UNITED STATES PATENT AND TRADEMARK OFFICE
`______________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________________
`APOTEX INC., APOTEX CORP., ARGENTUM PHARMACEUTICALS LLC,
`ACTAVIS ELIZABETH LLC, TEVA PHARMACEUTICALS USA, INC., SUN
`PHARMACEUTICAL INDUSTRIES, LTD., SUN PHARMACEUTICAL
`INDUSTRIES, INC., AND SUN PHARMA GLOBAL FZE,
`Petitioners,
`V.
`NOVARTIS AG,
`Patent Owner.
`______________________
`Case IPR2017-008541
`U.S. Patent No. 9,187,405
`______________________
`DECLARATION OF JEROLD CHUN, M.D., PH.D.
`
`
`Mail Stop Patent Board
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`ALEXANDRIA, VA 22313-1450
`
`
`
`
` 1 Cases IPR2017-01550, IPR2017-01946, and IPR2017-01929 have been joined
`with this proceeding.
`
`
`
`
`
`Apotex v. Novartis
`IPR2017-00854
`NOVARTIS 2098
`
`
`______________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________________
`APOTEX INC., APOTEX CORP., ARGENTUM PHARMACEUTICALS LLC,
`ACTAVIS ELIZABETH LLC, TEVA PHARMACEUTICALS USA, INC., SUN
`PHARMACEUTICAL INDUSTRIES, LTD., SUN PHARMACEUTICAL
`INDUSTRIES, INC., AND SUN PHARMA GLOBAL FZE,
`Petitioners,
`V.
`NOVARTIS AG,
`Patent Owner.
`______________________
`Case IPR2017-008541
`U.S. Patent No. 9,187,405
`______________________
`DECLARATION OF JEROLD CHUN, M.D., PH.D.
`
`
`Mail Stop Patent Board
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`ALEXANDRIA, VA 22313-1450
`
`
`
`
` 1 Cases IPR2017-01550, IPR2017-01946, and IPR2017-01929 have been joined
`with this proceeding.
`
`
`
`
`
`Apotex v. Novartis
`IPR2017-00854
`NOVARTIS 2098
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`
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`I, Jerold Chun, M.D., Ph.D., declare as follows:
`
`I.
`
`Introduction
`I am a non-practicing M.D. and neuroscientist currently running a lab
`1.
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`at the Sanford Burnham Prebys Medical Discovery Institute. Among other things, I
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`research drugs like fingolimod that affect the sphingosine 1-phosphate (SIP)
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`signaling system in the body. I was a co-author of the Webb reference (Ex. 2014)
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`and headed the department and analyzed data from scientists who conducted the
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`experiments Webb reports. Novartis has asked me to address the declaration of
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`pharmacologist Dr. Leslie Z. Benet in this matter (Ex. 1047), focusing in particular
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`on Dr. Benet’s interpretation of the Webb reference.
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`2.
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`In Webb, my research team and I reported on experiments we
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`conducted with fingolimod while at Merck Research Laboratories. We tested
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`fingolimod (also called FTY720, or just FTY) in an accepted multiple sclerosis (MS)
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`animal model, the experimental autoimmune encephalitis (EAE) system. (Ex. 2014
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`at 108.) Our version of EAE used mice and had several unique features that I discuss
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`below.
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`3.
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`Before we did our experiments, multiple papers had reported that
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`fingolimod was a novel immuno-modulator. Scientists believed fingolimod worked
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`primarily by interacting with the sphingosine pathway in the body to induce
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`lymphocytes to die or to remain in lymph nodes and out of circulating blood.
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`IPR2017-00854
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`Unpublished data at the time supported the involvement of S1P receptors, which
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`could be involved in the disruption of lymphocyte trafficking and egress from lymph
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`nodes. This in turn could reduce the number of pathogenic, circulating lymphocytes
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`available to participate in an adverse immune system reaction, such as by attacking
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`a newly-transplanted organ or the body’s own tissues as part of an autoimmune
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`disease.
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`4.
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`This mechanism for modulating the immune system was unlike any
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`others that had been discovered before. Prior immuno-modulators had acted
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`primarily either by killing immune system cells or inhibiting their multiplication in
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`the body in response to a stimulus. Emerging data suggested that fingolimod instead
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`was involved in redirecting trafficking of immune system cells within the body. (Id.)
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`Given ambiguity and uncertainties about this new apparent mechanism of action,
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`much was unknown about fingolimod’s potential use in humans for treating MS.
