent No. 7,919,499)
`Decl. of Sara K. Quinney, Pharm.D., Ph.D. in Supp. of Pet’s Reply to PO’s Resp.
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`University Department of Biostatistics in 2009. I joined the Indiana University
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`School of Medicine as an Assistant Research Professor in 2009, and since 2013, I
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`have been an Assistant Professor in the Division of Clinical Pharmacology and in
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`the Department of Obstetrics and Gynecology at the Indiana University School of
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`Medicine. Since 2013, I have also been a member of the Center for Computational
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`Biology and Bioinformatics and since 2015, I have been an Associate Director of
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`the Indiana CTSI Disease and Therapeutic Modeling Program within the Indiana
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`University School of Medicine.
`
`7.
`
`Since 2009, I have designed and directed a number of clinical PK
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`studies, primarily in pregnant women. For instance, I conducted a PK study to
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`evaluate the effect of pregnancy on the PK of nifedipine administered to women
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`with preterm labor. In collaboration with other investigators at IUSM, I have
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`evaluated the impact of pharmacogenomic variants in CYP3A enzymes on the PK
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`and PD of betamethasone for fetal lung maturation. I am currently conducting a
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`study in women in their third trimester of pregnancy to evaluate the effect of
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`hepatitis C virus (HCV) on the clearance of buprenorphine. Therefore, I am well
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`versed in the design and conduct of clinical pharmacology studies, especially
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`studies of PK, PD, and pharmacogenomics.
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`8. My research also encompasses the area of opiate use disorder. I have
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`conducted a clinical study evaluating the relationship between exposure of R- and
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`AMN1062
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`IPR2018-00943
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`Case IPR2018-00943 (Patent No. 7,919,499)
`Decl. of Sara K. Quinney, Pharm.D., Ph.D. in Supp. of Pet’s Reply to PO’s Resp.
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`S-methadone and its metabolites in maternal and neonatal blood (and plasma) and
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`the severity of neonatal abstinence syndrome. I have also worked on a number of
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`studies evaluating the buprenorphine therapy in pregnant women with opioid use
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`disorder who receive treatment through the IU Maternal Fetal Medicine clinic.
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`These studies include retrospective chart reviews to evaluate the impact of group
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`care, breastfeeding, concurrent medications, and hepatitis C infection on maternal
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`(e.g., withdrawal) and neonatal outcomes (e.g., neonatal abstinence syndrome). I
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`am currently conducting a study of the effect of hepatitics C virus (HCV) on the
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`pharmacokinetics of buprenorphine during the third trimester of pregnancy. Thus, I
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`am familiar with conducting studies in individuals with opioid use disorders and
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`their clinical care.
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`9.
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`Since 2000, I have been involved in research regarding PK drug-drug
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`interactions and personalized therapy through understanding of inter-individual
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`differences in PK/PD. I utilize in vitro and in vivo (clinical) data to develop
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`computational PK models to explain the effect of drug metabolizing enzyme
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`inhibition on the PK of co-administered drugs. My work in drug interaction
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`research also utilizes electronic data sources, such as electronic health records
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`(EHR) and the Food and Drug Association’s Adverse Event Reporting System
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`(FAERS) to identify drug combinations that have increased risk of clinical adverse
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`drug events, such as myopathy. Increased risk of adverse events in the presence of
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`Case IPR2018-00943 (Patent No. 7,919,499)
`Decl. of Sara K. Quinney, Pharm.D., Ph.D. in Supp. of Pet’s Reply to PO’s Resp.
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`multiple medications can often be explained through PK-related drug-drug
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`interactions.
