UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
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`v.
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`YEDA RESEARCH & DEVELOPMENT CO. LTD.,
`Patent Owner.
`
`
`Case IPR2015-00644
`Patent 8,399,413
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`
`
`DECLARATION OF ROBERT WILLIAM GRISTWOOD, PH.D.
`IN SUPPORT OF YEDA’S PATENT OWNER RESPONSE
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`YEDA EXHIBIT NO. 2134
`MYLAN PHARM. v YEDA
`IPR2015-00644
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`YEDA RESEARCH & DEVELOPMENT CO. LTD.,
`Patent Owner.
`
`
`Case IPR2015-00644
`Patent 8,399,413
`
`
`
`DECLARATION OF ROBERT WILLIAM GRISTWOOD, PH.D.
`IN SUPPORT OF YEDA’S PATENT OWNER RESPONSE
`
`
`
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`
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`YEDA EXHIBIT NO. 2134
`MYLAN PHARM. v YEDA
`IPR2015-00644
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`I. Introduction ........................................................................................................ 1
`II. Qualifications .................................................................................................. 1
`III. Summary of Opinions .................................................................................... 4
`IV. Pharmacology Background ........................................................................... 4
`V. The Pharmacokinetic Data in the SBOA Were Not Empowered to
`Predict Therapeutic Activity in Humans ............................................................... 7
`A. The Skilled Pharmacologist Would Not Have Considered
`Pharmacokinetic Data Useful for Predicting the Therapeutic Effects of
`Glatiramer Acetate ............................................................................................... 7
`B. The Skilled Pharmacologist Would Have Understood that the
`Pharmacokinetic Data Reported in the SBOA for Monkeys Do Not
`Accurately Reflect the Pharmacokinetics of Glatiramer Acetate .................. 13
`1.
` The Reported Monkey Pharmacokinetic Data Reflect Iodine
`Radioactivity, Not GA Concentration ........................................................... 15
`2.
` The Reported Monkey Pharmacokinetic Data are Internally
`Inconsistent ....................................................................................................... 22
`VI. The SBOA Discloses That Increased Dosages of Glatiramer Acetate
`Would Lead to Increased Side Effects and Also could Affect Its
`Pharmacokinetics ................................................................................................... 27
`VII. Conclusion ..................................................................................................... 30
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`TABLE OF CONTENTS
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`YEDA EXHIBIT NO. 2134
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`I.
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`INTRODUCTION
`1.
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`I, Robert William Gristwood, have personal knowledge of the facts set
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`forth in this Declaration and am competent to testify to the same.
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`2.
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`I have been retained by Yeda Research and Development Co. Ltd.
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`(“Respondent”) in this proceeding regarding U.S. Patent No. 8,399,413 (“the ’413
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`patent”).
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`3.
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`I hereby offer this Declaration in support of Patent Owner’s Response
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`to Petition for Inter Partes Review of the ’413 patent regarding the skilled
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`pharmacologist’s understanding and interpretation of the pharmacokinetic data
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`included in the Summary Basis for Approval for Copaxone® 20 mg (1996)
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`(“SBOA”) (Ex. 1007) as of August 20, 2009.
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`II. QUALIFICATIONS
`4.
`I am a pharmacologist with nearly forty years of experience in the
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`pharmaceutical industry.
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`5.
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`As set forth in more detail in my current CV (Ex. 2130), I received a
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`B.Sc. from North East London Polytechnic in 1976 and a Ph.D. in pharmacology
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`through a Smith Kline collaboration with University of Oxford in 1982.
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`Throughout my career, I have worked at a number of companies in the
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`pharmaceutical industry.
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`6. While obtaining my B.Sc., I worked as a pharmacologist within the
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`medicinal Biology Department of Pfizer UK from 1974-1975.
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`7.
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`Between 1976 and 1996 I worked within and/or had responsibility for
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`the pharmacology departments of Smith Kline & French (“SK&F”) (now part of
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`GlaxoSmithKline), Laboratorios Almirall, and Chiroscience Limited. At SK&F, I
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`was an Associate Director of Pharmacology. At Almirall, I was Director of
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`Biological Science. At Chiroscience, I was Head of Biology (R&D).