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`5. When we conducted the experiments reported in Webb from 2000-
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`2002, reducing the number of lymphocytes circulating in the blood had already been
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`reported as a likely marker of efficacy in organ transplant experiments. 2 One of our
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` 2 Dr. Benet and others in this proceeding call this mechanism “lymphocyte
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`suppression.” At the time, we called this mechanism “lymphopenia,” or
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`2
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`U.S. Patent No. 9,187,405
`goals was to assess whether the same measure would be useful for MS. We
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`concluded that lymphocyte suppression was an effective albeit incomplete marker
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`of likely efficacy for the disease, and that “a threshold of about 70% depletion of
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`peripheral lymphocytes was required to see any efficacy” in the SJL mouse EAE
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`model system. (Ex. 2014 at 118.).
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`6.
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`Dr. Benet does not appear to question our general conclusion that
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`lymphocyte suppression could be a useful efficacy marker so long as suppression
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`surpassed a minimum threshold. Dr. Benet instead questions what that threshold
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`was. He argues that Webb data shows that only 60% suppression was required for
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`efficacy, not 70%. He bases that conclusion on the paper’s description of the average
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`effects of one dose in one group of tested mice. (Ex. 1047 at ¶¶ 40-48).
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`7.
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`Dr. Benet appears to have misunderstood our paper. Our conclusion
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`that 70% suppression was needed for “any efficacy” was the product of our
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`collective judgment based on a totality of data presented in our paper. The average
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`effect of one dose in one group of mice was just one piece of data. We also assessed
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`the effects of different doses in individual mice; the ability of a dose to produce
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`“lymphocyte sequestration.” I will use the terminology Dr. Benet adopted in his
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`declaration. My understanding is that the terms “lymphocyte suppression,”
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`“lymphopenia,” and “lymphocyte sequestration” are synonymous here.
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`U.S. Patent No. 9,187,405
`sustained clinical improvement; and other facts to reach our conclusions. As those
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`with experience running EAE experiments know, the model has a subjective aspect
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`that requires judgment-calls when interpreting results. Among other reasons, this is
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`due to the inherently imprecise scoring system used to evaluate a clinical level of
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`disease in tested rodents, as I discuss further below.
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`8.
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`The nine researchers on our team concluded that about 70%
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`suppression was needed for any efficacy in EAE, and the peer reviewers at the
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`Journal of Neuroimmunology did not question that conclusion. Our goal had been
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`to find a lymphocyte level that assured a clear and reproducible efficacy signal with
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`FTY720 treatment. In this model, 70% and 60% are close and generally consistent
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`with “about 70%” stated in our Discussion. In other words, our conclusion that about
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`70% reduction in peripheral blood lymphocyte levels was required for any efficacy
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`was not a mistake; it was the result of collective judgment based on multiple data
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`sources and an appreciation of the subjective nature of determining clinical scores
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`in this model. Dr. Benet’s critique of that judgment misunderstands the EAE system,
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`and our paper.
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`9.
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` I elaborate upon these issues further below, after first setting out my
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`background and research experience.
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`II. Experience and Qualifications
`I am currently a Professor and Senior Vice President, Neuroscience
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`Drug Discovery at Sanford Burnham Prebys (SBP) Medical Discovery Institute in
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`La Jolla, CA. I conduct basic and translational research and oversee development
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`of neuroscience programs having commercial and/or philanthropic potential. I am
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`also an Adjunct Professor in the Departments of Pharmacology and Neuroscience at
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`the University of California at San Diego (UCSD) School of Medicine, and in the
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`Department of Molecular and Cellular Neuroscience at The Scripps Research
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`Institute (TSRI).
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`11.
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`I received my M.D. and Ph.D. (Neuroscience) degrees through the
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`Medical Scientist Training Program at Stanford University School of Medicine.
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`After receiving my degrees, I was a Helen Hay Whitney Postdoctoral Fellow at the
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`Whitehead Institute
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`for Biomedical Research–Massachusetts Institute of
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`Technology.
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`12.
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`I then joined the faculty at the UCSD School of Medicine, where I
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`became Professor of Pharmacology and Neurosciences and directed
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`the
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`Neurosciences Graduate Program. While at UCSD, my laboratory identified the first
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`receptor for what are now known as lysophospholipid receptors that include S1P
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`receptors. I subsequently became Senior Director and Department Head of
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`Molecular Neuroscience at Merck Research Laboratories, and later returned to
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`academia as Professor at TSRI, before my current position at SBP.