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`10. My research also focuses on other aspects of PK modeling, including
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`mechanistic PBPK modeling, population PK modeling, and noncompartmental PK
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`modeling. In addition to the clinical studies of nifedipine, betamethasone, and
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`buprenorphine noted above, I also have analyzed data from the multi-center
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`National Institute of Health (NIH)-funded Obstetric Pharmacology Research Unit’s
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`(OPRU’s) opportunistic PK studies in pregnancy on nifedipine and proton pump
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`inhibitors. I have developed PBPK models of a number of compounds, including
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`clarithromycin and 8-prenylnaringenin, a component of hops. Utilizing
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`noncompartmental and population modeling approaches, I have estimated the renal
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`clearance of iohexol, a marker of glomerular filtration rate, in patients before and
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`after gastric bypass surgery. I currently serve as the clinical pharmacology and PK
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`expert for the NIH-funded Model Organism Development & Evaluation for
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`Late-Onset Alzheimer’s Disease (MODEL-AD) consortium, where I lead the
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`design and analysis of PK studies of potential AD therapies in mouse models.
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`11.
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`I have published 105 papers in peer-reviewed journals and given 11
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`invited lectures. I am involved in 12 active research grants, seven pending research
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`grants, and have participated in nine completed research grants.
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`6
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`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
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`Case IPR2018-00943 (Patent No. 7,919,499)
`Decl. of Sara K. Quinney, Pharm.D., Ph.D. in Supp. of Pet’s Reply to PO’s Resp.
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`12. Throughout my career, I have held various leadership positions in my
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`field, including but not limited to Associate Director of the Indiana CTSI Disease
`
`and Therapeutic Response Modeling Program (2015-present), a member of the
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`Indiana CTSI Core Pilot Project Grant Review Committee (2014-2017),
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`Biomedical Research Grant Review Committee Member (2018-present), Chair of
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`the 5th Annual CTSI Therapeutic and Disease Modeling Symposium (2015), and
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`Co-Chair of the Physiologically-Based Pharmacokinetic Modeling in Vulnerable
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`Populations: Pregnant Women, Breastfeeding Infants, Neonates, and Young
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`Children Symposium at the 2019 American Society for Clinical Pharmacology and
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`Therapeutics Annual Meeting in Washington, D.C.
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`13.
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`I have served as a reviewer for 16 academic journals, including but
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`not limited to Drug Metabolism and Disposition, Clinical Pharmacology and
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`Therapeutics, Journal of Clinical Pharmacology, Clinical Pharmacokinetics, and
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`CPT: Pharmacometrics and Systems Pharmacology.
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`14. Accordingly, I believe I am an expert in the field of pharmacology,
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`pharmacokinetics, and pharmacokinetic modeling,
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`including generation of
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`pharmacokinetic profiles and associated data processing, analysis, and
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`characterization for various drugs.
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`15. As of April 22, 2004, I was completing my second doctorate degree in
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`the pharmacy field and was familiar with the state of the art and the level of
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`IPR2018-00943
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`Case IPR2018-00943 (Patent No. 7,919,499)
`Decl. of Sara K. Quinney, Pharm.D., Ph.D. in Supp. of Pet’s Reply to PO’s Resp.
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`knowledge, expertise, and technology available in the field at that time. I also
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`believe that, because of my education, experience, and interactions with students at
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`all levels (undergraduate, Master, M.D., Pharm.D., and Ph.D.) and scientists,
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`researchers, and administrators at all levels in this field, both in academia and
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`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
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`who a person of ordinary skill in the art was as of April 22, 2004, and what such a
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`person would know from my review of the literature in connection with my
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`consideration of the ’499 Patent.
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`III. SUMMARY OF OPINIONS
`I have been asked to provide my opinions on the ’499 Patent and
`16.
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`various references discussed in this IPR proceeding, in view of the state of the art
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`around April 2004, which is the priority date of the ’499 Patent.
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`17.
`
`In addition, I have been asked to respond to the opinions set forth in
`
`Dr. Berkland and Dr. O’Brien’s declarations (Exs. 2055; 2056), the arguments set
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`forth in Alkermes’ Patent Owner’s Preliminary Response (“POPR”) and Patent
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`Owner’s Response (“Resp.”), and the decision set forth in the Board’s Institution
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`Decision (“ID”). I do so below and explain various disagreements I have with
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`these opinions and arguments. My silence on a particular opinion does not mean I
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`agree with that opinion.
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`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
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`Case IPR2018-00943 (Patent No. 7,919,499)
`Decl. of Sara K. Quinney, Pharm.D., Ph.D. in Supp. of Pet’s Reply to PO’s Resp.
