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 LAWRENCE STEINMAN, M.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 2022
`
`
`______________________
`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 LAWRENCE STEINMAN, M.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 2022
`
`
`
`TABLE OF CONTENTS
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`Introduction and Summary ........................................................................... 1
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`Experience and Qualifications ..................................................................... 5
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`The June 2006 State of the Art and the Invention ........................................ 9
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`A. Multiple Sclerosis ......................................................................................... 9
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`B. Existing MS Therapies in June 2006 ......................................................... 14
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`C. Fingolimod ................................................................................................. 16
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`D. Research into Fingolimod Dosing as of June 2006 .................................... 21
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`i. Transplant Studies .............................................................................. 22
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`ii. Fingolimod EAE Studies .................................................................... 33
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`iii. Kappos 2005—Phase II Human MS Study ........................................ 44
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`E. The Invention and Patent ............................................................................ 46
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`F. Later Data Confirming the Invention’s
`Surprising Results ....................................................................................... 53
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`Analysis of the Petition .............................................................................. 55
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`
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`A. The Person of Skill and Claim Construction .............................................. 56
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`B. The Obviousness Grounds ......................................................................... 60
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`i. Teaching Away and Unexpected Results ........................................... 60
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`ii. Ground 1: Kovarik and Thomson ...................................................... 73
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`iii. Ground 2: Chiba, Budde, Kappos 2005 ............................................. 82
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`C. The Anticipation Ground: Kappos 2010 ................................................... 84
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`Conclusion .................................................................................................. 87
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`ii
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`I, Lawrence Steinman, M.D., declare as follows:
`
`
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`Introduction and Summary
`1.
`I am a physician with thousands of current and former multiple sclerosis
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`patients; a researcher with over 550 publications related to neurological and
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`immunological disorders; a professor at Stanford University; and a member of the
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`National Academy of Sciences. I set out my full experience and qualifications
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`below. I submit this declaration for Patent Owner Novartis AG in opposition to
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`Petitioners’ challenge to U.S. Patent No. 9,187,405.
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`2.
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`The ’405 Patent claims a method of dosing the drug fingolimod for
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`patients with Relapsing-Remitting Multiple Sclerosis (RRMS). Novartis scientists
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`Peter Hiestand and Christian Schnell discovered that doses less than half those
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`previously thought effective could help victims suffering from the disease. Novartis
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`applied for a patent in June 2006, and the U.S. Patent and Trademark Office (PTO)
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`awarded claims to a 0.5 mg daily dose. Novartis sells fingolimod at that dose for
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`RRMS under the brand-name Gilenya®.
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`3.
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`Petitioners challenge the PTO’s award of the Patent. Petitioners say
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`references published before June 2006 would have made a 0.5 mg daily dose obvious
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`to someone with skill in the field. In addition, the Patent’s specification allegedly
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`does not support parts of the claims, which Petitioners say opens the Patent to
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`challenge as anticipated by a paper published after June 2006. In support of their
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`challenges, Petitioners rely on a declaration from an MS clinician, Dr. Barbara
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`Giesser. (Ex. 1002.) The Petitions’ challenges are misguided.
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`4.
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`By June 2006, research had shown that fingolimod could suppress the
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`immune system by sequestering white blood cell lymphocytes in lymphatic tissue
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`away from the blood stream. Scientists believed this mechanism might protect
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`against organ rejection and/or autoimmune diseases by reducing the number of
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`circulating lymphocytes available to attack transplanted organs or the body’s own
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`tissues. One such autoimmune disease was RRMS, in which the body’s immune
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`system attacks the central nervous system (CNS).
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`5.
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`Studies showed, however, that only substantial lymphocyte suppression
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`provided any clinical benefit. Multiple papers reported that at least 80% reduction
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`was needed to reduce organ rejection. Another paper—“Webb”(Ex. 2014)—found
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`in an established RRMS model that “a threshold of about 70% depletion of
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`peripheral lymphocytes was required to see any efficacy[.]” (Id. at 118.) Less
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`suppression correlated with no clinical benefit. Human studies further showed that
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`only daily doses of 1.0 mg or higher could suppress lymphocytes to these levels.
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`Lower doses could not, including 0.5 mg daily. Hence, the literature in June 2006
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`taught that 0.5 mg daily would not be effective for RRMS.