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`8.
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`In May 1996, I established Stevenage Biosciences Ltd. (now
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`Cambridge BioConsultants Ltd.), of which I am Director and Principal Consultant.
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`Cambridge BioConsultants provides biological consultancy services to
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`pharmaceutical companies.
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`9.
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`In January 1998, I co-founded Arachnova Limited, a company that
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`specialised in identifying new therapeutic uses for existing drugs as well as
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`providing consultancy services to the pharmaceutical industry. I was Research and
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`Development Director for this company until 2007.
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`10.
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`In September 2000, I co-founded Arachnova Therapeutics Ltd., which
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`was a venture capital backed pharmaceutical company that specialised in the
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`development and commercialization of projects largely identified by Arachnova
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`Ltd.
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`11.
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`In January 2007, I co-founded Acacia Pharma Ltd., now known as
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`Acacia Pharma PLC, a venture capital backed pharmaceutical company focused on
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`hospital based supportive care, particularly cancer supportive care. I am currently
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`Chief Scientific Officer of this company.
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`12.
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`I have written many scientific papers and presented many lectures in
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`the field of pharmacology. I am also a member, or have been a member, of a
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`number of scientific organizations, including the British Pharmacological Society,
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`Society of Medicines Research, and the Biochemical Society. I have been an
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`editor of several pharmacological journals, including the British Journal of
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`Pharmacology (1992 – 1997), the Journal of Cardiovascular Pharmacology (1987 –
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`1995), Expert Opinion on Investigational Drugs (1992 – 2006), and Current
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`Opinion in Anti-Inflammatory and Immunomodulatory Investigational Drugs
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`(1997 – 2000).
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`13.
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`Throughout my career, I have conducted pharmacological studies and
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`research using human and animal models in support of the development of many
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`drugs and dosing regimens. Many of these studies involved characterizing and
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`analyzing the pharmacokinetic and pharmacodynamic properties of a drug in
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`humans and/or animals.
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`14.
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`I consider myself an expert in the field of pharmacology.
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`15.
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`I am being compensated at my usual consulting rate of $400 per hour
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`for my time on this matter. My compensation does not depend in any way on the
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`outcome of these proceedings.
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`III. SUMMARY OF OPINIONS
`16.
`I have been asked to provide my opinions concerning what the skilled
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`pharmacologist would have understood from the pharmacokinetic data reported in
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`the SBOA as of August 20, 2009.
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`17.
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`In forming my opinions, I have relied upon my knowledge and
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`experience, the references identified in Attachment A, and any other references
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`identified herein.
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`IV. PHARMACOLOGY BACKGROUND
`18. Designing an effective dosing regimen generally requires an
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`understanding of how a drug interacts with the human body.1 The traditional
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`method has been to perform pharmacokinetic/pharmacodynamics (PK/PD)
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`modeling, a technique that establishes a relationship between the administered drug
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`dose, the concentration in an accessible body fluid, and the effect caused by that
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`1
`B. Meibohm and H. Derendorf, Basic concepts of
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`pharmacokinetic/pharmacodynamic (PK/PD) modelling.35(10) INT’L J
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`CLINICAL PHARMACOLOGY THERAPEUTICS, 401-413 (1997) (Ex. 2038) at
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`2.
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`4
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`concentration.2 Broadly speaking, pharmacokinetics describe how the body reacts
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`to a drug in terms of absorption, distribution, metabolism and excretion.3
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`Pharmacodynamics describe how a drug affects the body by linking drug
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`concentration to drug efficacy.4
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`19.
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`In the simplest examples of drug effect, there is a direct relationship
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`between the concentration of drug in the measured fluid, e.g., plasma, and the
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`pharmacologic effect. When the concentration is plotted versus effect, one can see
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`that there is a concentration below which no effect is observed and a concentration
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`above which no greater effect is achieved. In between these concentrations, the
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`effect usually increases with increasing concentration, as shown in the figure
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`below.