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`18. Finally, I have been asked to review and evaluate the declarations of
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`Dr. Park (Exs. 1030, 1061) on the issues discussed herein. I have done so, and,
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`except where indicated otherwise below, I agree with Dr. Park’s opinions and
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`conclusions he set forth.
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`IV. BACKGROUND ON PHARMACOKINETICS
`“Pharmacokinetics” (PK) describes the movement of drug into
`19.
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`(absorption or input), within (distribution), and out of (metabolism and excretion)
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`the body. (Ex. 10821, at 2.) While pharmacodynamics is often described as
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`studying the “effect of the drug on the body,” PK is often described as the
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`1 Exhibit 1082 is a commonly used textbook in Pharmacokinetics, which is widely
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`distributed and relied upon by experts in the field to explain pharmacokinetic
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`theory to students. The copy I used in preparing this declaration was my own copy,
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`which I was assigned and purchased for IPPH 575, Clinical Pharmacokinetics, in
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`August, 1998, while a pharmacy student at Purdue University. I also used this
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`book during my graduate studies at Purdue University and as the textbook for the
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`pharmacokinetic didactics course during my NIH T32 Clinical Pharmacology
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`Fellowship at Indiana University. As faculty in the T32 Clinical Pharmacology
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`Fellowship, we continue to assign the Rowland and Tozer textbook (now
`
`version 4) to clinical pharmacology fellows and pharmacology and pharmacy
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`graduate students from IUSM and Purdue University.
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`Case IPR2018-00943 (Patent No. 7,919,499)
`Decl. of Sara K. Quinney, Pharm.D., Ph.D. in Supp. of Pet’s Reply to PO’s Resp.
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`opposite: studying the “effect of the body on the drug.” The two areas of study are,
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`however, inextricably connected and both are important components of the field of
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`clinical pharmacology.
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`20.
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`“Pharmacodynamics” (PD) describes how the concentration of a drug
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`at its site of action is related to the magnitude of the clinical effect observed.
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`Pharmacodynamics studies the relationship between a drug’s biochemical and
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`physiological effects and its mechanism of action. (Id. at 3.) One of the most basic
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`skills for a clinical pharmacologist or pharmacokineticist is the ability to test a drug
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`and gather the PK/PD data that describe a drug’s behavior.
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`21. The driving force for pharmacodynamic (i.e., therapeutic or toxic)
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`events following drug dosing is the concentration of drug at the site of action. As
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`the site of action is often inaccessible as a source for drug measurement, the
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`concentration of drug in the blood (or plasma) is typically used as a surrogate. In
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`other words, the PD effects of a drug are driven by its concentration at the site of
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`action, which is correlated with its concentration in blood. The time course of the
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`PD effect is driven or controlled by the PK properties of the drug from a given
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`dosage form. Because of this, it is important to be able to describe the plasma
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`concentration-time profile of a drug after it is administered to a patient. A stylized
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`single-dose plasma concentration-time profile resulting from oral dosing is
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`depicted below.
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`10
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`IPR2018-00943
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`Case IPR2018-00943 (Patent No- 7,919,499)
`Decl. of Sara K. Quinney, Pharm.D., Ph.D. in Supp. of Pet’s Reply to PO’s Resp.
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`
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`(See,
`
`e.g., Ex. 1082,
`
`at 44 (displaying exemplary curve with identified
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`parameters).)
