Declaration of Jennifer Dressman, Ph.D.
`
`IPR2017-01648
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`Aurobindo Pharrna USA Inc.
`
`Petitioners,
`
`V.
`
`Andrx Labs, LLC
`Patent Owner
`
`Case IPR2017—01648
`
`US. Patent No. 6,866,866
`
`DECLARATION OF JENNIFER DRESSMAN, PH.D.
`
`Andrx 2010
`
`Aurobindo v. Andrx
`
`|PR2017-01648
`
`

`

`Declaration of Jennifer Dressman, Ph.D.
`
`IPR2017-01648
`
`TABLE OF CONTENTS
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`Page
`
`QUALIFICATIONS ........................................................................................ 1
`
`II.
`
`SUMIVIARY OF OPINIONS ........................................................................... 5
`
`III.
`
`INFORMATION CONSIDERED ................................................................... 5
`
`IV.
`
`A PERSON OF ORDINARY SKILL IN THE ART ...................................... 5
`
`LEGAL PRINCIPLES ..................................................................................... 6
`
`VI.
`
`CLAIM CONSTRUCTION ............................................................................ 8
`
`VII.
`
`BACKGROUND ............................................................................................. 8
`
`A.
`
`State of the Art in November 2000 ....................................................... 8
`
`B.
`
`Tmax and Other Pharmacokinetic Parameters of a Drug’s Dosage Form
`............................................................................................................. 10
`
`C.
`
`The ”866 Patent ................................................................................... 12
`
`VIII.
`
`PRIOR ART RELIED ON BY PETITIONER .............................................. 13
`
`A.
`
`B.
`
`Cheng ................................................................................................... 1 3
`
`Timmins ............................................................................................... 1 5
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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 TIlVIh/IINS. 18
`
`CLAIMS 1-25 ARE NOT OBVIOUS IN VIEW OF CHENG AND
`
`TIlVIMINS ...................................................................................................... 23
`
`A.
`
`Independent Claim 1 is Not Obvious Over Cheng and Timmins ....... 26
`
`1.
`
`A POSA Would Understand Timmins to Teach Increased
`
`Gastric Residence Time, Not a Particular Mean Tmax Value or
`
`Range Thereof........................................................................... 34
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`

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`Declaration of Jennifer Dressman, Ph.D.
`
`IPR201 7-01 648
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`2.
`
`A POSA Would Not Read Timmins to Teach a me Value in
`
`the Claimed Range .................................................................... 34
`
`3.
`
`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.
`
`Dependent Claims 2-25 Are Not Obvious Over Cheng and Timmins
`............................................................................................................. 45
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`Claims 2-3 and 23-24 Are Not Obvious Over Cheng and
`Timmins .................................................................................... 45
`
`Claims 4-5 Are Not Obvious Over Cheng and Timmins ......... 46
`
`Claims 6-24 Are Not Inherently Obvious Over Cheng and
`Timmins .................................................................................... 49
`
`Claims 6-7 and 23-24 Are Not Obvious Over Cheng and
`Timmins .................................................................................... 5 l
`
`Claims 8-10 Are Not Obvious Over Cheng and Timmins ....... 52
`
`Claims 1 1-12 Are Not Obvious Over Cheng and Timmins ..... 53
`
`Claims l3-l4 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
`
`10.
`
`Claim 21 Is Not Obvious Over Cheng and Timmins ............... 59
`
`ll.
`
`Claim 22 Is Not Obvious Over Cheng and Timmins ............... 6O
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`XI.
`
`OBJECTIVE INDICIA SUPPORT THE NON-OBVIOUSNESS OF THE
`
`CHALLENGED CLAIMS ............................................................................ 61
`
`XII.
`
`CONIPENSATION ........................................................................................ 65
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`XIII.
`
`AVAILABILITY FOR CROSS EXAIVIINATION ....................................... 66
`
`XIV.
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`ILIRAT ........................................................................................................... 67
`
`_ii_
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`

