IPR2017-01648
`Declaration of Jennifer Dressman, Ph.D.
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`Aurobindo Pharma USAInc.
`
`Petitioners,
`
`Vv.
`
`Andrx Labs, LLC
`Patent Owner
`
`Case [PR2017-01648
`U.S. Patent No. 6,866,866
`
`DECLARATION OF JENNIFER DRESSMAN,PH.D.
`
`Andrx 2010
`Aurobindo vy. Andrx
`IPR201 7-01648
`
`
`Declaration of Jennifer Dressman, Ph.D.
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`Aurobindo Pharma USAInc.
`
`Petitioners,
`
`Vv.
`
`Andrx Labs, LLC
`Patent Owner
`
`Case [PR2017-01648
`U.S. Patent No. 6,866,866
`
`DECLARATION OF JENNIFER DRESSMAN,PH.D.
`
`Andrx 2010
`Aurobindo vy. Andrx
`IPR201 7-01648
`
`
`
`IPR2017-01648
`Declaration of Jennifer Dressman, Ph.D.
`
`TABLE OF CONTENTS
`
`Page
`
`QUALIFICATIONS 2.00... cence cence cece ccc e tee ce cess tees ecaaecceeecueeeesseetseeseeees 1
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`I.
`
`SUMMARYOF OPINIONS........00.cccecccecc cece e ete ects eeeeeeeetneetnsescteeeteeeseees 5
`
`HI.
`
`INFORMATION CONSIDERED 1.0.00... eccccccce cece cece eee cence cnteescteeeteeeeneees 5
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`IV.
`
`A PERSON OF ORDINARY SKILL IN THE ART...ee 5
`
`LEGAL PRINCIPLES |... 0 occcccececc cence cece eects ececee eee eeseeeeesaeesnneeesiteseueeeneess 6
`
`VI.
`
`CLAIM CONSTRUCTION ..0...cccccccccccececcecee eee eeee ceases ceeecseeeeseeetseesseeeens 8
`
`VIL.
`
`BACKGROUND 2.0... cocci ccc cece ete e cess cette cies ceeeeeeeeeseseeesaeesniseseiteseueeeseess 8
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`A.
`
`B.
`
`State of the Art in November 2000 .0000......00ccceeecceee cece ee eceeeeeeteeeeeees 8
`
`Tmax and Other Pharmacokinetic Parameters of a Drug’s Dosage Form
`bee cceeeeeeeeeeeeceeeeecaeecaaecceeeecueeeeseeeseeesceeeeceseseeaeeceeeeceseessieesiceeseeeseeeseieeeas 10
`
`C.
`
`The °866 Patent 2.0.0.0 cece cece erect eee eeeeeesneeeceeecneeessieesnneeeeeeees 12
`
`VII.
`
`PRIOR ART RELIED ON BY PETITIONER... cceccceeecceeeecteeteteeteees 13
`
`A, CHD. cccccececcceceecteeeeccseeescsseeecssaeeeesneeeecesseeessieeesseeessutesstaaeeeas 13
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`B. Tams. eee eee cece cence cceeeecneeeeceeeeeeeeseeeeneaeeseneesceeecueesnseenseees 15
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`IX.
`
`DR. AKHLAGHI CANNOT OPINE RELIABLY ON THE °866 PATENT
`
`DUE TO HER LACK OF EXPERTISE IN THE RELEVANT FIELD AND
`
`LACK OF UNDERSTANDING OF THE DISCLOSURE OF TIMMINS..18
`
`CLAIMS 1-25 ARE NOT OBVIOUS IN VIEW OF CHENG AND
`
`TIMMINS0nn nr reader tneetienennnirrenieesiiaes 23
`
`A.—Independent Claim 1 is Not Obvious Over Cheng and Timmins....... 26
`
`l.
`
`A POSA Would Understand Timmins to Teach Increased
`Gastric Residence Time, Not a Particular Mean Ta, Value or
`Range Thereot..........cccccccccccceececesseeecesssesessreeesseeessneesssaeeseas 34
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`
`
`IPR2017-01648
`Declaration of Jennifer Dressman, Ph.D.
`
`2.
`
`3.