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`2
`Id.
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`Id. at 3
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`Id.
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`3
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`4
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`20. While a well-characterized PK/PD model can guide predictions of the
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`likely outcome of a particular dose or dosing frequency regimen, to be of any
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`predictive value, the measured concentration must of course be related to its
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`pharmacodynamic effect, and the model must accurately reflect this relationship.
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`Accordingly, it is generally understood that “pharmacokinetic information can only
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`be used to make predictions about drug effects if the concentration effect
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`relationship has thoroughly been defined under the circumstances in question.”5
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`5
`Id. at 13.
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`V. THE PHARMACOKINETIC DATA IN THE SBOA WERE NOT
`EMPOWERED TO PREDICT THERAPEUTIC ACTIVITY IN
`HUMANS
`21.
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`I understand that Mylan’s expert, Dr. Peroutka, has asserted that the
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`person of ordinary skill in the art would have relied upon pharmacokinetic data
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`reported for monkeys in the SBOA in developing a dosing regimen for human
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`administration of GA.6 Specifically, Dr. Peroutka contends that the POSA would
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`have concluded from the SBOA that GA has an 80 hour half-life in humans, and
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`would have relied upon this 80 hour half-life to predict whether a particular GA
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`dosage regimen would be successful in treating relapsing-remitting multiple
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`sclerosis (“RRMS”).7 I disagree with these assertions.
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`A. The Skilled Pharmacologist Would Not Have Considered
`Pharmacokinetic Data Useful for Predicting the Therapeutic
`Effects of Glatiramer Acetate
`22. As discussed above, pharmacokinetic data can generally be used to
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`predict therapeutic efficacy of a drug. However, it is self-evident that reliance on
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`6
`IPR2015-00643, Corrected Declaration Of Stephen J. Peroutka, M.D., Ph.D.
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`dated 3/3/15 (IPR2015-00643, Ex. 1003) at ¶ 120; IPR2015-00644, Corrected
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`Declaration Of Stephen J. Peroutka, M.D., Ph.D. dated 3/3/15 (IPR2015-00644,
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`Ex. 1003) at ¶ 127.
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`7
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`IPR2015-00643, Ex. 1003 at ¶¶ 120; 131-34; IPR2015-00644, Ex. 1003 at
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`¶¶ 127; 148-41.
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`pharmacokinetic data for this purpose necessarily presupposes that drug plasma
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`concentration is related to efficacy, as may be the case with a typical small
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`molecule drug. The skilled pharmacologist would have recognized that this
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`assumption does not hold with respect to GA, and therefore would have considered
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`the SBOA’s pharmacokinetic data unsuitable for predicting the effectiveness of a
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`GA dosing regimen.
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`23.
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`The SBOA itself discloses that Teva told the FDA that GA “exerts its
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`effects locally at the s.c. injection site, and therefore its systemic distribution is
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`irrelevant.”8 The SBOA reviewer agreed that GA’s plasma concentrations were
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`unrelated to its efficacy, stating that “the appropriate bioavailability is constituted
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`by the intact drug that reaches the immune system through the lymph nodes that
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`drain the area of the local s.c. injection site,” and therefore “the PK of the parent
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`drugs and degradation products are not very important from the perspective of
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`efficacy.”9
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`24. Accordingly, the SBOA reviewer expressly distinguished GA from
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`typical drugs for which pharmacokinetics could be useful for predicting efficacy.
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`The SBOA reviewer acknowledged that “[h]uman PK data are normally used to
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`estimate systemic exposure to a drug. For many drugs, this systemic exposure data
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`8
`Ex. 1007 at 249.
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`9
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`Id. at 152, 243.
