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`IPR2017-01648
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`Aurobindo Pharrna USA Inc.
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`Petitioners,
`
`V.
`
`Andrx Labs, LLC
`Patent Owner
`
`Case IPR2017—01648
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`US. Patent No. 6,866,866
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`DECLARATION OF JENNIFER DRESSMAN, PH.D.
`
`Andrx 2010
`
`Aurobindo v. Andrx
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`|PR2017-01648
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`
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`Declaration of Jennifer Dressman, Ph.D.
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`IPR2017-01648
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`TABLE OF CONTENTS
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`Page
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`QUALIFICATIONS ........................................................................................ 1
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`II.
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`SUMIVIARY OF OPINIONS ........................................................................... 5
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`III.
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`INFORMATION CONSIDERED ................................................................... 5
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`IV.
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`A PERSON OF ORDINARY SKILL IN THE ART ...................................... 5
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`LEGAL PRINCIPLES ..................................................................................... 6
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`VI.
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`CLAIM CONSTRUCTION ............................................................................ 8
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`VII.
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`BACKGROUND ............................................................................................. 8
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`A.
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`State of the Art in November 2000 ....................................................... 8
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`B.
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`Tmax and Other Pharmacokinetic Parameters of a Drug’s Dosage Form
`............................................................................................................. 10
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`C.
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`The ”866 Patent ................................................................................... 12
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`VIII.
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`PRIOR ART RELIED ON BY PETITIONER .............................................. 13
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`A.
`
`B.
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`Cheng ................................................................................................... 1 3
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`Timmins ............................................................................................... 1 5
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`IX.
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`DR. AKHLAGHI CANNOT OPINE RELIABLY ON THE ”866 PATENT
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`DUE TO HER LACK OF EXPERTISE IN THE RELEVANT FIELD AND
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`LACK OF UNDERSTANDING OF THE DISCLOSURE OF TIlVIh/IINS. 18
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`CLAIMS 1-25 ARE NOT OBVIOUS IN VIEW OF CHENG AND
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`TIlVIMINS ...................................................................................................... 23
`
`A.
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`Independent Claim 1 is Not Obvious Over Cheng and Timmins ....... 26
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`1.
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`A POSA Would Understand Timmins to Teach Increased
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`Gastric Residence Time, Not a Particular Mean Tmax Value or
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`Range Thereof........................................................................... 34
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`
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`Declaration of Jennifer Dressman, Ph.D.
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`IPR201 7-01 648
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`2.
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`A POSA Would Not Read Timmins to Teach a me Value in
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`the Claimed Range .................................................................... 34
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`3.
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`The Remaining Rationales Presented in the Petition and Dr.
`Akhlaghi’s Declaration Would Not Provide a Dosage Form
`Having a Tmax in the Claimed Range ........................................ 42
`
`B.
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`Dependent Claims 2-25 Are Not Obvious Over Cheng and Timmins
`............................................................................................................. 45
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`1.
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`2.
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`3.
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`4.
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`5.
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`6.
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`7.
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`8.
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`9.
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`Claims 2-3 and 23-24 Are Not Obvious Over Cheng and
`Timmins .................................................................................... 45
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`Claims 4-5 Are Not Obvious Over Cheng and Timmins ......... 46
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`Claims 6-24 Are Not Inherently Obvious Over Cheng and
`Timmins .................................................................................... 49
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`Claims 6-7 and 23-24 Are Not Obvious Over Cheng and
`Timmins .................................................................................... 5 l
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`Claims 8-10 Are Not Obvious Over Cheng and Timmins ....... 52
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`Claims 1 1-12 Are Not Obvious Over Cheng and Timmins ..... 53
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`Claims l3-l4 Are Not Obvious Over Cheng and Timmins ..... 55
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`Claims 15-17 Are Not Obvious Over Cheng and Timmins ..... 56
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`Claims 18-20 Are Not Obvious Over Cheng and Timmins ..... 58
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`10.
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`Claim 21 Is Not Obvious Over Cheng and Timmins ............... 59
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`ll.
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`Claim 22 Is Not Obvious Over Cheng and Timmins ............... 6O
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`XI.