`
`22-
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`To develop a single-dose plasma concentration-time profile,
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`the
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`clinical pharmacologist or pharmacokineticist will, after administering a drug (e.g.,
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`intravenously or orally),
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`take reasonably frequent blood samples for a time
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`sufficient to characterize the entire profile. The blood samples, or a fluid derived
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`fi'om blood (e.g., plasma or serum), are treated and submitted to an analytical
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`procedure from which one can obtain a quantitative value for the concentration of
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`the drug (and/or metabolites of that drug) in the blood sample. The resulting
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`concentration-time profile can be plotted and analyzed, by using either
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`compartmental or noncompartmental methods. (Exs.1082, at 42-44, 315-318;
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`Case IPR2018-00943 (Patent No. 7,919,499)
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`10832, at 445-449.) Compartmental methods involve developing a mathematical
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`model, or equation, which closely approximates the plotted concentration-time
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`profile. (Ex. 1083, at 1-109.) Properties of interest (e.g., an integral or a maximum
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`concentration value) may then be determined from the mathematical model, which
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`is itself an approximation of the actual concentration-time data. In contrast,
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`noncompartmental methods involve approximating properties of interest directly
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`from
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`the observed concentration-time data
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`itself, without developing a
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`mathematical model. (Id. at 409-417.) Both methods are typically done using a
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`computer software, although noncompartmental and simple compartmental models
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`may be plotted on semi-log graph paper and analyzed by hand. Regardless of what
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`method is used, one obtains estimates of the values of the PK parameters for the
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`drug.
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`2 Exhibit 1083 is a commonly used textbook in pharmacokinetics that was initially
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`published in 1982. The copy I used in preparing this declaration (reprinted in 2007)
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`is part of our Disease and Therapeutic Response Modeling Program reference
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`library, and used by fellows in the program since its inception in 2009. This
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`textbook is widely distributed and relied upon by professors today and has been
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`since the first edition was published in 1975.
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`Case IPR2018-00943 (Patent No. 7,919,499)
`Decl. of Sara K. Quinney, Pharm.D., Ph.D. in Supp. of Pet’s Reply to PO’s Resp.
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`23. Following a single oral dose of a drug, the plasma concentration-time
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`profile can be used to estimate the Cmax (maximum plasma drug concentration
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`achieved), the Tmax (time after dosing corresponding to the Cmax), the t½
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`(half-life of the drug in the blood), and the AUC (extent of total exposure to the
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`drug, as measured by the total area under the plasma concentration vs time curve)
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`from time zero to time infinity. (Ex. 1082, at 24.) These parameters are functions
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`of the drug’s absorption, volume of distribution (V), and clearance (CL) from the
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`body. The AUC is a function of the amount of drug that gets absorbed into the
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`systemic circulation and the clearance of the drug from the blood. Given that
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`elimination is linear, the AUC can be used to estimate extent of absorption.
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`(Ex. 1082, at 45.) The figure above
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`is
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`that of a characteristic plasma
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`concentration-time curve for an immediate-release dosage form, i.e., one designed
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`not to delay release and subsequent absorption with first-order elimination.
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`24. Often, a POSA will want to depict graphically the PK profile of a drug
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`administered to multiple subjects. Placing the profile for each subject on a single
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`graph may, however, be cumbersome and confusing. It is therefore common for a
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`POSA to prepare an average plasma concentration-time profile by plotting the
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`average plasma concentrations of all subjects, with the standard deviation or
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`standard error, at each sample time. This is what is typically displayed in
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`publications or regulatory documents. Such a graph provides a useful indication of
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`Case IPR2018-00943 (Patent No. 7,919,499)
`Decl. of Sara K. Quinney, Pharm.D., Ph.D. in Supp. of Pet’s Reply to PO’s Resp.
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`the PK behavior of the dosage form across multiple subjects and of PK parameters
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`such as AUC. A graph of this type is similar to the one included above, but derives
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`its data from a population (as described), rather than an individual, and observed
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`data is plotted at discreet points for each sampling time.
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`25. The drug’s dosage form, its formulation, and route of administration
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`affect the shape of the plasma concentration-time curve. For a drug administered
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`by IV bolus, Cmax typically occurs immediately after dosing and is equivalent to
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`the Dose/Volume of Distribution. (Ex. 1082, at 20.) For other routes of
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`administration, such as intramuscular or subcutaneous injection, drug absorption
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`processes delay the Tmax and reduce Cmax. Tmax and Cmax are functions of the
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`time required for the drug to undergo dissolution and move from the site of
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`administration, e.g., subcutaneous or intramuscular site, into the blood stream.
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`Thus, in general, the Cmax for an immediate-release solid drug dosage form will
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`be higher and occur earlier (i.e., shorter Tmax) than if the drug is administered as a
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`“delayed-release” dosage form. And a long-acting depot formulation, for example
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`a subcutaneous injection such as that at issue here, may have an even longer Tmax.