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`13.
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`I have authored more than 300 scientific papers and am recognized in
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`Thomson Reuters’ World’s Most Influential Scientific Minds citation list. I am also
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`a member of numerous editorial, advisory, and review boards; and I have received
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`many awards, including from the NIH, Alfred P. Sloan Foundation, The
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`Klingenstein Fund, and The March of Dimes.
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`14. While at Merck, I worked extensively with fingolimod (FTY720). At
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`the time, Merck had a program to try to develop a competing immuno-modulator
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`that interacted with the S1P system. As noted above, I headed the department of
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`Molecular Neuroscience and was lead scientist on S1P projects for neuroscience
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`applications and in that connection was involved in studying fingolimod intensely.
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`Some of that work is published in the Webb paper.
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`15. After leaving Merck, I remained involved with fingolimod as a
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`professor of Molecular Biology at TSRI. At that time, TSRI had a major research
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`relationship with Novartis Institute of Biomedical Research (NIBR). NIBR
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`supported my research on fingolimod mechanisms of action (MOAs), particularly
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`involving use of S1P receptor “knock-out” mice that I had generated in my academic
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`laboratory. My laboratory has continued to perform MOA studies on fingolimod
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`and other S1P receptor modulators.
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`U.S. Patent No. 9,187,405
`16. My work here has been to aid counsel in interpreting Webb, and provide
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`technical and historical perspective on what was known at the time about FTY720
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`(fingolimod), its effects, and MOAs. I have spent approximately 12 hours working
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`on this project as of the date of my declaration.
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`III. Analysis
`In addressing Dr. Benet’s opinions, I first provide a background on
`17.
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`EAE models, and our plan for using EAE to test certain hypotheses in our Webb
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`experiments. I then describe how we conducted our studies, and our finding that
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`fingolimod had to suppress “about 70%” of the circulating lymphocytes to provide
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`“any efficacy.” I conclude in addressing Dr. Benet’s apparent misunderstandings of
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`the biological limitations of using EAE and differences between single data points
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`vs. ultimate conclusions.
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`A. The EAE Model of RRMS
`18. EAE experiments are generally conducted in rodents, typically rats or
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`mice. EAE models simulate aspects of MS by introducing myelin-related peptides
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`or proteins via immunization, prompting an immune response in the immunized
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`rodent. Lymphocytes become sensitized to the foreign peptides or proteins,
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`whereupon they recognize and attack the host animal’s own nervous system tissue
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`that shares immunologically recognized antigens and epitopes. This process is a T
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`cell-driven disease that only partially recapitulates MS, and it requires the entry of
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`pathogenic T cells into the CNS after which clinical signs occur after several days
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`post-immunization. Typical signs include tail-droop, weakness, lethargy, paralysis
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`to various degrees, or even death. (See Webb, Ex. 2014 at 109-10.)
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`19. Through these mechanisms, the EAE system mimics certain aspects of
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`human MS. For instance, in MS, as in EAE, subsets of the patient’s own immune
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`cells attack her/his central nervous system (CNS) to produce demyelination and
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`neurodegeneration, though in MS the analogous CNS dysfunctions occur over a far
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`longer period of time (decades compared to weeks in EAE rodents), and generally
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`to a lesser degree (for instance, MS usually is not considered a fatal disease, whereas
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`EAE can be fatal to rodents). (See id. at 109, 118.)
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`20. As described in Webb, at least two prior papers had reported on
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`fingolimod EAE studies in rats. (Id. at 109 (citing Ex. 2008, Brinkman 2002, and
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`Ex. 1028, Fujino).) The models in those papers were “monophasic;” that is, they
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`gave rise to a single bout of clinical disability following immunization with the
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`peptide/protein in the tested animal. Using that model, both studies had tested
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`fingolimod’s ability to prevent EAE “prophylactically,” i.e., when the drug was
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`given simultaneously with the foreign proteins, before disease signs had developed.
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`EAE requires T cell entry into the CNS to produce clinical disease. Thus, any agent
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`preventing CNS entry would nullify initiating EAE disease, a scenario never
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`U.S. Patent No. 9,187,405
`encountered in human MS (since a patient must first present with clinical symptoms
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`before treatment is initiated).