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`is, in turn, used for comparison to animal toxicology study data in the rational
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`choice of a clinical dosing range that will hopefully maintain drug efficacy while
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`avoiding toxicity. These human systemic exposure data can also be used to adjust
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`the human dose when necessary.”10 However, the reviewer found this typical
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`approach inapplicable to GA on the grounds that “the appropriate bioavailability
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`with respect to drug efficacy is not systemic exposure, but rather is drug exposure
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`at the local lymph nodes that drain the s.c. injection site. Therefore, I would agree
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`with the Sponsor that, in terms of drug efficacy, human PK data would most likely
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`be of limited usefulness.”11
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`25.
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`That pharmacokinetics continued to be considered irrelevant to GA’s
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`efficacy through August 20, 2009, is confirmed by published literature in the field.
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`For example, Varkony reported that “systemic distribution of [GA] is irrelevant to
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`effects following s.c. administration and systemic concentrations of GA or its
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`metabolites are not indicative of drug activity or exposure to the immune
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`system.”12
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`10
`Id. at 251-52.
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`11
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`Id. at 252
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`12 H. Varkony, et al., The Glatiramoid Class Of Immunomodulator Drugs,
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`10(4) EXPERT OPINION PHARMACOTHERAPY, 656-68 (2009) (Ex. 2046) at
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`5.
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`26.
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`In fact, as of August 20, 2009, as of August 20, 2009, GA had never
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`even been detected in plasma following administration of the approved, 20 mg
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`dose.13 While Dr. Peroutka asserts that some references suggest that GA is
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`systemically bioavailable, this assertion is incorrect.14
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`27. Dr. Peroutka contends that the product label for Copaxone states that
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`GA “is believed to enter the systemic circulation intact.”15 This is untrue. With
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`respect to systemic circulation, the Copaxone® label merely leaves open the
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`possibility that some GA, or GA degradant, may reach systemic circulation:
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`“[s]ome fraction of the injected material, either intact or partially hydrolyzed, is
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`presumed to enter the lymphatic circulation, enabling it to reach regional lymph
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`nodes, and some may enter the systemic circulation intact.”16
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`28. Dr. Peroutka also contends that the formation of systemic antibodies
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`to GA in GA-treated patients supports the hypothesis that GA is systemically
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`13 O. Neuhaus, et al., Pharmacokinetics and pharmacodynamics of the
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`interferon-betas, glatiramer acetate, and mitoxantrone in multiple sclerosis, 259
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`(1-2) J NEUROLOGICAL SCI., 27-37 (2007) (Ex. 2012) at 3.
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`14
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`IPR2015-00643, Ex. 1003 at ¶¶ 125-28; IPR2015-00644, Ex. 1003 at
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`¶¶ 132-35.
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`15
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`16
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`IPR2015-00643, Ex. 1003 at ¶ 125; IPR2015-00644, Ex. 1003 at ¶ 132.
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`Copaxone® U.S. Product Label (2001) (Ex. 1047) at 1 (emphasis added).
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`available in the blood after subcutaneous injection.17 This is also incorrect. It is
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`well-known that injected drugs can lead to the generation of systemic antibodies
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`without involvement of the systemic circulation.18 Similarly, in an example of
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`transcutaneous immunization, adjuvants activate Langerhans cells in the skin,
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`which migrate to the draining lymph to orchestrate robust immune
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`responses.19 Indeed, transcutaneous immunization has been utilized to generate
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`antibodies to a toxin that would otherwise cause toxic effects if the compound
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`itself were to enter systemic circulation.20
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`17
`IPR2015-00643, Ex. 1003 at ¶ 125; IPR2015-00644, Ex. 1003 at ¶ 132.
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`18
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`PH Lambert and PE Laurent, Intradermal vaccine delivery: will new
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`delivery systems transform vaccine administration? 26(26) VACCINE, 3197-208
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`(2008) (Ex. 2039).
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`19 GM Glenn, et al., Transcutaneous immunization and immunostimulant
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`strategies, 23(4) IMMUNOLOGY AND ALLERGY CLINICS OF N. AM., 787-
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`813 (2003) (Ex. 2040) at 6-7; CD Partidos, et al., Immunity under the skin:
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`potential application for topical delivery of vaccines, 21(7-8) VACCINE, 776-80
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`(2003) (Ex. 2041) at 1-2.