`
`A POSA Would Not Read Timmins to Teach a Tax Value in
`the Claimed Range .............c ccc cceeecceeeeeeccntteeeeeetsteeeseeeenriaes 34
`
`The Remaining Rationales Presented in the Petition and Dr.
`Akhlaghi’s Declaration Would Not Provide a Dosage Form
`Having a Tex 1n the Claimed Range «000.00 eee 42
`
`B.
`
`Dependent Claims 2-25 Are Not Obvious Over Cheng and Timmins
`bee cceeeeeeeeeeeeceeeeecaeecaaecceeeecueeeeseeeseeesceeeeceseseeaeeceeeeceseessieesiceeseeeseeeseieeeas 45
`
`1.
`
`2.
`
`3.
`
`4.
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`5.
`
`6.
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`7.
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`8.
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`9.
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`10.
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`11.
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`Claims 2-3 and 23-24 Are Not Obvious Over Cheng and
`TUIMIMIDS ooo... eee cece ccc e cece cence eeceeeceeeeseeecenaeeceeeecneeeecieeensereneetey 45
`
`Claims 4-5 Are Not Obvious Over Cheng and Timmins......... A6
`
`Claims 6-24 Are Not Inherently Obvious Over Cheng and
`THIMIMINS 0... eee eee cece ce eee ceeeeeeceeeeccaaaeeceaaeeeeseeeessseeeeesseeeeteees A9
`
`Claims 6-7 and 23-24 Are Not Obvious Over Cheng and
`TUIMIMIDS ooo... eee cece ccc e cece cence eeceeeceeeeseeecenaeeceeeecneeeecieeensereneetey 5]
`
`Claims 8-10 Are Not Obvious Over Cheng and Timmins....... 52
`
`Claims 11-12 Are Not Obvious Over Cheng and Timmins.....53
`
`Claims 13-14 Are Not Obvious Over Cheng and Timmins.....55
`
`Claims 15-17 Are Not Obvious Over Cheng and Timmins.....56
`
`Claims 18-20 Are Not Obvious Over Cheng and Timmins.....58
`
`Claim 21 Is Not Obvious Over Cheng and Timmins............... 59
`
`Claim 22 Is Not Obvious Over Cheng and Timmimns............... 60
`
`Al.
`
`OBJECTIVE INDICIA SUPPORT THE NON-OBVIOUSNESS OF THE
`
`CHALLENGED CLAIMS00.0... .ccccece cece ccecceccee eee cece ccnaeecaeeceeeeesieettseeeetiees 61
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`All.
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`COMPENSATION 200... .0ccccccccececccecce cee eeeceeececeeeeseeceeneeensaeeciaeeseseeesieeeeneeeesees 65
`
`AIT.
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`AVAILABILITY FOR CROSS EXAMINATION.......000.cccececceeeeeeeeeees 66
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`XIV.
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`JURAT oiec cece ccc cece cceeecceeecceeeeeceeessseeecseeeeeeensaeec:eeeeseeecieestseeeseees 67
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`-iu-
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`IPR2017-01648
`Declaration of Jennifer Dressman, Ph.D.
`
`I, Jennifer Dressman, Ph.D., declare as follows:
`
`1.
`
`My nameis Jennifer Dressman.
`
`I
`
`QUALIFICATIONS
`
`2.
`
`The opinions below are based on my background and experience,
`
`including my over 40 years of professional and educational experiencein the fields
`
`of pharmaceutics and biopharmaceutics, including formulation of drugs for oral
`
`administration, in vitro pharmaceutical testing, and calculation and analysis of
`
`pharmacokinetic (“PK”) parameters.
`
`3.
`
`My qualifications as an expert in these areas are established by my
`
`curriculum vitae, which 1s attached hereto as Appendix A, and the publications
`
`cited therein.
`
`[ have set forth below representative relevant experience.
`
`4,
`
`] received a Bachelor of Pharmacy from the Victorian College of
`
`Pharmacy in Melbourne, Australia in 1976.