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`OBJECTIVE INDICIA SUPPORT THE NON-OBVIOUSNESS OF THE
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`CHALLENGED CLAIMS ............................................................................ 61
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`XII.
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`CONIPENSATION ........................................................................................ 65
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`XIII.
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`AVAILABILITY FOR CROSS EXAIVIINATION ....................................... 66
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`XIV.
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`ILIRAT ........................................................................................................... 67
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`_ii_
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`
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`Declaration of Jennifer Dressman, PhD.
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`lPR2017-01648
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`1, Jennifer Dressman, Ph.D., declare as follows:
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`1.
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`My name is Jennifer Dressman.
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`I.
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`QUALIFICATIONS
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`2.
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`The opinions below are based on my background and experience,
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`including my over 40 years of professional and educational experience in the fields
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`of pharmaceutics and biopharrnaceutics, including formulation of drugs for oral
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`administration, in vitro pharmaceutical testing, and calculation and analysis of
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`pharmacokinetic (“PK”) parameters.
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`3.
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`My qualifications as an expert in these areas are established by my
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`curriculum vitae, which is attached hereto as Appendix A, and the publications
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`cited therein.
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`I have set forth below representative relevant experience.
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`4.
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`1 received a Bachelor of Pharmacy from the Victorian College of
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`Pharmacy in Melbourne, Australia in 1976.
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`l eamed a Master of Science in
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`Pharmaceutical Chemistry from the University of Kansas in 1979 and a Ph.D. in
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`Pharmaceutical Chemistry also from the University of Kansas in 1981 under the
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`supervision of Prof. Takeru Higuchi, who was known as the “father of physical
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`pharmacy.” See Takeru Higuchi biography, Kansas Historical Society,
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`https://www.kshs.org/kansapedia/takeru—higuchi/ 16878 (last visited May 30,
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`2018).
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`Declaration of Jennifer Dressman, PhD.
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`lPR201 7-01 648
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`5.
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`While I was earning my graduate degrees, I was a research assistant at
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`the University of Kansas. After I finished my Ph.D., I worked for one year as a
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`Research Pharmacist at the Burroughs Wellcome Company in Greenville, North
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`Carolina.
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`I then worked for a year as a Senior Research Chemist at INTERX
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`Research Corporation in Lawrence, Kansas, where I conducted research, inter alia,
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`on predicting dosage form performance in the gastrointestinal tract.
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`6.
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`From 1983 to 1994, I was an Assistant Professor, and then later an
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`Associate Professor of Pharmaceutics with tenure at the University of l\/lichigan.
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`While there, I taught many courses, including, among others, undergraduate
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`courses in pharmaceutics and a graduate course on principles of oral drug
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`absorption.
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`1 also conducted research, most of which focused on understanding
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`gastrointestinal physiology as it relates to oral drug absorption, and on designing
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`formulations to improve the performance of orally administered drugs and
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`dissolution tests to predict in viva drug performance.
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`7.
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`In 1994, I was appointed as a Professor of Pharmaceutical Technology
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`at JW Goethe University in Frankfurt, Germany. Since that time, I have taught
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`lectures, seminars, and practical courses in the fields of pharmaceutics,
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`biopharmaceutics, pharmacokinetics, and pharmaceutical technology. Notable
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`examples include “Biopharmaceutics and dosage form driven pharmacokinetics,”
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`IPR201 7-01 648
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`“Design, manufacture and quality control of pharmaceutical dosage forms,”
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`“Utilization of drugs in pharmacy practice,” and “Good manufacturing practice.”
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`8.
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`At JW Goethe University, the primary focus of my research has
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`continued to be oral drug absorption and predicting in viva drug performance using
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`biorelevant dissolution testing and physiologically based pharmacokinetic
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`(“PBPK”) modeling. Biorelevant media are those that simulate conditions in the
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`gastrointestinal tract before or after a meal has been ingested. They are
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`specifically designed to be used in dissolution testing to predict the in viva
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`performance of drugs and drug formulations after oral administration.
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`9.
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`In 2002, I was appointed the Director of the Institute of
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`Pharmaceutical Technology at the JW Goethe University. In that capacity, I am
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`responsible for over 30 staff dedicated to teaching and research activities in
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`pharmaceutical technology. I also manage the budget and organization of the
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`institute.