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`20
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`C Ghose, et al., Transcutaneous immunization with Clostridium difficile
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`toxoid A induces systemic and mucosal immune responses and toxin A-neutralizing
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`antibodies in mice, 75(6) INFECTION AND IMMUNITY, 2326-32 (2007) (Ex.
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`29. Dr. Peroutka also appears to interpret statements by Lobel21 and
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`Simpson22 that GA is “bioavailable” to mean that it is “systemically
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`bioavailable.”23 Again, this is wrong. The term “bioavailable,” used by both Lobel
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`and Simpson to describe GA, can be used to refer either to “the fractional extent to
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`which a dose of drug reaches its site of action or a biological fluid from which the
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`drug has access to its site of action,” depending upon its context.24 Immediately
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`prior to characterizing GA as “bioavailable,” Lobel indicates that GA is either low
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`2042); GM Glenn, et al., Transcutaneous immunization with cholera toxin protects
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`mice against lethal mucosal toxin challenge, 161(7) J. IMMUNOLOGY, 3211-4
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`(1998) (Ex. 2043).
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`21
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`E. Lobel, et al., Copolymer-1, 21(2) DRUGS OF THE FUTURE, 131-134
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`(1996) (Ex. 1022).
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`22 D. Simpson, et al., Glatiramer acetate: a review of its use in relapsing-
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`remitting multiple sclerosis, 16(12) CNS DRUGS, 825-50 (2002) (Ex. 1029).
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`23
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`IPR2015-00643, Ex. 1003 at ¶¶ 125, 127-28; IPR2015-00644, Ex. 1003 at
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`¶¶ 132, 134-35.
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`24
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`Benet et al., Pharmacokinetics: The Dynamics of Drug Absorption,
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`Distribution, and Elimination, in THE PHARMACOLOGICAL BASIS OF
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`THERAPEUTICS, 3 (Alfred Goodman Gilman ed. 1996) (Ex. 1021) at 12-13
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`(emphasis in original).
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`or not detectable in serum.25 Simpson similarly precedes its characterization of
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`GA as “bioavailable” by explaining that GA is not required to be present in the
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`serum to exert its action.26 Given this context, Lobel’s and Simpson’s use of the
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`term “bioavailable” are clearly intended to indicate that GA is available at its site
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`of action, not that it is present in plasma.
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`30.
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`Based upon the disclosure of the SBOA itself, as well as
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`contemporaneous literature, the skilled pharmacologist would have understood that
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`GA’s concentration in systemic circulation was entirely irrelevant to its efficacy,
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`and would therefore have had no basis to rely upon pharmacokinetic data to predict
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`GA’s efficacy or design a dosing regimen.
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`B.
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`The Skilled Pharmacologist Would Have Understood that the
`Pharmacokinetic Data Reported in the SBOA for Monkeys Do
`Not Accurately Reflect the Pharmacokinetics of Glatiramer
`Acetate
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`31.
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`The pharmacokinetic data relied upon by Dr. Peroutka to support an
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`80 hour half-life for GA are found at page 197 of the SBOA.27 The experiment
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`involved administering iodine-labelled GA subcutaneously to eight cynomolgus
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`monkeys, and taking blood samples at various times between predose and 72
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`25
`Ex. 1022 at 3.
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`26
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`27
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`Ex. 1029 at 10.
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`IPR2015-00643, Ex. 1003 at ¶ 129; IPR2015-00644, Ex. 1003 at ¶ 136.
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`hours.28 For each sample, total radioactivity and TCA-precipitable radioactivity
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`were measured. Pharmacokinetic parameters associated with total plasma
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`reactivity and TCA-precipitable radioactivity were derived and reported in Tables
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`7.1 and 7.2. These tables are reproduced below.
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`28
`Ex. 1007 at 193-97.
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`1.