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`Declaration of Jennifer Dressman, PhD.
`
`lPR2017-01648
`
`1, Jennifer Dressman, Ph.D., declare as follows:
`
`1.
`
`My name is Jennifer Dressman.
`
`I.
`
`QUALIFICATIONS
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`2.
`
`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
`
`of pharmaceutics and biopharrnaceutics, 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
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`curriculum vitae, which is attached hereto as Appendix A, and the publications
`
`cited therein.
`
`I have set forth below representative relevant experience.
`
`4.
`
`1 received a Bachelor of Pharmacy from the Victorian College of
`
`Pharmacy in Melbourne, Australia in 1976.
`
`l eamed 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 as the “father of physical
`
`pharmacy.” See Takeru Higuchi biography, Kansas Historical Society,
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`https://www.kshs.org/kansapedia/takeru—higuchi/ 16878 (last visited May 30,
`
`2018).
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`

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`Declaration of Jennifer Dressman, PhD.
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`lPR201 7-01 648
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`5.
`
`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
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`Research Corporation in Lawrence, Kansas, where I conducted research, inter alia,
`
`on predicting dosage form performance in the gastrointestinal tract.
`
`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 l\/lichigan.
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`While there, I taught many courses, including, among others, undergraduate
`
`courses in pharmaceutics and a graduate course on principles of oral drug
`
`absorption.
`
`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.
`
`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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`

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`Declaration of Jennifer Dressman, PhD.
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`IPR201 7-01 648
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`“Design, manufacture and quality control of pharmaceutical dosage forms,”
`
`“Utilization of drugs in pharmacy practice,” and “Good manufacturing practice.”
`
`8.
`
`At JW Goethe University, the primary focus of my research has
`
`continued to be oral drug absorption and predicting in viva drug performance using
`
`biorelevant dissolution testing and physiologically based pharmacokinetic
`
`(“PBPK”) modeling. Biorelevant media are those that simulate conditions in the
`
`gastrointestinal tract before or after a meal has been ingested. They are
`
`specifically designed to be used in dissolution testing to predict the in viva
`
`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
`
`pharmaceutical technology. I also manage the budget and organization of the
`
`institute.
`
`10.
`
`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
`
`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
`
`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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`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
`
`career, I have also supervised over 60 doctoral theses and have delivered well over
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`100 invited presentations.
`
`11.
`
`I am also a member, and have served on various committees, of
`
`several professional organizations in the pharmaceutical field, including the
`
`American Association of Pharmaceutical Scientists, the International Association
`
`for Pharmaceutical Technology, and the Federation Internationale Pharmaceutique.
`
`I also have served on the editorial boards of numerous preeminent journals in the
`
`pharmaceutical field.
`
`I am 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
`
`Pharmaceutical Scientists; in 2010, I was elected to the College of Fellows of the
`
`Controlled Release Society; and in 2015, I was elected to be a Fellow of the
`
`Federation Internationale Pharmaceutique. In 2010, I was awarded the Silver
`
`Medal of Honor from the International Association for Pharmaceutical
`
`Technology, and in 2008, I was awarded the Distinguished Scientist Award from
`
`the Federation Internationale Pharmaceutique. In May 2017, I received the Nagai
`
`-4-
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`

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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
`
`Pharmaceutical Science and Technology of Japan. In addition, in 2017, I received
`
`the award for the best academic paper in the field of pharmacokinetic modeling
`
`and simulation from SIMCYP.
`
`II.
`
`SUD/[MARY OF OPINIONS
`
`13.
`
`It is 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 Intemational Patent Application Publication No.
`
`WO 99/47128 (hereinafter “Timmins,” EX. 1003).
`
`14.
`
`It is 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.
`
`III.
`
`INFORMATION CONSIDERED
`
`15. A list of the materials I have considered in rendering my opinions is
`
`attached hereto as Appendix B.
`
`IV. A PERSON OF ORDINARY SKILL IN THE ART
`
`16.
`
`I understand that Patent Owner has proposed a definition of a person
`
`of ordinary skill in the art (“POSA”), which defines a POSA as a person who, at
`
`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,
`
`biopharmaceutics, medicinal chemistry, pre-formulation, or formulation
`
`experience, research, or training. In addition, I understand that Patent Owner”s
`
`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
`
`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
`
`Petitioner’s definition, I am at least a person of ordinary skill in the art, and have
`
`been since well before the November 3, 2000 filing date of the ”866 patent. My
`
`opinions expressed herein are the same regardless of whether the Patent Owner”s
`
`definition or the Petitioner’s definition of a POSA applies.
`
`V.
`
`LEGAL PRINCIPLES
`
`18.
`
`l have been informed and understand that, under 35 U.S.C. § 103, a
`
`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.
`
`The obviousness analysis involves several factual inquires, including: (i) the scope
`
`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
`
`existence of objective indicia of non-obviousness (“secondary considerations”).
`
`19.
`
`In connection with obviousness, I have been informed and understand
`
`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.
`
`I also understand that if a
`
`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 “obvious to try” to
`
`support obviousness requires a finite number of identified, predictable solutions
`
`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 is likely to be
`
`successful. I also understand that it is incorrect to evaluate obviousness from a
`
`hindsight perspective using the teachings of the patent at issue as a guide.
`
`21.
`
`l have also been informed and understand that objective indicia of
`
`non-obviousness (also known as “secondary considerations”) can provide evidence
`
`-7-
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`