`
`I earned a Master of Science in
`
`Pharmaceutical Chemistry from the University of Kansas in 1979 and a Ph.D. in
`
`Pharmaceutical Chemistry also from the University of Kansas in 1981 under the
`
`supervision of Prof. Takeru Higuchi, who was known asthe “‘father of physical
`
`pharmacy.” See Takeru Higuchi biography, Kansas Historical Society,
`
`https://www.kshs.org/kansapedia/takeru-higuchi/16878 (last visited May 30,
`
`2018).
`
`
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`IPR2017-01648
`Declaration of Jennifer Dressman, Ph.D.
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`5.
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`While I was earning my graduate degrees, I was a research assistant at
`
`the University of Kansas. After I finished my Ph.D., I worked for one year as a
`
`Research Pharmacist at the Burroughs Wellcome Company in Greenville, North
`
`Carolina. I then worked for a year as a Senior Research Chemist at INTERx
`
`Research Corporation in Lawrence, Kansas, where I conducted research, inter alia,
`
`on predicting dosage form performancein the gastrointestinaltract.
`
`6.
`
`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 Michigan.
`
`While there, I taught many courses, including, among others, undergraduate
`
`courses 1n pharmaceutics and a graduate course on principles of oral drug
`
`absorption.
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`I also conducted research, most of which focused on understanding
`
`gastrointestinal physiology as it relates to oral drug absorption, and on designing
`
`formulations to improve the performanceof orally administered drugs and
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`dissolution tests to predict in vivo drug performance.
`
`7.
`
`In 1994, I was appointed as a Professor of Pharmaceutical Technology
`
`at JW Goethe University in Frankfurt, Germany. Since that time, I have taught
`
`lectures, seminars, and practical courses in the fields of pharmaceutics,
`
`biopharmaceutics, pharmacokinetics, and pharmaceutical technology. Notable
`
`examples include “Biopharmaceutics and dosage form driven pharmacokinetics,”
`
`
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`IPR2017-01648
`Declaration of Jennifer Dressman, Ph.D.
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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.”
`
`8.
`
`At JW Goethe University, the primary focus of my research has
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`continued to be oral drug absorption and predicting in vivo drug performance using
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`biorelevant dissolution testing and physiologically based pharmacokinetic
`
`(“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 vivo
`
`performance of drugs and drug formulations after oral administration.
`
`9.
`
`In 2002, I was appointed the Director of the Institute of
`
`Pharmaceutical Technology at the JW Goethe University. In that capacity, I am
`
`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.
`
`10.
`
`Tama named author on over 230 peer-reviewed publications and over
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`25 reviewarticles in the fields of pharmaceutics and biopharmaceutics. Of these
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`articles, approximately 60 have addressed the relationship between formulation
`
`and pharmacokinetics. 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.
`
`I am a named
`
`_3-
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`IPR2017-01648
`Declaration of Jennifer Dressman, Ph.D.
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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.
`
`11.
`
`Iam 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
`
`for Pharmaceutical Technology, and the Fédération Internationale Pharmaceutique.
`
`I also have served on the editorial boards of numerous preeminent journals in the
`
`pharmaceutical field. Iam currently an associate editor of the European Journal of
`
`Pharmaceutics and Biopharmaceutics and the Journal of Pharmacy and
`
`Pharmacology.
`
`12.
`
`Over the course of my career, I have also received various awards and
`
`other honors for my work in the pharmaceutical chemistry and technology fields.
`
`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 Fellowsof the
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`Controlled Release Society; and in 2015, I was elected to be a Fellow of the
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`Fédération Internationale Pharmaceutique. In 2010, I was awarded the Silver
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`Medal of Honorfrom the International Association for Pharmaceutical
`
`Technology, and in 2008, I was awarded the Distinguished Scientist Award from
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`the Fédération Internationale Pharmaceutique. In May 2017, I received the Nagai
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`_4-
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`
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`IPR2017-01648
`Declaration of Jennifer Dressman, Ph.D.
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`International Woman Researcher of the Year Award from the Association of
`
`Pharmaceutical Science and Technology of Japan. In addition, in 2017, I received
`
`the award for the best academic paperin the field of pharmacokinetic modeling
`
`and simulation from SIMCYP.
`
`I.
`
`SUMMARY OF OPINIONS
`
`13.