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`10.
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`I am a named author on over 230 peer-reviewed publications and over
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`25 review articles in the fields of pharmaceutics and biopharmaceutics. Of these
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`articles, approximately 60 have addressed the relationship between formulation
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`and pharmacokinetics.
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`I am also an author of 5 books and 10 book chapters in the
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`area of pharmaceutics, including two books devoted to oral drug absorption and
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`one book specifically on pharmaceutical dissolution testing.
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`I am a named
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`Declaration of Jennifer Dressman, PhD.
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`IPR2017-01648
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`inventor on over 20 patents, all of which relate to oral dosage forms. During my
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`career, I have also supervised over 60 doctoral theses and have delivered well over
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`100 invited presentations.
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`11.
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`I am also a member, and have served on various committees, of
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`several professional organizations in the pharmaceutical field, including the
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`American Association of Pharmaceutical Scientists, the International Association
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`for Pharmaceutical Technology, and the Federation Internationale Pharmaceutique.
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`I also have served on the editorial boards of numerous preeminent journals in the
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`pharmaceutical field.
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`I am currently an associate editor of the European Journal of
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`Pharmaceutics and Biopharmaceutics and the Journal of Pharmacy and
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`Pharmacology.
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`12.
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`Over the course of my career, I have also received various awards and
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`other honors for my work in the pharmaceutical chemistry and technology fields.
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`For example, in 1991 , I was elected to be a Fellow of the American Association of
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`Pharmaceutical Scientists; in 2010, I was elected to the College of Fellows of the
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`Controlled Release Society; and in 2015, I was elected to be a Fellow of the
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`Federation Internationale Pharmaceutique. In 2010, I was awarded the Silver
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`Medal of Honor from the International Association for Pharmaceutical
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`Technology, and in 2008, I was awarded the Distinguished Scientist Award from
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`the Federation Internationale Pharmaceutique. In May 2017, I received the Nagai
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`Declaration of Jennifer Dressman, PhD.
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`IPR2017-01648
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`International Woman Researcher of the Year Award from the Association of
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`Pharmaceutical Science and Technology of Japan. In addition, in 2017, I received
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`the award for the best academic paper in the field of pharmacokinetic modeling
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`and simulation from SIMCYP.
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`II.
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`SUD/[MARY OF OPINIONS
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`13.
`
`It is my opinion that claims 1-25 of U. S. Patent No. 6,866,866
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`(hereinafter “the ”866 patent”) are non-obvious under 35 U.S.C. § 103 over
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`International Patent Application Publication No. WO 99/47125 (hereinafter
`
`“Cheng,” EX. 1002) in View of Intemational Patent Application Publication No.
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`WO 99/47128 (hereinafter “Timmins,” EX. 1003).
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`14.
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`It is also my opinion that objective indicia further demonstrate the
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`non-obviousness of claims 1-25 of the ”866 patent, including addressing a long-felt
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`but unmet need, copying by others, and unexpected results.
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`III.
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`INFORMATION CONSIDERED
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`15. A list of the materials I have considered in rendering my opinions is
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`attached hereto as Appendix B.
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`IV. A PERSON OF ORDINARY SKILL IN THE ART
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`16.
`
`I understand that Patent Owner has proposed a definition of a person
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`of ordinary skill in the art (“POSA”), which defines a POSA as a person who, at
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`the time of the invention, held a degree in pharmacy, chemistry, chemical
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`Declaration of Jennifer Dressman, PhD.
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`lPR2017-01648
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`engineering, or a related field with at least three to five years of pharmacokinetics,
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`biopharmaceutics, medicinal chemistry, pre-formulation, or formulation
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`experience, research, or training. In addition, I understand that Patent Owner”s
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`proposed definition indicates that such a person would be familiar, at the time of
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`the invention, with the methods used in formulating oral dosage forms, modified
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`release dosage forms, and osmotic delivery, and have an understanding of the
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`fundamental principles as to how osmotic dosage forms behave and function.
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`Patent Owner Preliminary Response, 15-16.
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`I agree with this definition.
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`17.