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`The Reported Monkey Pharmacokinetic Data Reflect
`Iodine Radioactivity, Not GA Concentration
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`32.
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`Iodine-125 is a radioisotope of iodine which can be easily detected
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`due to its emission of gamma radiation.29 Iodine radiolabelling of proteins or
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`peptides generally involves attaching an iodine-125 atom to the aromatic ring of a
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`tyrosine residue.30 This technique is commonly used to study the fate of proteins
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`and other complex molecules that may otherwise be difficult to detect in the
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`relevant environment.31 Once iodinated, the molecule itself may be readily
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`detected, even when present in only small amounts, by measuring the radioactivity
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`emitted by the iodine-125 atom.32
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`33. While iodine radiolabelling can be a useful technique for measuring
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`low concentrations of complex molecules, it suffers from some well-known
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`drawbacks. First and foremost, the introduction of an iodine-125 atom into a
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`molecule can cause dramatic changes to the molecule’s chemical and biological
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`29
`Randall, et al., Approaches to the Analysis of Peptides, in PEPTIDE AND
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`PROTEIN DRUG DELIVERY (V. Lee, ed.) (1991) (Ex. 2103) at 22.
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`Id.
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`Id. at 20-22.
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`Id. at 21.
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`30
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`31
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`32
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`properties, e.g., how it interacts with enzymes and receptors in the body.33
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`Because of these differences, the iodine-labelled molecule often exhibit different
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`pharmacokinetic behavior than the natural molecule.34
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`34. Another drawback associated with iodine radiolabelling is that the
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`quantified species is not actually the iodinated molecule, but rather the
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`radioactivity emitted by the iodine itself.35 This distinction is of particular concern
`
`where either degradation of the molecule or deiodination is expected. In such
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`instances, the measured radioactivity may no longer reflect the concentration of the
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`iodinated parent molecule, but rather the total concentration of the iodinated parent
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`molecule plus any iodinated degradation products, including iodine-125 labeled
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`33
`Ex. 2103 at 22; H. Schmeisser, et al., Radioiodination of human interferon-
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`alpha2 interferes with binding of C-terminal specific antibodies. 238 J.
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`IMMUNOLOGICAL METHODS, 81-5 (2000) (Ex. 2050) at 1; YM Efimova, et
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`al., Changes in the secondary structure of proteins labeled with 125I: CD
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`spectroscopy and enzymatic activity studies, 264(1) J. OF RADIOANALYTICAL
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`AND NUCLEAR CHEMISTRY, 91-96 (2005) (Ex. 2051) at 1.
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`34
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`35
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`Ex. 2050 at 1; Ex. 2051 at 1; Ex. 2103 at 22.
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`Ex. 2103 at 21.
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`amino acids, and free iodide.36 Accordingly, the skilled pharmacologist
`
`understood that “studies on the kinetics, metabolism and elimination of proteins or
`
`peptides which employ an 125I-label should be interpreted cautiously.”37
`
`35.
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`Some techniques exist to minimize the extent of this overestimation.
`
`For example, it is known that proteins and large peptides generally precipitate from
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`trichloroacetic acid (“TCA”).38 By adding TCA to a sample containing the
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`radiolabelled molecule of interest and collecting the precipitate, smaller
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`degradation products may be removed. While an improvement, this technique still
`
`relies upon measuring total radioactivity in the sample (albeit, a sample that has
`
`had smaller molecules removed), and therefore is likewise unable to distinguish
`
`between the radiolabelled parent molecule, larger degradation products that retain
`
`the iodine label, and the iodine label attached to other large molecules.39
`
`36
`Ex. 2103 at 21; Wroblewski VJ. Mechanism of deiodination of 125I-human
`
`growth hormone in vivo. Relevance to the study of protein disposition. Biochem
`
`Pharmacol. 1991 Jul 25;42(4):889-97 (Ex. 2079) at 1, 8.
`
`37
`
`38
`
`Ex. 2079 at 5.