`
` Itis my opinion that claims 1-25 of U.S. Patent No. 6,866,866
`
`(hereinafter “the °866 patent”) are non-obvious under 35 U.S.C. § 103 over
`
`International Patent Application Publication No. WO 99/47125 (hereinafter
`
`“Cheng,” Ex. 1002) in view of International Patent Application Publication No.
`
`WO 99/471 28 (hereinafter “Timmins,” Ex. 1003).
`
`14.
`
`Itis also my opinion that objective indicia further demonstrate the
`
`non-obviousness of claims 1-25 of the ’866 patent, including addressing a long-felt
`
`but unmet need, copying by others, and unexpected results.
`
`Ii.
`
`INFORMATION CONSIDERED
`
`15. A list of the materials I have considered in rendering my opinionsis
`
`attached hereto as Appendix B.
`
`IV. A PERSON OF ORDINARYSKILL IN THE ART
`
`16.
`
`J understand that Patent Ownerhas proposed a definition of a person
`
`of ordinary skill in the art (“POSA”), which defines a POSAas a person who, at
`
`the time of the invention, held a degree in pharmacy, chemistry, chemical
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`
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`IPR2017-01648
`Declaration of Jennifer Dressman, Ph.D.
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`engineering, or a related field with at least three to five years of pharmacokinetics,
`
`biopharmaceutics, medicinal chemistry, pre-formulation, or formulation
`
`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
`
`the invention, with the methods used in formulating oral dosage forms, modified
`
`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.
`
`Patent Owner Preliminary Response, 15-16.
`
`I agree with this definition.
`
`17.
`
`I understand that Petitioner has proposed a slightly different definition
`
`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 November3, 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
`
`definition or the Petitioner’s definition of a POSA applies.
`
`V.
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`LEGAL PRINCIPLES
`
`18.
`
`J 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
`
`been obvious to one of ordinary skill in the art at the time the invention was made.
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`The obviousnessanalysis involves several factual inquires, including: (1) the scope
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`and content of the prior art; (41) the differences between the prior art and the claim;
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`-6-
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`IPR2017-01648
`Declaration of Jennifer Dressman, Ph.D.
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`(111) the level of ordinary skill in the art at the time of the invention; and (iv) the
`
`existence of objective indicia of non-obviousness (“secondary considerations”).
`
`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
`
`of ordinary skill in the art to combine or modify the relevant teachings in the prior
`
`art to obtain the claimed invention, and one of ordinary skill in the art must have
`
`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
`
`its intended purpose, then there can be no suggestion or motivation to make the
`
`proposed modification.
`
`20.
`
`Furthermore, I understand that the rationale of “obviousto try” to
`
`support obviousness requires a finite numberof identified, predictable solutions
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`and a claimed invention is not obvious when a skilled artisan would have to vary
`
`all parameters or try each of numerous possible choices until one possibly arrived
`
`at a successful result, where the prior art gave no indication of which parameters
`
`were critical or direction as to which of many possible choices 1s likely to be
`
`successful. I also understand thatit 1s incorrect to evaluate obviousness from a
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`hindsight perspective using the teachingsof the patent at issue as a guide.
`
`21.
`
`Ihave also been informed and understand that objective indicia of
`
`non-obviousness (also known as “secondary considerations”) can provide evidence
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`_7-
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`IPR2017-01648
`Declaration of Jennifer Dressman, Ph.D.
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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
`
`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
`
`22.
`
`[understand that the parties in this proceeding have agreed that the
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`term “Tmax” 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
`
`of the drug attains the highest plasma concentration of drug attained within the
`
`dosing interval (7.e., about 24 hours).” Decision on Institution at 7; the °866 patent
`
`at col. 7, ll. 49-53; Petition at 24; and Patent Owner Preliminary Responseat 18.
`
`I
`
`agree with this construction. Patent Owneralso proposed constructions for the
`
`claimed terms “membrane,” “dinnertime,” and “at dinner.” Patent Owner
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`Preliminary Response at 16-18. The °866 patent also defines terms such as
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`“AUC,” “Crax,” and “mean.” °866 patent, col. 7,1. 40 —col. 8,1. 14.
`
`I agree with
`
`these constructions and definitions as well.
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`VIL BACKGROUND
`
`A.
`
`State of the Art in November 2000
`
`23.