`
`I understand that Petitioner has proposed a slightly different definition
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`of POSA. Petition at 11. Under either the Patent Owner’s definition or the
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`Petitioner’s definition, I am at least a person of ordinary skill in the art, and have
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`been since well before the November 3, 2000 filing date of the ”866 patent. My
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`opinions expressed herein are the same regardless of whether the Patent Owner”s
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`definition or the Petitioner’s definition of a POSA applies.
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`V.
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`LEGAL PRINCIPLES
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`18.
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`l have been informed and understand that, under 35 U.S.C. § 103, a
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`patent claim is considered obvious if the subject matter as a whole would have
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`been obvious to one of ordinary skill in the art at the time the invention was made.
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`The obviousness analysis involves several factual inquires, including: (i) the scope
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`and content of the prior art', (ii) the differences between the prior art and the claim,
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`Declaration of Jennifer Dressman, PhD.
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`IPR2017-Ol 648
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`(iii) the level of ordinary skill in the art at the time of the invention; and (iv) the
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`existence of objective indicia of non-obviousness (“secondary considerations”).
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`19.
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`In connection with obviousness, I have been informed and understand
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`that there must have been some reason or motivation that would have led a person
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`of ordinary skill in the art to combine or modify the relevant teachings in the prior
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`art to obtain the claimed invention, and one of ordinary skill in the art must have
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`had a reasonable expectation of success in doing so.
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`I also understand that if a
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`proposed modification would render the prior art being modified unsatisfactory for
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`its intended purpose, then there can be no suggestion or motivation to make the
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`proposed modification.
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`20.
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`Furthermore, I understand that the rationale of “obvious to try” to
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`support obviousness requires a finite number of identified, predictable solutions
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`and a claimed invention is not obvious when a skilled artisan would have to vary
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`all parameters or try each of numerous possible choices until one possibly arrived
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`at a successful result, where the prior art gave no indication of which parameters
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`were critical or direction as to which of many possible choices is likely to be
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`successful. I also understand that it is incorrect to evaluate obviousness from a
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`hindsight perspective using the teachings of the patent at issue as a guide.
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`21.
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`l have also been informed and understand that objective indicia of
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`non-obviousness (also known as “secondary considerations”) can provide evidence
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`Declaration of Jennifer Dressman, PhD.
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`lPR2017-Ol 648
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`that a challenged claim is not obvious. Objective indicia may include satisfying a
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`long-felt but unmet need, unexpected results, commercial success, and copying by
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`others.
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`I understand that for objective indicia to be given weight, there must be a
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`nexus between the evidence and the claimed invention.
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`VI. CLAIM CONSTRUCTION
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`22.
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`I understand that the parties in this proceeding have agreed that the
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`term “Tmm” recited in the claims should be construed as “the time period which
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`elapses after administration of the dosage form at which the plasma concentration
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`of the drug attains the highest plasma concentration of drug attained within the
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`dosing interval (119., about 24 hours)” Decision on Institution at 7', the ’866 patent
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`at col. 7, ll. 49—53; Petition at 24', and Patent Owner Preliminary Response at 18.
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`I
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`agree with this construction. Patent Owner also proposed constructions for the
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`claimed terms “membrane,” “dinnertime,” and “at dinner.
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`Patent Owner
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`)3
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`Preliminary Response at 16-18. The ’866 patent also defines terms such as
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`“AUC,” “Cmax,” and “mean.” ”866 patent, col. 7, l. 40 — col. 8, l. 14.
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`I agree with
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`these constructions and definitions as well.
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`VII. BACKGROUND
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`A.
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`State of the Art in November 2000
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`23.
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`I understand that Petitioner has challenged the validity of claims 1-25
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`of the ”866 patent, which issued from US. Patent Application No. 09/705,630
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`Declaration of Jennifer Dressman, PhD.
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`lPR2017-01648
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`(hereinafter “the ’630 application”), which application was filed November 3,
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`2000. At the time of filing of the ”630 application in November 2000, metformin
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`hydrochloride, a short-acting drug used to treat non-insulin—dependent diabetes
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`mellitus (NIDDM), was marketed as Glucophage® by Bristol-Myers Squibb in the
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`United States. See the ”866 patent, col. 1 ll. 56-57, 61-63. At the time, there was
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`no fixed dosage regimen for Glucophage® to manage hyperglycemia in patients
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`with diabetes mellitus — instead, dosages were individualized to each patient using
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`500 mg, 850 mg, or 1,000 mg immediate release tablets based on both
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`effectiveness and tolerance, while not exceeding the maximum recommended dose
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`of 2,550 mg per day. Id. col. 1 l. 63 — col. 2 l. 2.