`
`Zellner M, Winkler W, Hayden H, Quantitative validation of different
`
`protein precipitation methods in proteome analysis of blood platelets,
`
`Electrophoresis, 26, 2481–2489 (2005) (Ex. 2092) at 1, 8.
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`39
`
`Ex. 2103 at 21.
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`36. As it relates to the monkey pharmacokinetic data reported in the
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`SBOA, it is important to note that the monkeys were injected not with GA, but
`
`rather with iodine-125 radiolabelled GA.40 For the reasons explained above, the
`
`skilled pharmacologist would have understood that the introduction of an iodine
`
`radiolabel into GA could greatly influence its pharmacokinetic properties. This
`
`issue was in fact identified by the SBOA reviewer as a “problem” associated with
`
`the methodology, who stated that “125I-labelling is known to change the PK
`
`properties of a peptide.”41 The skilled pharmacologist would have therefore
`
`understood that the pharmacokinetic results reported in the SBOA were not
`
`necessarily reflective of the pharmacokinetics of GA, and would therefore have
`
`had no reason to expect GA to possess these same pharmacokinetic parameters.
`
`37.
`
`The skilled pharmacologist would have further understood that these
`
`data were not even reflective of the pharmacokinetics of iodinated GA.
`
`38.
`
`Table 7.1 reports pharmacokinetic data derived from the measurement
`
`of total plasma radioactivity.42 As explained above, total radioactivity measures
`
`the concentration of all present iodinated species. While the injected molecule is
`
`purported to be iodine-125 radiolabelled GA, it was known that GA was subject to
`
`40
`Ex. 1007 at 197.
`
`Id. at 149.
`
`Id. at 197.
`
`41
`
`42
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`rapid degradation upon subcutaneous injection.43 It was further known that
`
`iodinated molecules were subject to enzymatic deiodination in vivo, whereby the
`
`iodine atom would be removed by deiodinases, resulting in free iodide.44 The free
`
`iodide ion could then be incorporated into naturally-occurring proteins, for
`
`example, thyroglobulin and albumin.45 Thus, the skilled pharmacologist would
`
`have understood that the total radioactivity present in the plasma reflected a
`
`combination of intact iodinated GA and iodinated degradation products, including
`
`any degradant that retained the iodine label, free iodide, and free iodide that had
`
`been reincorporated into other proteins. This understanding is confirmed by the
`
`reviewer’s comments in the SBOA.46
`
`39.
`
`Pharmacokinetic parameters calculated from these plasma
`
`radioactivity measurements would therefore not reflect the pharmacokinetics of
`
`iodinated GA, but rather would reflect a combination of the pharmacokinetic
`
`
`43
`Ex. 2012 at 3.
`
`44
`
`45
`
`Ex. 2079 at 8.
`
`J. Vijlder, Primary congenital hypothyroidism: defects in iodine pathway.
`
`EUROPEAN JOURNAL OF ENDOCRINOLOGY, 149, 247-256 (2003) (Ex.
`
`2102) at 2, 5.
`
`46
`
`Ex. 1007 at 149, 152.
`
`
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`19
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`parameters of all of these species. The skilled pharmacologist would therefore not
`
`have expected GA to possess the pharmacokinetic properties reported in Table 7.1.
`
`40.
`
`Table 7.2 reports pharmacokinetic data derived from the measurement
`
`of TCA-precipitable radioactivity.47 Like the previous table, these data were
`
`derived by measuring radioactivity of monkey plasma samples following
`
`subcutaneous administration of iodinated GA.48 The difference between the data in
`
`the two tables is that the radioactivity measurements underlying Table 7.2 were of
`
`the TCA-precipitable portion of the plasma.49 As explained above, the process of
`
`TCA precipitation would have removed some of the iodinated impurities, e.g.,
`
`small degradation products, thus reducing the measured radioactivity. However,
`
`the skilled pharmacologist would have understood that the radioactivity measured
`
`for the TCA-precipitable fraction still did not reflect iodinated GA, but rather a
`
`combination of intact iodinated GA and larger iodinated degradation products, as
`
`well as free iodide that had been reincorporated into other plasma proteins.50 The
`
`skilled pharmacologist would have therefore recognized that the pharmacokinetic
`
`parameters derived from these measurements, including the half-life, were not
`
`47
`Id. at 197.