`
`J understand that Petitioner has challenged the validity of claims 1-25
`
`of the ’866 patent, which issued from U.S. Patent Application No. 09/705,630
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`
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`IPR2017-01648
`Declaration of Jennifer Dressman, Ph.D.
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`(hereinafter “the °630 application’), which application was filed November3,
`
`2000. At the time offiling of the °630 application in November 2000, metformin
`
`hydrochloride, a short-acting drug used to treat non-insulin-dependentdiabetes
`
`mellitus (NIDDM), was marketed as Glucophage® by Bristol-Myers Squibb in the
`
`United States. See the °866 patent, col. 1 Il. 56-57, 61-63. At the time, there was
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`no fixed dosage regimen for Glucophage® to manage hyperglycemia in patients
`
`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
`
`of 2,550 mg per day.
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`/d. col. 1 1. 63 —col. 21. 2.
`
`24.
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`However, because metformin 1s a short-acting drug, patients had to
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`take the medication two or three times each day.
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`/d. at col. 2 Il. 4-6. Such frequent
`
`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.
`
`See id. at col. 1 Il. 14-18; col. 2 IL 4-8; col. 20 Il. 16-18.
`
`25.
`
`Thus, at the time ofthe filing of the °630 application, there was a need
`
`in the field for a safe and effective dosage form of metformin that would enable
`
`patients with type 2 diabetes to take their medication on a once-a-day basis,
`
`thereby improving patient compliance and reducing adverse events.
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`
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`IPR2017-01648
`Declaration of Jennifer Dressman, Ph.D.
`
`B.
`
`Tmax and Other Pharmacokinetic Parameters of a Drug’s Dosage
`Form
`
`26.
`
` Asexplained above, Tina refers to “the time period which elapses after
`
`administration of the dosage form at which the plasma concentration of the drug
`
`attains the highest plasma concentration of drug attained within the dosing interval
`
`(1.e., about 24 hours).” Decision on Institution at 7; the °866 patent at col. 7, IL.
`
`49-53, Petition at 24; and Patent Owner Preliminary Response at 18. A Tax fora
`
`single patient is a discrete variable — its value can only be one of the time points at
`
`whichthe patient’s blood was sampled. Tima data for a population of patients is
`
`generally expressed as a median Tax, with a minimum Ty and maximum Trax
`
`reported (7.e., “median Tox (minimum Tre, Maximum Tme),” see, e.g., Timmins at
`
`Example 5), but can also be expressed as a mean Tmax, as described in the *866
`
`patent, e.g., claim 1. For the former, the median Tie. represents a Ta, Value in an
`
`ordered set of values where there is an equal number of values below and above
`
`the Tax Value, or alternatively the arithmetic mean of the two middle valuesif
`
`there is no one middle number. Paper 12, Decision on Institution at 12, n6.
`
`27.
`
`The mimmum Tyax 1s the single lowest Tina, Value obtained from the
`
`population of patients, while the maximum Ty. 1s the single highest Tia value
`
`obtained from the population of patients. A mean Tia. 1s the arithmetic average of
`
`all the individual Ty2, Values reported for all the patients in the study. As
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`IPR2017-01648
`Declaration of Jennifer Dressman, Ph.D.
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`acknowledged by Dr. Akhlaghi, a mean Tax 18 a single value, not a range of
`
`values. Akhlaghi Deposition at 72:21-74:1. As also acknowledged by Dr.
`
`Akhlaghi, calculation of a single mean Tax value from a population of patients
`
`requires access to the underlying raw data (7.e., the individual Ty, recorded for
`
`each individual patient). Akhlaghi Deposition at 70:8-11;71:11-21.
`
`28.