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`24.
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`However, because metformin is a short-acting drug, patients had to
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`take the medication two or three times each day. Id. at col. 2 ll. 4-6. Such frequent
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`dosing typically led to reduced patient compliance and increased adverse events,
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`including the potentially dangerous side-effects of anorexia, nausea, and vomiting.
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`See id. at col. 1 ll. 14-18; col. 2 ll. 4-8; col. 20 ll. 16-18.
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`25.
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`Thus, at the time of the filing of the ”630 application, there was a need
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`in the field for a safe and effective dosage form of metformin that would enable
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`patients with type 2 diabetes to take their medication on a once-a-day basis,
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`thereby improving patient compliance and reducing adverse events.
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`Declaration of Jennifer Dressman, PhD.
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`lPR2017-Ol 648
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`B.
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`Tm and Other Pharmacokinetic Parameters of a Drug’s Dosage
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`Form
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`26.
`
`As explained above, Tmax refers to “the time period which elapses after
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`administration of the dosage form at which the plasma concentration of the drug
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`attains the highest plasma concentration of drug attained within the dosing interval
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`(i.e., about 24 hours)” Decision on Institution at 7', the ”866 patent at col. 7, ll.
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`49—53; Petition at 24', and Patent Owner Preliminary Response at 18. A Tmax for a
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`single patient is a discrete variable — its value can only be one of the time points at
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`which the patient”s blood was sampled. Tmax data for a population of patients is
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`generally expressed as a median Tmax, with a minimum Tmax and maximum Tmax
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`reported (119. , “median me (minimum Tnm, maximum Tm“)? see, e.g, Timmins at
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`Example 5), but can also be expressed as a mean Tnm, as described in the ”866
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`patent, e.g., claim 1. For the former, the median Tmax represents a Tmax value in an
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`ordered set of values where there is an equal number of values below and above
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`the PM value, or alternatively the arithmetic mean of the two middle values if
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`there is no one middle number. Paper 12, Decision on Institution at 12, H6.
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`27.
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`The minimum Tmax is the single lowest Tmax value obtained from the
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`population of patients, while the maximum Tnm is the single highest me value
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`obtained from the population of patients. A mean Tmm is the arithmetic average of
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`all the individual Tmax values reported for all the patients in the study. As
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`Declaration of Jennifer Dressman, PhD.
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`lPR2017-01648
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`acknowledged by Dr. Akhlaghi, a mean Tmax is a single value, not a range of
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`values. Akhlaghi Deposition at 72:21-74: 1. As also acknowledged by Dr.
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`Akhlaghi, calculation of a single mean Tmaxvalue from a population of patients
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`requires access to the underlying raw data (11:2,, the individual Tmax recorded for
`
`each individual patient). Akhlaghi Deposition at 70:8-1 l', 71 : l l -21.
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`28.
`
`The Tmm of a drug’s dosage form does not provide any conclusive
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`information, either expressly or inherently, about the in vitro dissolution profiles,
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`or about the dosage form’s further pharrnacokinetic parameters, including width at
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`50% of the height of a mean plasma concertation/time curve, the ratio of mean Cmm
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`value to mean plasma level at about 24 hours after the administration, the mean
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`Cmax values, the ratio of the dosage form’s mean AUC0—24hr5 to an immediate release
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`dosage form’s mean AUC0-24hIs, the dosage form’s mean AUCO-24hrs, the dosage
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`form’s mean AUCO-24hrs and mean me values, the dosage form”s mean AUC0-24hIs
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`and mean Cmax values at the lSt day of administration and 14th day of
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`administration, the mean l1/2 of the claimed dosage form, or in general the precise
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`shape of the plasma concentration/time curve. These other parameters would be
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`important contributory information for a skilled person developing an oral dosage
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`form of metformin in November 2000. For this reason, it is my opinion that such a
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`person would not have focused on mec in isolation. Such an approach could only
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`lPR2017-01648
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`have been taken with the benefit of hindsight, whichl understand is impermissible
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`in the obviousness analysis.