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`21. We wanted to conduct experiments more clinically relevant to human
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`relapsing-remitting MS (RRMS), the most common form of MS. In this disease,
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`attacks usually occur in a relapse-remission-relapse pattern over time (rather than
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`only once), typically over a period of years. We consequently adopted a
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`“multiphasic” or relapsing-remitting EAE model, in which multiple repeated attacks
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`were separated by periods of remission. (Ex. 2014 at 118.) In addition, we sought
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`to test fingolimod not only prophylactically but also therapeutically, after symptoms
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`developed in the tested mice. (Id. at 109, 114.) That would allow us to assess
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`fingolimod’s performance in a context more akin to actual clinical practice, where
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`patients present with symptoms after RRMS has already taken hold.
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`B. Our Experiments and Conclusions
`22. Webb describes our methods. For the primary studies, we injected
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`“SJL” mice with a 20 amino acid residue synthetic peptide matching sequences on
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`a mouse myelin protein (PLP) plus pertussis toxin. The peptide induced EAE while
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`the toxin amplified the disease to facilitate measurement of a drug’s effects. We
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`divided mice into control and test groups. In addition, we had another control group
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`given just pertussis toxin (and not PLP), to allow us to determine the toxin’s effects
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`on certain measurements that I address below. (Id. at 115.)
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`23. We administered two different forms of fingolimod to the tested mice.
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`In some experiments, we administered fingolimod orally in a water mixture. In other
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`experiments, we administered fingolimod-phosphate (FTY-P) by injection.
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`Research had shown that fingolimod was a “pro-drug” that became active in the
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`body only upon being phosphorylated in vivo to form the active agent, FTY-P.
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`(Brinkman 2002, Ex. 2008 at 21454-56; Fujino, Ex. 1028 at 76.) By giving FTY-P
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`by injection, we sought to reduce the risk that our results would be colored by
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`complications of prodrug metabolism in the mouse digestive system or elsewhere.
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`(Webb, Ex. 2014 at 114.)
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`24. After inducing EAE, we weighed afflicted mice and assessed their
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`clinical disease daily using a scoring system similar what other EAE studies had
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`used:
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`• 0 = healthy mouse
`• 1 = flaccid tail
`• 2 = hind limb weakness
`• 3 = paralysis of one or both hind limbs
`• 4 = forelimb paralysis
`• 5 = death
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`(Id. at 110.)
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`25. As can be seen, this scoring system requires fundamentally subjective
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`judgment on the part of a research team. Even with careful observation and training
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`of individuals scoring disease, natural variation in the behavior of the tested mice
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`can make drawing precise mouse clinical scoring difficult, especially for scores less
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`than 3. We would euthanize mice that became completely paralyzed (i.e., were
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`scored as a “4” on our scale). (Id.)
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`26. We recorded results for individual mice in spreadsheets, a standard
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`operating procedure for EAE, although we only reported averaged results for groups
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`of mice in our paper, which is also standard. (See id. at 114-17.) We did not report
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`the results from individual mice, nor would the Journal have provided the space
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`needed to do so. But we did make clear that the results in individual mice could vary
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`substantially from the average, as they almost always do in EAE.
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`27. As we reported, the mice in our experiments suffered “[m]ortality …
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`from between about 10% and 30%.” Mouse deaths received a clinical score of 5,
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`but the average clinical scores we reported throughout the paper were consistently
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`below 5. (See, e.g., id. at 112.) As a result, the distribution of results ranged above
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`and below the averages, often to a substantial degree. For instance, if a group of
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`four mice were scored at the widely varying levels 1, 2, 4, and 5, their average
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`response would be reported as a “3.”
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`28. We tested a variety of doses in different experiments. Most pertinent
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`here, we tested FTY-P doses of 0.03 mg/kg; 0.3 mg/kg; and 1.0 mg/kg in groups of
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`four mice each, excluding replicates. We administered the drug starting 14 days
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`after injecting the PLP peptide to induce EAE, when symptoms from the first EAE
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`attack were at their peak. We continued administering the drug for 12 days,
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`measured average clinical score per day for each group, and also totaled the clinical
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`scores for each group over the 12-day administration period. We then compared the
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`results to an averaged control group that received no treatment. (Id. at 114-115.)
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`29. The results are set out in Figure 5. Our analysis showed that 0.03 mg/kg
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`had no statistically significant effect on average clinical scores over the 12-day
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`period we assessed; that 0.3 mg/kg had a statistically significant effect in that same
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`period; and that 1.0 mg/kg had a greater significant effect. In addition, Figure 5(A)
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`shows that the highest dose administered—1.0 mg/kg—produced a sustained effect
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`on clinical scores even after dosing was terminated on day 25, and thus was not
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`subject to the naturally occurring relapses and remissions of the SJL model (e.g.,
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`PLP controls, Figs. 5A, 8A). (Id. at 115-17.)