`
`The Tma of a drug’s dosage form does not provide any conclusive
`
`information, either expressly or inherently, about the in vitro dissolution profiles,
`
`or about the dosage form’s further pharmacokinetic parameters, including width at
`
`50% of the height of a mean plasma concertation/time curve, the ratio of mean Cra
`
`value to mean plasmalevel at about 24 hours after the administration, the mean
`
`Cmax Values, the ratio of the dosage form’s mean AUC.24nrs to an immediate release
`
`dosage form’s mean AUC-24hrs, the dosage form’s mean AUCo.24nrs, the dosage
`
`form’s mean AUC0-24hrs and mean Crax Values, the dosage form’s mean AUC-24n1s
`
`and mean Cmax Values at the 18‘ day of administration and 14" day of
`
`administration, the mean ti/2 of the claimed dosage form, or in general the precise
`
`shape of the plasma concentration/time curve. These other parameters would be
`
`important contributory information for a skilled person developing an oral dosage
`
`form of metformin in November 2000. For this reason, it is my opinion that such a
`
`person would not have focused on Tax in isolation. Such an approach could only
`
`-ll-
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`IPR2017-01648
`Declaration of Jennifer Dressman, Ph.D.
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`have been taken with the benefit of hindsight, which I understand is impermissible
`
`in the obviousness analysis.
`
`C.
`
`The ’866 Patent
`
`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
`
`°866 patent developed Fortamet®, a novel extended release dosage form of
`
`metformin. Results from clinical studies demonstrated that Fortamet® was
`
`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
`
`Approval Letter,” Ex. 2001); Fortamet® FDA Label (Rev. 02/10) at 8-12, 28 (Ex.
`
`2002). The FDA approved Fortamet® for use in managing type 2 diabetes on
`
`April 27, 2004. See Fortamet® FDA Approval Letter (Ex. 2001). See, also, Patent
`
`OwnerPreliminary Responseat 6-7.
`
`30.
`
`Claim 1, the only independent claim of the ’866 patent, recites:
`
`1. 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
`
`-|2-
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`IPR2017-01648
`Declaration of Jennifer Dressman, Ph.D.
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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 (Tiax) of the metformin
`from 5.5 to 7.5 hours after administration following dinner.
`
`31.
`
`Claims 2-25 ultimately depend from claim 1 and recite additional
`
`limitations, including narrower ranges of mean Tmax, the composition of the dosage
`
`form, in vitro dissolution profiles of the dosage form, and further pharmacokinetic
`
`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 (Cmax) over the mean plasma concentration at 24 hours post-
`
`administration, the mean Cmax values, the ratios of the mean AUCo-24nrs to an
`
`immediate release dosage form’s AUCo.24nrs, the mean AUCo-24nr values, the mean
`
`Cmax and the mean AUCo-24nr values, the mean Cra and mean AUCo-24hr values at
`
`the 1* and 14" days of administration, and the meanhalf-life (ti2) values.
`
`VII. PRIOR ART RELIED ON BY PETITIONER
`
`32.
`
`J 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
`
`Core.” Chengattitle. Cheng discloses a “controlled release antihyperglycemic
`
`tablet ... comprising a core containing the antihyperglycemic drug, a
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`IPR2017-01648
`Declaration of Jennifer Dressman, Ph.D.
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`semipermeable membrane coating the core and at least one passageway 1n the
`
`membrane.” Cheng at Abstract.
`
`34.
`
`Cheng teaches that a key feature ofits tablet is that it “does not
`
`contain an expanding polymer.” Cheng at Abstract (emphasis added). In fact, as
`
`acknowledged by Dr. Akhlaghi, the goal of Cheng is “to provide a controlled or
`
`sustained release formulation for an antihyperglycemic drug that does not employ
`
`an expanding polymer.” Cheng at 3, Il. 3-6 (emphasis added); see Akhlaghi
`
`Deposition at 83:15-18.
`
`35.
`
`Cheng also teaches that another key feature ofits tablet is that it
`
`“provide[s] therapeutic levels of the drug throughout the day with peak plasma
`
`levels [(.e., Tmax)] being obtained between 8-12 hours after administration”
`
`following dinner. Cheng at 4, Il. 3-9. Again, as acknowledged by Dr. Akhlaghi,
`
`Cheng emphasizesthat its disclosure is directed to “a controlled or sustained
`
`release formulation for an antihyperglycemic drug that obtains peak plasmalevels
`
`approximately 5-/2 hours after administration,” and that “a controlled or sustained
`
`release formulation for an antihyperglycemic drug that can provide continuous and
`
`non-pulsating therapeutic levels of an antihyperglycemic drug to an animal or
`
`human in need of such treatment over a twelve hour to twenty-four hour period.”