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`C.
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`The ’866 Patent
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`29.
`
`The ”866 patent, entitled “Controlled Release Metformin
`
`Compositions,” issued from the ”630 application. The named inventors are Chih-
`
`Ming Chen, Xiu-Xiu Cheng, Steve Jan, and Joseph Chou. The inventors of the
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`”866 patent developed Fortamet®, a novel extended release dosage form of
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`metformin. Results from clinical studies demonstrated that Fortamet® was
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`comparable to immediate-release metformin in terms of efficacy and safety, while
`
`providing for a more convenient once-daily dosage regimen. See Apr. 27, 2004
`
`Letter from the FDA Approving NDA 21 -574 (hereinafter “the Fortamet® FDA
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`Approval Letter,” EX. 2001); Fortamet® FDA Label (Rev. 02/10) at 8-12, 28 (EX.
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`2002). The FDA approved Fortamet® for use in managing type 2 diabetes on
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`April 27, 2004. See Fortamet® FDA Approval Letter (EX. 2001 ). See, also, Patent
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`Owner Preliminary Response at 6-7.
`
`30.
`
`Claim 1, the only independent claim of the ”866 patent, recites:
`
`l. A controlled release oral dosage form for the reduction of
`serum glucose levels in human patients with NIDDM,
`comprising an effective dose of metformin or a pharmaceutically
`acceptable salt thereof and a controlled-release carrier to control
`the release of said metformin or pharmaceutically acceptable salt
`thereof from said dosage form, said dosage form being suitable
`for providing once-a-day oral administration of the metformin or
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`Declaration of Jennifer Dressman, PhD.
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`IPR2017-01648
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`pharmaceutically acceptable salt thereof, wherein following oral
`administration of a single dose, the dosage form provides a mean
`time to maximum plasma concentration (Tmmc) of the metformin
`from 5.5 to 7.5 hours after administration following dinner.
`
`3 1.
`
`Claims 2-25 ultimately depend from claim 1 and recite additional
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`limitations, including narrower ranges of mean Tmm, the composition of the dosage
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`form, in vitro dissolution profiles of the dosage form, and further pharmacokinetic
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`parameters related to the dosage form, such as the width at 50% of the height of a
`
`mean plasma concentration/time curve, the ratios of the mean maximum plasma
`
`concentration (CHM) over the mean plasma concentration at 24 hours post-
`
`administration, the mean Cmax values, the ratios of the mean AUCO-24hrs to an
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`immediate release dosage form’s AUC0-24hIs, the mean AUC0.24hI values, the mean
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`GM and the mean AUC0-24hI values, the mean Cmm and mean AUC0-24hI values at
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`the lSt and 14th days of administration, and the mean half-life (ti/2) values.
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`VIII. PRIOR ART RELIED ON BY PETITIONER
`
`32.
`
`I understand that Petitioner has alleged that claims 1-25 of the ”866
`
`Patent are obvious over Cheng in view of Timmins. Petition at 40-53.
`
`A.
`
`Cheng
`
`33.
`
`Cheng is titled “Controlled Release Oral Tablet Having a Unitary
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`Core.” Cheng at title. Cheng discloses a “controlled release antihyperglycemic
`
`tablet
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`comprising a core containing the antihyperglycemic drug, a
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`lPR2017-Ol 648
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`semipermeable membrane coating the core and at least one passageway in the
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`membrane.” Cheng at Abstract.
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`34.
`
`Cheng teaches that a key feature of its tablet is that it “does not
`
`contain an expanding polymer.” Cheng at Abstract (emphasis added). In fact, as
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`acknowledged by Dr. Akhlaghi, the goal of Cheng is “to provide a controlled or
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`sustained release formulation for an antihyperglycemic drug that does not employ
`
`an expanding polymer.” Cheng at 3, ll. 3-6 (emphasis added); see Akhlaghi
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`Deposition at 83: 15-18.
`
`35.