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`26. An example of a PK profile for depot naltrexone is shown in Fig. 1 of
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`Comer (Ex. 1010) (reproduced below) and Fig. 7 of Nuwayser.
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`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
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`Case IPR2018-00943 (Patent No. 7,919,499)
`Decl. of Sara K. Quinney, Pharm.D., Ph.D. in Supp. of Pet’s Reply to PO’s Resp.
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`V. A PERSON OF ORDINARY SKILL IN THE ART
`I understand Dr. Berkland’s definition of a POSA is someone with a
`27.
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`Master’s degree and two or three years’ experience, or a Ph.D. or M.D. with at
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`least one or two years’ experience in the field of controlled-release formulations.
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`(Ex. 2055, at 28.) As Dr. Berkland notes, this field includes pharmaceutical
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`scientists, clinicians, and formulation scientists. I understand from the ’499 Patent
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`that AUC, or “area under the curve,” which is a pharmacokinetic property of a
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`certain dose of a pharmaceutical formulation in a patient population, is a key
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`feature
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`in
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`the claimed subject matter. Furthermore, I understand from
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`Dr. Berkland’s declaration that pharmacokinetic profiles, properties, methods of
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`their calculation, and the meaning of this data is a focus of the case at present.
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`Accordingly, I believe that a Pharm.D. or Ph.D. in pharmaceutical sciences or
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`clinical pharmacology also has relevant expertise in the field of the invention. My
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`Case IPR2018-00943 (Patent No. 7,919,499)
`Decl. of Sara K. Quinney, Pharm.D., Ph.D. in Supp. of Pet’s Reply to PO’s Resp.
`
`definition is largely consistent with those of both Dr. Berkland and Dr. Park, my
`
`opinions do not change if their definitions are adopted.
`
`VI. THE ’499 PATENT
`I understand that the ’499 Patent (Ex. 1001) was issued on April 5,
`28.
`
`2011, from an application filed on March 17, 2005. The ’499 Patent states on its
`
`face that it claims the benefit of a U.S. Provisional Application filed April 22, 2004
`
`(“the Provisional Application”) (Ex. 1032). Therefore, I have been advised by
`
`counsel to assume that the earliest possible effective filing date for the ’499 Patent
`
`is April 22, 2004. I have also been advised by counsel to assume that all of the
`
`references cited in the grounds in the Petition are prior art.
`
`29. 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 resulting serum AUC of naltrexone is about
`
`three times greater than what is achieved by administration of 50 mg/day oral
`
`administration of naltrexone. (Ex. 1001, 21:2-8, 22:15-22.) The amount of
`
`naltrexone in the formulation at issue here ranges from about 310 mg to about
`
`480 mg of naltrexone. I note, however, that at the time, a POSA would know a
`
`good deal about naltrexone. Sustained-release naltrexone formulations have been
`
`known since at least the early 1980s and these included delivery of naltrexone from
`
`16
`
`AMN1062
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`
`
`Case IPR2018-00943 (Patent No. 7,919,499)
`Decl. of Sara K. Quinney, Pharm.D., Ph.D. in Supp. of Pet’s Reply to PO’s Resp.
`
`PLGA polymers. (Exs. 1025, at 704; 1012, at 2.) Half-life data, minimum plasma
`
`concentration data, and other PK/PD information date back that far as well.
`
`(Exs. 2025 (t1/2 = 1.7 to 3.7 hours; 1 ng/ml minimum effective concentration); 1012
`
`(t1/2 = about 2 hours; 1 ng/ml minimum effective concentration).) Further,
`
`naltrexone was known for use in treating narcotic and alcohol dependence.
`
`(Exs. 1025; 1012; 1019; 1022; 1024.) So a POSA reviewing the prior art, including
`
`Comer and Nuwayser, would do so with that information in mind.
`
`A. The Claimed AUC Differential Is Not Unexpected
`30. 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 pharmacokinetic properties of the long-acting
`
`depot formulation tested resulted in an AUC that was about three times that
`
`observed from 50 mg/day oral dosing.