`
`Chengat 3, ll. 7-17 (emphasis added), Akhlaghi Deposition at 85:8-19.
`
`_14-
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`IPR2017-01648
`Declaration of Jennifer Dressman, Ph.D.
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`36.
`
`Thus, Cheng explicitly describes that its purpose is to provide a
`
`dosage form lacking an expanding polymer that provides a mean Tmax. value
`
`between 8-12 hours, which is longer than -- and outside the range of -- the mean
`
`Tmax Values recited 1n claim 1 of the *866 patent (7.e., 5.5 to 7.5 hours). Cheng’s
`
`Example 3 discloses a dosage form that provides a mean Tax of 10 hours. Cheng
`
`at Example 3, Figure 8.
`
`B.
`
`Timmins
`
`37.
`
`Timminsis titled “Biphasic Controlled Release Delivery System for
`
`High Solubility Pharmaceuticals and Method.” Timmins discloses a “biphasic
`
`controlled release delivery system for pharmaceuticals which have high water
`
`solubility, such as the antidiabetic metformin [hydrochloride] salt, ... which
`
`provides a dosage form that has prolonged gastric residence.” Timminsat
`
`Abstract. Timminsteaches that the goal of its dosage form 1s to achieve
`
`“prolonged gastric residence,” to maximize contact between released drug and the
`
`site of the absorption for metformin, which Timminsindicates is primarily in the
`
`upper small gastrointestinal (“GI’’) tract. Timminsat 14, Il. 6-12.
`
`38.
`
`Timminsindicates that the prolonged gastric residence time of the
`
`dosage formsdisclosed therein is due to the “swelling of the system.” Timminsat
`
`11, ll. 8-12. Timmins further teachesthat its tablet “swells up to approximately
`
`three timesits dry size following hydration” of the polymers used 1n the fabrication
`
`-145-
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`IPR2017-01648
`Declaration of Jennifer Dressman, Ph.D.
`
`of the tablet. Timminsat 30, Il. 13-16. Notably, the formulation of Example 3 of
`
`Timmins (which is used in Example 5) includes a swelling polymer (sodium
`
`carboxymethylcellulose). Timmins at Examples 3, 5.
`
`39.
`
`Timminsalso teaches that the formulations disclosed therein “will
`
`provide for an extended release formulation of drug with minimal interpatient
`
`variability in pharmacokinetic parameters.” Timminsat 14, Il. 20-23 (emphasis
`
`added). Consistent with this teaching, Example 5 of Timminsstates that when its
`
`dosage form was administered in vivo to patients, “[i]nterpatient variability in
`
`pharmacokinetic parameters was acceptable as illustrated by the mean parameters
`
`(%CV)” given for Cmax and AUC. Timmins at Example 5; 34, Il. 24-29.
`
`40.
`
`Timmins in Example 5 discloses administration to a group of patients!
`
`either a dosage form of metformin hydrochloride prepared according to Example 3
`
`(i.e., a dosage form that includes an expanding polymer) or Glucophage®. While
`
`the focus of Timmins 1s on improving gastric residence time, rather than Tex,
`
`Timmins doesreport that the median Tina, value obtained for the patient group
`
`‘In Example 5, Timmins teaches that 24 patients were dosed with Example 3 or
`
`Glucophage® tablets following dinner. However,it is not clear from Timmins
`
`whetherall 24 patients or a portion of the 24 patients (e.g., 12 patients) received
`
`the dosage form of Example 3.
`
`-16-
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`IPR2017-01648
`Declaration of Jennifer Dressman, Ph.D.
`
`dosed with Example was 5 hours, with the lowest individual Tina, value observedat
`
`4 hours and the highest individual Tne, value observed at 8 hours. Nowhere does
`
`Timmins mention a mean Tmax Value for Example 5, or even a range in whichthat
`
`mean Tax must fall. Timmins does not teach a mean Tyax Value between 5.5 to 7.5
`
`hours, as I understand is required by independentclaim 1 of the *866 patent.
`
`41.