`
`Cheng also teaches that another key feature of its tablet is that it
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`“provide[s] therapeutic levels of the drug throughout the day with peak plasma
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`levels [(z'.e. , Tmaxfl being obtained between 8-12 hours after administration”
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`following dinner. Cheng at 4, ll. 3-9. Again, as acknowledged by Dr. Akhlaghi,
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`Cheng emphasizes that its disclosure is directed to “a controlled or sustained
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`release formulation for an antihyperglycemic drug that obtains peak plasma levels
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`approximately 8-12 hours after administration,” and that “a controlled or sustained
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`release formulation for an antihyperglycemic drug that can provide continuous and
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`non-pulsating therapeutic levels of an antihyperglycemic drug to an animal or
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`human in need of such treatment over a twelve hour to twenty-four hour perio .”
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`Cheng at 3, ll. 7-17 (emphasis added); Akhlaghi Deposition at 85:8-19.
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`Declaration of Jennifer Dressman, PhD.
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`IPR2017-Ol 648
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`36.
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`Thus, Cheng explicitly describes that its purpose is to provide a
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`dosage form lacking an expanding polymer that provides a mean me value
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`between 8-12 hours, which is longer than -- and outside the range of -- the mean
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`Tmax values recited in claim 1 of the ”866 patent (11:2,, 5.5 to 7.5 hours). Cheng’s
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`Example 3 discloses a dosage form that provides a mean Tnm of 10 hours. Cheng
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`at Example 3, Figure 8.
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`B.
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`Timmins
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`37.
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`Timmins is titled “Biphasic Controlled Release Delivery System for
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`High Solubility Pharmaceuticals and Method.” Timmins discloses a “biphasic
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`controlled release delivery system for pharmaceuticals which have high water
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`solubility, such as the antidiabetic metformin [hydrochloride] salt,
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`which
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`provides a dosage form that has prolonged gastric residence.” Timmins at
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`Abstract. Timmins teaches that the goal of its dosage form is to achieve
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`“prolonged gastric residence,” to maximize contact between released drug and the
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`site of the absorption for metformin, which Timmins indicates is primarily in the
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`upper small gastrointestinal (“GI”) tract. Timmins at 14, ll. 6-12.
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`38.
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`Timmins indicates that the prolonged gastric residence time of the
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`dosage forms disclosed therein is due to the “swelling of the system.” Timmins at
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`ll, ll. 8-12. Timmins further teaches that its tablet “swells up to approximately
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`three times its dry size following hydration” of the polymers used in the fabrication
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`Declaration of Jennifer Dressman, PhD.
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`IPR201 7-01 648
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`of the tablet. Timmins at 30, ll. 13-16. Notably, the formulation of Example 3 of
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`Timmins (which is used in Example 5) includes a swelling polymer (sodium
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`carboxymethylcellulose). Timmins at Examples 3, 5.
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`39.
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`Timmins also teaches that the formulations disclosed therein “will
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`provide for an extended release formulation of drug with minimal inierpaiiem‘
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`variability in pharmacokinetic parameters.” Timmins at 14, ll. 20-23 (emphasis
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`added). Consistent with this teaching, Example 5 of Timmins states that when its
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`dosage form was administered in vivo to patients, “[i]nterpatient variability in
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`pharmacokinetic parameters was acceptable as illustrated by the mean parameters
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`(%CV)” given for Cmm and AUC. Timmins at Example 5', 34, ll. 24-29.
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`40.
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`Timmins in Example 5 discloses administration to a group of patients1
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`either a dosage form of metformin hydrochloride prepared according to Example 3
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`(i.e., a dosage form that includes an expanding polymer) or Glucophage®. While
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`the focus of Timmins is on improving gastric residence time, rather than Tmax,
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`Timmins does report that the median Tmax value obtained for the patient group
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`1 ln Example 5, Timmins teaches that 24 patients were dosed with Example 3 or
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`Glucophage® tablets following dinner. However, it is not clear from Timmins
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`whether all 24 patients or a portion of the 24 patients (9.g. , 12 patients) received
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`the dosage form of Example 3.
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`Declaration of Jennifer Dressman, PhD.