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`30. We also measured lymphocyte levels in the treated and untreated mice,
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`and reported averaged results for each dosing group. This analysis was complicated
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`by the fact that mice are small animals. Only limited samples of blood can be
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`collected beyond which adverse events occur. As the paper reports, we took only
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`three measurements during the 12-day course of treatment—at the beginning,
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`middle, and end—plus two measurements after treatment was finished. (See id. at
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`110.)
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`31. Another complication was that pertussis toxin alone elevates average
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`lymphocyte levels, as we described in the paper. (Id. at 115.) The elevated levels
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`dissipated over the course of several weeks. This made measuring peripheral blood
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`lymphocyte reductions from baseline a challenge; the baseline itself moved during
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`the course of the experiment as a result of pertussis toxin and other variables (noted
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`below). We attempted to correct for this variation by using a control group of mice
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`that had received pertussis toxin alone—but not PLP—as establishing the baseline
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`level of lymphocytes against which we assessed suppression in the treated EAE
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`mice. (Id.)
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`32. Our results are shown in Figure 6. As with Figure 5, Figure 6 shows a
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`clear dose-response relationship—higher fingolimod doses suppressed lymphocytes
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`to a greater degree than lower doses. In addition, Figure 6(C) shows a correlation
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`between lymphocyte suppression and a reduction in cumulative clinical scores over
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`the 12-day period when the drug was being administered. The four conditions
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`represented by bar-graphs each correspond to the average suppression for the control
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`or one of the three dose groups we tested.
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`33. As averaged data, these figures do not report on variation among
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`individual mice in lymphocyte suppression and moreover are presented as standard
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`error of the mean (see 2.2 Lymphopenia assays) that obfuscates individual
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`variability. Any given dose could have a widely varying effect on lymphocyte levels
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`in any given mouse. Some mice would respond to lower doses with higher
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`suppression, and vice versa. These differences in how individual mice responded to
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`FTY-P were thus obscured by statistical use of standard error of the mean.
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`34. However, those individual observations did inform our overall
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`conclusion that “a threshold of about 70% depletion of peripheral lymphocytes was
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`required to see any efficacy[.]” (Id. at 118.) It is common in academic papers to
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`report conclusions like this in the Discussion. Practical constraints imposed by
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`journals prevent the publication of all the underlying data, such as data from each
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`individual mouse. We thus highlighted the basic conclusion of “about 70%” in the
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`Discussion to inform the readers.
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`35. We submitted our findings to the Journal of Neuroimmunology and
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`underwent a rigorous peer review process that involved at least 2 external peer
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`reviewers and further revisions and reviews before acceptance. The reviewers did
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`not question our conclusion that about 70% suppression was required in our model.
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`Our paper was published in 2004. To my knowledge, our conclusion that about 70%
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`suppression is needed for efficacy in SJL EAE has never been retracted or criticized
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`in any peer-reviewed paper.
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`C. Dr. Benet’s Apparent Misunderstandings
`36. Dr. Benet makes two mistakes in his reading of Webb. First, he
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`incorrectly argues that our conclusion that about 70% suppression was needed for
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`any efficacy was not supported by our data. Second, he mistakenly argues that our
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`paper suggests maximum suppression at 70% is enough for efficacy, rather than
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`sustained average suppression at that level.
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`37.
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`In support of his argument that the Webb data do not support the
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`conclusion that about 70% suppression was needed for any efficacy, Dr. Benet points
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`to the average effects of the 0.3 mg/kg dose reported in Figures 5 and 6. That dose
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`on average suppressed clinical scores to a statistically significant degree, but on
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`average also suppressed lymphocytes by about 60%. From this, Dr. Benet concludes
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`that our data showed that 60% suppression had efficacy, less than the 70% we
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`concluded was needed in the discussion section of our paper. (Ex. 1047. At ¶¶ 42-
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`48.)
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`38. The subjective nature of EAE clinical scoring renders distinctions of
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`“about 70%” and 60% virtually moot. Our goal was to provide – in our concluding
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`statements in the Discussion – conclusions that could be examined and reproduced
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`by others. Those conclusions were not based solely on the averages reported in
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`Figures 5 and 6 in isolation. Rather, we drew our conclusions using all of our data
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`that included individual mice. We saw a striking pattern in that data that only mice
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`with about 70% or greater suppression in lymphocytes compared to baseline showed
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`sustained clinical efficacy produced by drug exposure. This was true regardless of
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`dose for individual mice, although more mice reached about 70% with increasing
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`dose.