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`Declaration of Jennifer Dressman, PhD.
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`lPR2017-Ol 648
`
`that a challenged claim is not obvious. Objective indicia may include satisfying a
`
`long-felt but unmet need, unexpected results, commercial success, and copying by
`
`others.
`
`I understand that for objective indicia to be given weight, there must be a
`
`nexus between the evidence and the claimed invention.
`
`VI. CLAIM CONSTRUCTION
`
`22.
`
`I understand that the parties in this proceeding have agreed that the
`
`term “Tmm” recited in the claims should be construed as “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 (119., about 24 hours)” Decision on Institution at 7', the ’866 patent
`
`at col. 7, ll. 49—53; Petition at 24', and Patent Owner Preliminary Response at 18.
`
`I
`
`agree with this construction. Patent Owner also proposed constructions for the
`
`claimed terms “membrane,” “dinnertime,” and “at dinner.
`
`Patent Owner
`
`)3
`
`Preliminary Response at 16-18. The ’866 patent also defines terms such as
`
`“AUC,” “Cmax,” and “mean.” ”866 patent, col. 7, l. 40 — col. 8, l. 14.
`
`I agree with
`
`these constructions and definitions as well.
`
`VII. BACKGROUND
`
`A.
`
`State of the Art in November 2000
`
`23.
`
`I understand that Petitioner has challenged the validity of claims 1-25
`
`of the ”866 patent, which issued from US. Patent Application No. 09/705,630
`
`

`

`Declaration of Jennifer Dressman, PhD.
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`lPR2017-01648
`
`(hereinafter “the ’630 application”), which application was filed November 3,
`
`2000. At the time of filing of the ”630 application in November 2000, metformin
`
`hydrochloride, a short-acting drug used to treat non-insulin—dependent diabetes
`
`mellitus (NIDDM), was marketed as Glucophage® by Bristol-Myers Squibb in the
`
`United States. See the ”866 patent, col. 1 ll. 56-57, 61-63. At the time, there was
`
`no fixed dosage regimen for Glucophage® to manage hyperglycemia in patients
`
`with diabetes mellitus — instead, dosages were individualized to each patient using
`
`500 mg, 850 mg, or 1,000 mg immediate release tablets based on both
`
`effectiveness and tolerance, while not exceeding the maximum recommended dose
`
`of 2,550 mg per day. Id. col. 1 l. 63 — col. 2 l. 2.
`
`24.
`
`However, because metformin is a short-acting drug, patients had to
`
`take the medication two or three times each day. Id. at col. 2 ll. 4-6. Such frequent
`
`dosing typically led to reduced patient compliance and increased adverse events,
`
`including the potentially dangerous side-effects of anorexia, nausea, and vomiting.
`
`See id. at col. 1 ll. 14-18; col. 2 ll. 4-8; col. 20 ll. 16-18.
`
`25.
`
`Thus, at the time of the 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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`Declaration of Jennifer Dressman, PhD.
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`lPR2017-Ol 648
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`B.
`
`Tm and Other Pharmacokinetic Parameters of a Drug’s Dosage
`
`Form
`
`26.
`
`As explained above, Tmax 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
`
`(i.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 Response at 18. A Tmax for a
`
`single patient is a discrete variable — its value can only be one of the time points at
`
`which the patient”s blood was sampled. Tmax data for a population of patients is
`
`generally expressed as a median Tmax, with a minimum Tmax and maximum Tmax
`
`reported (119. , “median me (minimum Tnm, maximum Tm“)? see, e.g, Timmins at
`
`Example 5), but can also be expressed as a mean Tnm, as described in the ”866
`
`patent, e.g., claim 1. For the former, the median Tmax represents a Tmax value in an
`
`ordered set of values where there is an equal number of values below and above
`
`the PM value, or alternatively the arithmetic mean of the two middle values if
`
`there is no one middle number. Paper 12, Decision on Institution at 12, H6.
`
`27.
`
`The minimum Tmax is the single lowest Tmax value obtained from the
`
`population of patients, while the maximum Tnm is the single highest me value
`
`obtained from the population of patients. A mean Tmm is the arithmetic average of
`
`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
`
`values. Akhlaghi Deposition at 72:21-74: 1. As also acknowledged by Dr.
`
`Akhlaghi, calculation of a single mean Tmaxvalue from a population of patients
`
`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.
`
`28.
`
`The Tmm 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 pharrnacokinetic parameters, including width at
`
`50% of the height of a mean plasma concertation/time curve, the ratio of mean Cmm
`
`value to mean plasma level at about 24 hours after the administration, the mean
`
`Cmax values, the ratio of the dosage form’s mean AUC0—24hr5 to an immediate release
`
`dosage form’s mean AUC0-24hIs, the dosage form’s mean AUCO-24hrs, the dosage
`
`form’s mean AUCO-24hrs and mean me values, the dosage form”s mean AUC0-24hIs
`
`and mean Cmax values at the lSt day of administration and 14th day of
`
`administration, the mean l1/2 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 mec in isolation. Such an approach could only
`
`-11-
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`Declaration of Jennifer Dressman, PhD.
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`lPR2017-01648
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`have been taken with the benefit of hindsight, whichl 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
`
`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
`
`-12-
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`