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`6.
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`Hiestand and Schnell adopted a fresh perspective to discover otherwise.
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`They used inventive techniques with an accepted MS model to focus later in the
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`disease than others had considered. Their experiments showed that doses almost
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`60% lower than the minimum doses in other studies could still provide a clinical
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`benefit. In other words, the inventors discovered that prior studies’ minimum doses
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`were more than double what was actually needed. Hiestand and Schnell further
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`discovered a novel marker of disease progression that validated their dosing
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`regimen, the drug’s inhibition of new blood vessel growth (a process called
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`“angiogenesis”). In 2010, the publication of human clinical trial results would
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`confirm that 0.5 mg daily could treat RRMS, reduce relapses, and slow disease
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`progression. None of this was obvious to a person of skill in June 2006.
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`7.
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`In arguing otherwise, Petitioners and Dr. Giesser do not address the data
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`showing that only doses higher than 0.5 mg daily could suppress lymphocytes
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`enough to affect RRMS. They instead argue that any amount of fingolimod
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`previously shown to suppress lymphocytes to any degree would have been an
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`obvious therapy. This is not correct. Prior studies repeatedly showed that only
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`substantial suppression provided a clinical benefit, and that much more than 0.5 mg
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`daily was needed to suppress lymphocytes enough in humans to be therapeutic.
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`Petitioners’ references say nothing different.
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`8.
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`For instance, in Ground 1, Petitioners cite “Kovarik” (Ex. 1004), a 2004
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`application for a patent on a loading dose regimen for drugs like fingolimod. A
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`“loading dose” is a higher dose administered before lower regular doses. The
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`invention here excludes loading doses, which generally are not used with MS drugs
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`anyway. Kovarik is thus inapplicable. Regardless, Petitioners argue that illustrative
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`examples in Kovarik presage the invention. But these examples merely describe
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`hypothetical daily dose ranges for unspecified diseases to illustrate Kovarik’s
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`loading dose method. They prescribe no particular daily dose in any actual disease.
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`To a person of skill, such generalized hypotheticals about an unspecified condition
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`would never trump the published dosing data specifically relevant to RRMS.
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`9.
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`In Ground 2, Petitioners say the “Kappos 2005” (Ex. 1007) report on
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`fingolimod’s human MS Phase II clinical trial results would have pointed to 0.5 mg
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`daily. This again is mistaken. The Phase II trial only tested doses of 1.25 mg and
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`5.0 mg daily—2.5x and 10x higher than the dose the inventors here discovered.
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`Kappos 2005 reports that 1.25 mg and 5.0 mg daily had similar therapeutic promise
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`for RRMS. (Id. at II/41.) While the doses’ similar efficacy was surprising, the
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`results still fit with the data showing that only doses 1.0 mg or higher would produce
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`therapeutic benefits—the lowest dose in the Phase II trial was above 1.0 mg daily.
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`Kappos 2005 said nothing about whether any dose lower than 1.0 mg would be
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`effective. As for Petitioners’ other references, “Budde” (Ex. 1008) was just a single-
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`dose safety study reporting data of limited use for a drug taken daily for a chronic
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`disease. And the Chiba patent (Ex. 1006) provided no information about specific
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`doses at all. For these and other reasons I detail below, none of Petitioners’
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`references presaged a 0.5 mg daily dose for RRMS.
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`10. Petitioners make a different argument in Ground 3. There they focus
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`on the parts of the Patent’s claims that exclude a loading dose regimen. Petitioners
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`say the Patent’s specification provides no support for excluding a loading dose,
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`which they argue opens the claims to challenge with the Phase III human trial results
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`in “Kappos 2010” (Ex. 1038). The premise, however, is flawed. The Patent
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`specification describes a RRMS dose of 0.5 mg “daily,” and nothing else. A person
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`of skill would read this description in context to mean once a day, no more and no
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`less. That dosing schedule necessarily excludes a loading dose. As Dr. Giesser
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`agrees, MS drugs do not employ loading doses, and the specification’s focus solely
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`on “daily” doses shows the inventors here contemplated none.
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`11.
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`I set forth my full analysis in the remainder of this declaration. I first
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`describe my experience and qualifications in more detail. I next describe the data
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`teaching away from the invention as of June 2006; the invention itself ; and the
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`surprising clinical trial results. I then address Petitioners’ arguments.