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`39. Other considerations informed our judgment too. “Efficacy” was a
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`qualitative and subjective judgment based not only on clinical score reduction, but
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`also on other assessments like survival. For instance, a reduction in score from 5
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`(death) to 4 (paralysis) would reduce average clinical scores, but would be of
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`questionable “efficacy” for our purposes; mice with a score of 4 were euthanized.
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`These judgment calls were affected by both the time of scoring (e.g., at one day a
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`sick animal could be a 3, but a day later could be found dead and become a 5), and
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`the decision to euthanize a sick, weakened animal, with an ambiguous paralysis (e.g.
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`an animal with a score of 3 that later develops into a 4 is euthanized)—these
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`differences could produce a clinical score swing of 40% (from 3 to 5), underscoring
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`the subjective nature of the EAE model and the important role of judgment in coming
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`to our final conclusions.
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`40. We also considered whether a mouse cohort showed sustained clinical
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`improvement after dosing was finished in making our judgment. As shown in Figure
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`5(A), the highest dose tested kept clinical symptoms in check for several days even
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`after administration ceased. (Ex. 2014 at 115.) That phenomenon was examined in
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`individual mice at different dosing levels in an effort to determine lymphocyte
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`levels, albeit with rough temporal resolution reflecting blood draw limitations. We
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`IPR2017-00854
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`considered this fact, too, in assessing efficacy—the connection between lymphocyte
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`suppression and sustained clinical improvement even after dosing ceased.
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`41.
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`In short, the EAE model is a subjective experimental model that
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`requires significant judgment to employ: this is not dissimilar to the practice of
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`medicine, particularly related to MS. We based our judgment that fingolimod
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`needed to suppress lymphocytes by about 70% based upon multiple criteria. The
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`average suppression and clinical score reduction levels of 60% Dr. Benet cites are
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`entirely consistent with our conclusion. The data Dr. Benet cited were but one
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`considered variable that lead to our ultimate conclusion.
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`42. Dr. Benet makes one other important error in reading Webb. He
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`concludes that our 70% benchmark should be assessed only against maximum
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`suppression levels, rather than average suppression. (Ex. 1047 at ¶ 53.) This theory
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`appears to second guess our conclusions without access to the actual underlying data;
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`and perhaps without the EAE experimental experience of the co-authors. Dr. Benet
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`erroneously over-interprets the noted Figures in our paper. Our presentation of
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`suppression at specific time points was merely a way one presents data in SJL EAE
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`experiments and are simply experimental norms.
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`43. To measure sustained average suppression—a much more accurate
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`assessment that would also capture known circadian variation in lymphocyte
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`numbers—we would have had to measure suppression for the entire dosing period
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`IPR2017-00854
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`in real-time. Such measurements may not even be feasible today, and were
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`absolutely not possible when the work was pursued and published. Even hourly
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`measurements would have been impossible since we could not bleed mice, which
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`have small blood volumes, to obtain sufficient volume for lymphocyte
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`measurements without bleeding to death. Thus, we were only able to measure
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`suppression levels at three points during dosing—the beginning, the middle, and the
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`end. That does not mean we concluded that only maximum suppression on only one
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`day was the relevant benchmark for efficacy. Our data permitted no conclusion on
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`that point.
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`44. However, I would expect that sustained suppression would be needed
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`for efficacy in humans, given the far longer and more unpredictable disease course
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`in MS as compared to EAE. I understand from counsel that this point will be
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`addressed further by Dr. Lawrence Steinman.
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`*
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`*
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`*
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`45. Under penalty of perjury, all statements made herein of my own
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`knowledge are true, and I believe all statements made herein on information and
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`belief to be true. I have been warned and am aware that willful false statements and
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`the like are punishable by fine or imprisonment or both under Section 1001 of Title
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`18 of the United States Code.
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`46.
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`IPR2017-00854
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`In signing this Declaration, I understand that it will be filed as evidence
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`in a contested case before the Patent Trial and Appeal Board of the United States
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`Patent and Trademark Office. I acknowledge that I may be subject to cross-
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`examination in the case and that cross-examination will take place in the United
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`States. If cross-examination is required of me, I will appear for cross-examination
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`within the United States during the time allotted.
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`March 22, 2018
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`______________________________
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`Jerold Chun, M.D., Ph.D.
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