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`lPR2017-01648
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`dosed with Example was 5 hours, with the lowest individual Tmax value observed at
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`4 hours and the highest individual Tmm value observed at 8 hours. Nowhere does
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`Timmins mention a mean Tmax value for Example 5, or even a range in which that
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`mean Tmax must fall. Timmins does not teach a mean Tmax value between 5.5 to 7.5
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`hours, as I understand is required by independent claim 1 of the ”866 patent.
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`41.
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`Furthermore, as acknowledged by Dr. Akhlaghi, Timmins does not
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`provide the individual Tmax values for the other patients receiving the Example 3
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`dosage form, and thus a mean Tmax value cannot be calculated from the data
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`presented in Example 5. Akhlaghi Deposition at 80:19-81 :1. While the Federal
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`Circuit suggested that the single mean Tmax value of Timmins would fall between
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`approximately 4.67 hours and 6.33 hours, neither the Petitioner, Dr. Akhlaghi, nor
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`the Federal Circuit provided any explanation as to where in that range the single
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`mean Tmm value of Timmins would be expected to fall. Sciele Pharma, Inc. v.
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`Lupin Ltd, 684 F.3d 1253, 1261 (Fed. Cir. 2012) (Ex. 1006) (hereinafter “the
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`Federal Circuit opinion”). In fact, Dr. Akhlaghi stated that with respect to trying to
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`determine where the single mean Tnm value of Timmins falls, “everybody is
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`guessing here.” Akhlaghi Deposition at 80:19-81 :1.
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`Declaration of Jennifer Dressman, PhD.
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`IPR2017-Ol 648
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`IX. DR. AKHLAGHI CANNOT OPINE RELIABLY ON THE ’866
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`PATENT DUE TO HER LACK OF EXPERTISE IN THE RELEVANT
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`FIELD AND LACK OF UNDERSTANDING OF THE DISCLOSURE
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`OF TIMlVIINS
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`42. While Petitioner’s declarant Dr. Akhlaghi has expertise in the area of
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`clinical pharmacology, after review of her declaration, accompanying CV and
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`deposition testimony, it is my opinion that she does not have the appropriate
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`experience and understanding of the prior art to offer an opinion on the alleged
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`obviousness of design and development of a controlled release dosage form, which
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`is the field of the ”866 patent.
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`43.
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`First, I have read Dr. Akhlaghi’s deposition transcript, and I believe
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`that she conceded that she is not an expert in formulation development of
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`controlled release dosage forms. Akhlaghi Deposition at 24:5-16', 33 :16-34:4.
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`Additionally, she admitted that she has never developed the same kinds of dosage
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`forms that are the subject of Timmins (113., expanding polymer-based dosage
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`forms) or Cheng (i.e., osmotic pump dosage forms). Akhlaghi Deposition at
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`33 : 16-22 (“‘Q: Your CV doesn't indicate that you've ever designed or developed an
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`osmotic pump dosage form. Correct? A: I did not develop an osmotic pump
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`dosage form. Q: And your CV doesn't indicate that you've ever designed an
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`expanding polymer dosage form? A: l have not done it”). This is consistent with
`
`my review of Dr. Akhlaghi’s CV (Exhibit 1020), which does not suggest that she
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`Declaration of Jennifer Dressman, PhD.
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`IPR2017-01648
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`has expertise in developing such solid oral dosage forms. Without this
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`background, I do not believe Dr. Akhlaghi is able to reliably opine on what a
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`person skilled in the art in November 2000 would understand from the teachings of
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`Timmins and Cheng.
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`44.
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`Furthermore, during her deposition, Dr. Akhlaghi was unable to
`
`convey a clear understanding of the subject matter of the claims of the ”866 patent.
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`For example, although Dr. Akhlaghi initially stated that the subject matter of the
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`”866 patent relates only to pharmacokinetic parameters, and not formulation
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`development, she subsequently admitted that her conclusion that there was a
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`motivation for a person skilled in the art to combine Timmins and Cheng to arrive
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`at the ”866 patent”s claims was based on a motivation to develop a controlled
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`release dosage form of metformin. Akhlaghi Deposition at 24:5-16, 32:20-33:15,
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`cf 86:2-22. In my opinion, her statements are contradictory and cannot be
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`reconciled with the specification and claims of the ”866 patent.
`
`45.
`
`It is