`
`31. Contrary to the assertions in the ’499 Patent, this does not strike me as
`
`unexpected or surprising. An oral formulation is subject to the well-known
`
`phenomenon of drug metabolism called the “first-pass effect,” whereby the
`
`concentration of a drug is greatly reduced following oral administration due to
`
`metabolism in the gut wall and the liver before the drug reaches the systemic
`
`circulation. In the particular case of naltrexone, a POSA knew at the time of the
`
`17
`
`AMN1062
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`
`
`Case IPR2018-00943 (Patent No. 7,919,499)
`Decl. of Sara K. Quinney, Pharm.D., Ph.D. in Supp. of Pet’s Reply to PO’s Resp.
`
`’499 Patent that oral naltrexone exhibited significant first pass effect, affecting its
`
`bioavailability to varying degrees. (Ex. 1084, at 33.)
`
`32. By contrast, a long-acting depot formulation is injected into the body,
`
`generally either intramuscularly or subcutaneously, and slowly diffuses into the
`
`blood stream without passing through the gastrointestinal tract or liver. Thus, a
`
`dose administered in a depot injection would by-pass this first-pass elimination and
`
`be expected to have nearly 100% bioavailability. Accordingly, it is well known and
`
`logical to a POSA that an intramuscularly or subcutaneously injected slow-release
`
`dosage form would provide a greater AUC than an oral one, given the more direct
`
`route to the blood stream of the injected form and potential for absorption-limited
`
`pharmacokinetics (i.e., the terminal half-life of the drug is controlled by the release
`
`profile not the elimination rate). (Ex. 1082 at 38-39.)
`
`33.
`
`In addition, after detailed review, I note that the specification does not
`
`provide any data to compare or actually allow one to calculate the allegedly
`
`“unexpected” AUC of the claimed formulation. Nor does it provide any data or
`
`value for the AUC of a 50 mg/day oral dosage regimen which would allow one to
`
`calculate the claimed differential (“differential”).
`
`18
`
`AMN1062
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`
`
`Case IPR2018-00943 (Patent No. 7,919,499)
`Decl. of Sara K. Quinney, Pharm.D., Ph.D. in Supp. of Pet’s Reply to PO’s Resp.
`
`
`The Claimed AUC Differential Is Not
`Correlated To Improved Therapeutic Effects
`Instead, the ’499 Patent appears to focus on the effects of the claimed
`
`B.
`
`34.
`
`formulation in treating alcohol dependence. Puzzlingly, the ’499 Patent does not
`
`appear to link any increased efficacy of its formulation to the supposedly
`
`“unexpected” AUC. The ’499 Patent does not suggest that it provided a cure to
`
`alcoholism or drug abuse. Indeed, using its own data, while the claimed depot
`
`injection tested against a placebo did reduce the rate at which some patient groups
`
`relapsed—11 out of 28 patients still relapsed during the 12-week test period.
`
`(Ex. 1001, 18:48-52.) Patients treated with the claimed injection also continued
`
`drinking heavily at a steady rate throughout the course of treatment, with a median
`
`of six days to first major drinking event following 380 mg injection (Ex 1001
`
`Figs. 1A-C.) Further, although the 3x increased AUC was presumably present
`
`regardless of gender, the claimed treatment method produced “no significant
`
`differences…between women treated with naltrexone 380 mg (n=67) and those
`
`receiving placebo.” (Ex. 1001, 15:22-25.)
`
`35.
`
`In addition, although the ’499 Patent is based on the premise that oral
`
`naltrexone provides a lower AUC than the claimed injectable formulation, the
`
`patent never shows that the claimed formulation works any better than oral
`
`naltrexone. Example 3 compares the “efficacy” of oral verse injectable naltrexone,
`
`19
`
`AMN1062
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`
`
`Case IPR2018-00943 (Patent No. 7,919,499)
`Decl. of Sara K. Quinney, Pharm.D., Ph.D. in Supp. of Pet’s Reply to PO’s Resp.
`
`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.” (Ex. 1001, 18:8-12.) Instead, as noted above, the
`
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