`
`Id.
`
`Id.
`
`Id. at 152, 198.
`
`48
`
`49
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`50
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`reflective of iodinated GA, but rather a combination of the pharmacokinetic
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`parameters of all of these species.
`
`41.
`
`Because the pharmacokinetic data reported for the monkey studies in
`
`the SBOA are derived from measurements of radioactivity, the skilled
`
`pharmacologist would have understood, as the SBOA reviewer did, that these data
`
`do not reflect the pharmacokinetic properties of GA, but rather of a complex
`
`combination of iodinated species.51 This is true for both total plasma radioactivity
`
`and TCA-precipitable radioactivity. Indeed, with respect to human PK data, the
`
`reviewer concluded that “the Sponsor actually has little or no idea what the plasma
`
`drug concentration would be in humans with subcutaneous administration of
`
`[GA].”52
`
`42.
`
`The skilled pharmacologist would therefore not have expected the
`
`half-life reported in Table 7.2 to reflect the half-life of GA, and would have had no
`
`reason to rely upon these data to predict whether a dosage regimen for the
`
`subcutaneous administration of GA to humans would have been successful for
`
`treating RRMS.
`
`
`51
`Id. at 198.
`
`52
`
`Id. at 280-81.
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`2.
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`The Reported Monkey Pharmacokinetic Data are Internally
`Inconsistent
`
`43.
`
`The skilled pharmacologist also would not have expected the TCA-
`
`precipitable half-life data reported for the monkey in the SBOA to reflect the half-
`
`life of GA for the additional reason that the data itself would have been considered
`
`inadequate for predicting pharmacokinetic behavior.
`
`44. A fundamental rule in deriving a half-life of a chemical species in
`
`plasma is that the plasma samples from which the half-life is derived should cover
`
`a time period of at least three half-lives.53 It was well known by August 20, 2009,
`
`that using a shorter sampling period could lead to a “very misleading” half-life
`
`estimate.54 Dr. Peroutka concludes that the SBOA monkey data reports a half-life
`
`of 80 hours.55 However, plasma samples were only taken from the monkeys
`
`through 72 hours.56 The skilled pharmacologist would not have considered an 80
`
`hour half-life derived from only 72 hours of data to be reliable, and therefore
`
`
`53
`PL Toutain PL and Bousquet-Mélou A., Plasma terminal half-life, 27(6) J.
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`VETERINARY PHARMACOLOGICAL THERAPY, 427-39 (2004) (Ex. 2052) at
`
`12.
`
`54
`
`55
`
`56
`
`
`
`Id.
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`IPR2015-00643, Ex. 1003 at ¶ 131; IPR2015-00644, Ex. 1003 at ¶ 138.
`
`Ex. 1007 at 197.
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`22
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`would not have expected GA to have a half-life of 80 hours based on the SBOA
`
`data. I understand that Dr. Peroutka testified at his deposition that samples must be
`
`taken over at least one half-life in order to accurately estimate half-life.57 Even
`
`under this less stringent criteria, the skilled pharmacologist would consider the
`
`monkey pharmacokinetic data reported in the SBOA insufficient for estimating
`
`half-life.
`
`45.
`
`The skilled pharmacologist also would have recognized that the
`
`monkey pharmacokinetic data reported in the SBOA was internally inconsistent.
`
`This inconsistency would have caused the skilled pharmacologist to further
`
`question the reliability of the reported pharmacokinetic data.
`
`46.
`
`Tables 7.1 and 7.2 report pharmacokinetic data for total plasma
`
`radioactivity and TCA-precipitable radioactivity respectively. Among these are
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`Cmax (the maximum concentration), Tmax (the time of maximum concentration) and
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`t1/2 (ha
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