`Declaration of Jennifer Dressman, PhD.
`
`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
`
`limitations, including narrower ranges of mean Tmm, 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 (CHM) over the mean plasma concentration at 24 hours post-
`
`administration, the mean Cmax values, the ratios of the mean AUCO-24hrs to an
`
`immediate release dosage form’s AUC0-24hIs, the mean AUC0.24hI values, the mean
`
`GM and the mean AUC0-24hI values, the mean Cmm and mean AUC0-24hI values at
`
`the lSt and 14th days of administration, and the mean half-life (ti/2) values.
`
`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
`
`Core.” Cheng at title. Cheng discloses a “controlled release antihyperglycemic
`
`tablet
`
`comprising a core containing the antihyperglycemic drug, a
`
`-13-
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`Declaration of Jennifer Dressman, PhD.
`
`lPR2017-Ol 648
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`semipermeable membrane coating the core and at least one passageway in the
`
`membrane.” Cheng at Abstract.
`
`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
`
`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, ll. 3-6 (emphasis added); see Akhlaghi
`
`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.
`
`IPR2017-Ol 648
`
`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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`

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`Declaration of Jennifer Dressman, PhD.
`
`IPR201 7-01 648
`
`of the tablet. Timmins at 30, ll. 13-16. Notably, the formulation of Example 3 of
`
`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
`
`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.
`
`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
`
`(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
`
`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.
`
`lPR2017-01648
`
`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
`
`mean Tmax must fall. Timmins does not teach a mean Tmax value between 5.5 to 7.5
`
`hours, as I understand is required by independent claim 1 of the ”866 patent.
`
`41.
`
`Furthermore, as acknowledged by Dr. Akhlaghi, Timmins does not
`
`provide the individual Tmax values for the other patients receiving the Example 3
`
`dosage form, and thus a mean Tmax 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 Tmax 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 in that range the single
`
`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
`
`Federal Circuit opinion”). In fact, Dr. Akhlaghi stated that with respect to trying to
`
`determine where the single mean Tnm value of Timmins falls, “everybody is
`
`guessing here.” Akhlaghi Deposition at 80:19-81 :1.
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`-17-
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`

`

`Declaration of Jennifer Dressman, PhD.
`
`IPR2017-Ol 648
`
`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
`
`OF TIMlVIINS
`
`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 opinion on the alleged
`
`obviousness of 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.
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`Additionally, she admitted that she has never developed the same kinds of dosage
`
`forms that are the subject of Timmins (113., 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: 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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`-18-
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`

`

`Declaration of Jennifer Dressman, PhD.
`
`IPR2017-01648
`
`has expertise in developing such solid oral dosage forms. Without this
`
`background, I do not believe Dr. Akhlaghi is 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 Cheng to 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,
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`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.
`
`It is