`
`Furthermore, as acknowledged by Dr. Akhlaghi, Timmins does not
`
`provide the individual Tj, Values for the other patients recerving the Example 3
`
`dosage form, and thus a mean Ty», Value cannot be calculated from the data
`
`presented in Example 5. Akhlaghi Deposition at 80:19-81:1. While the Federal
`
`Circuit suggested that the single mean Te value of Timmins would fall between
`
`approximately 4.67 hours and 6.33 hours, neither the Petitioner, Dr. Akhlaghi, nor
`
`the Federal Circuit provided any explanation as to where 1n that range the single
`
`mean Ta Value of Timmins would be expected to fall. Sciele Pharma, Inc. v.
`
`Lupin Lid., 684 F.3d 1253, 1261 (Fed. Cir. 2012) (Ex. 1006) (hereinafter “the
`
`Federal Circuit opinion”). In fact, Dr. Akhlaghi stated that with respectto trying to
`
`determine where the single mean Tax value of Timminsfalls, “everybody is
`
`guessing here.” Akhlaghi Deposition at 80:19-81:1.
`
`-|7-
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`
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`IPR2017-01648
`Declaration of Jennifer Dressman, Ph.D.
`
`IX. DR. AKHLAGHI CANNOT OPINE RELIABLY ON THE ’866
`
`PATENT DUE TO HER LACK OF EXPERTISE IN THE RELEVANT
`
`FIELD AND LACK OF UNDERSTANDING OF THE DISCLOSURE
`
`OF TIMMINS
`
`42. While Petitioner’s declarant Dr. Akhlaghi has expertise in the area of
`
`clinical pharmacology, after review of her declaration, accompanying CV and
`
`deposition testimony, it is my opinion that she does not have the appropriate
`
`experience and understanding of the prior art to offer an opimion on the alleged
`
`obviousnessof design and development of a controlled release dosage form, which
`
`is the field of the °866 patent.
`
`43.
`
`First, I have read Dr. Akhlaghi’s deposition transcript, and I believe
`
`that she conceded that she is not an expert in formulation development of
`
`controlled release dosage forms. Akhlaghi Deposition at 24:5-16; 33:16-34:4.
`
`Additionally, she admitted that she has never developed the same kinds of dosage
`
`formsthat are the subject of Timmins(7.e., expanding polymer-based dosage
`
`forms) or Cheng (i.e., osmotic pump dosage forms). Akhlaghi Deposition at
`
`33:16-22 (Q: Your CV doesn't indicate that you've ever designed or developed an
`
`osmotic pump dosage form. Correct? A: I did not develop an osmotic pump
`
`dosage form. Q: And your CV doesn't indicate that you've ever designed an
`
`expanding polymer dosage form? A: I 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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`-1|&-
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`IPR2017-01648
`Declaration of Jennifer Dressman, Ph.D.
`
`has expertise in developing such solid oral dosage forms. Without this
`
`background, I do not believe Dr. Akhlaghiis able to reliably opine on what a
`
`person skilled in the art in November 2000 would understand from the teachings of
`
`Timmins and Cheng.
`
`44,
`
`Furthermore, during her deposition, Dr. Akhlaghi was unable to
`
`convey a clear understanding of the subject matter of the claims of the °866 patent.
`
`For example, although Dr. Akhlaghi initially stated that the subject matter of the
`
`°866 patent relates only to pharmacokinetic parameters, and not formulation
`
`development, she subsequently admitted that her conclusion that there was a
`
`motivation for a person skilled in the art to combine Timmins and Chengto arrive
`
`at the °866 patent’s claims was based on a motivation to develop a controlled
`
`release dosage form of metformin. Akhlaghi Deposition at 24:5-16, 32:20-33:15;
`
`cf, 86:2-22. In my opinion, her statements are contradictory and cannot be
`
`reconciled with the specification and claims of the ’866 patent.
`
`45.
`
`Itis my opinion that the ’866 patent 1s directed to the design and
`
`development of a controlled release oral dosage form of metformin or a
`
`pharmaceutically acceptable salt thereof for the reduction of serum glucose levels
`
`in human patients with NIDDM.Infact, this is explicitly the subject matter of
`
`claim 1. °866 Patent at clam 1 (reciting “a controlled release oral dosage form for
`
`the reduction of serum glucose levels in human patients with NIDDM, comprising
`
`-|19-
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`IPR2017-01648
`Dec
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