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` Experience and Qualifications
`12.
`I am a Stanford University professor in the Departments of Neurology
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`and Neurological Sciences, Pediatrics, and Genetics. I also hold the George A.
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`Zimmermann endowed chair as Professor of Neurology and Neurological Sciences
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`and Pediatrics at the Stanford University School of Medicine. I served as chair of
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`the Stanford University Interdepartmental Program in Immunology from 2003-2011.
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`13. Before joining the Stanford University faculty in 1980, I completed
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`residencies and internships at Stanford University Hospital. I also previously held a
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`postdoctoral fellowship in Chemical Immunology at the Weizmann Institute of
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`Science, where I worked with Dr. Michael Sela. At the time, Dr. Sela was
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`developing glatiramer acetate, an MS drug still in use today under the brand name
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`Copaxone®.
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`14. My medical degree is from Harvard University. I also served as a
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`National Institutes of Health Fellow in Chemical Neurobiology at Harvard
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`University.
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`15. My professional
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`interests
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`relate primarily
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`to neurology and
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`immunology. I also develop and test drug therapies for autoimmune conditions.
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`Aspects of my research led to the development of Tysabri® (natalizumab), an FDA-
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`approved antibody used for MS. I am also a MS specialist at the Stanford Multiple
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`Sclerosis Center where I regularly manage the long-term care of patients. Over the
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`course of my career, I estimate I have cared for about 4,000-5,000 MS patients.
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`16.
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`I have authored or co-authored over 550 academic publications,
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`including original peer-reviewed publications, reviews, and book chapters in the
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`field of neurology and immune biology. Many of my publications are directed to
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`understanding the mechanisms underlying the development and progression of MS,
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`and identifying related strategies for therapeutic intervention. I list my publications
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`in my CV, Exhibit 2023.
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`17.
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`I have served as a member and scientific advisor on many boards,
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`including for Centocor, Roche Biosciences, and Receptos SAB. Receptos is a San
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`Diego based company developing second generation selective sphingosine-1-
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`phosphate receptor modulators similar to fingolimod. I am also an advisory
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`committee member for non-profit institutions such as the National Academy of
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`Sciences and the National Academy of Medicine committee for Multiple Sclerosis
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`& Other Neurologic Disorders in Veterans of the Persian Gulf & Post-9/11 Wars.
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`18.
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`I have founded several companies focused on developing novel
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`therapeutic molecules for immune system conditions. Tolerion Inc. is a clinical-
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`stage biopharmaceutical that develops novel products for autoimmune diseases.
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`Atreca Inc. applies human immune response technology to identify new cancer
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`therapeutics. Cardinal Therapeutics Inc. seeks to develop MS therapies based on
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`anti-inflammatory compounds. I also founded Transparency Life Sciences, an open
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`innovation patient-centric company that develops drug candidates for immune-
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`related conditions.
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`19.
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`I am a named inventor on several patents, including therapeutic
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`methods for MS and other autoimmune diseases. Examples include U.S. Pat. Nos.
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`4,695,459; 6,531,130; 6,329,499; 6,740,638; 7,030,098; 7,070,780; and 8,252,775.
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`20.
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`I have received honors and awards for my work in immunosuppression,
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`such as (a) the 2004 John M. Dystel Prize from the American Academy of Neurology
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`and the National MS Society; (b) the 2011 Charcot Prize for Lifetime Achievement
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`in MS research; and (c) the 2015 Anthony Cerami Award in Translational Medicine
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`from the Feinstein Institute and Molecular Medicine. I have also twice received the
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`Senator Jacob Javits Neuroscience Investigator Award by the National Institute of
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`Neurological Diseases and Stroke.
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`21.
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`In 2009, I was elected to the Institute of Medicine, now known as the
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`National Academy of Medicine. In 2015, the National Academy of Sciences elected
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`me as a member. Our website describes membership as follows: “Members are
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`elected to the National Academy of Sciences in recognition of their distinguished
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`and continuing achievements in original research. Membership is a widely accepted
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`mark of excellence in science and is considered one of the highest honors that a
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`scientist can receive.” My election citation cites “groundbreaking discoveries on the
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`molecular basis for relapsing multiple sclerosis,” including identifying a protein that
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`“was critical for lymphocyte homing” to the brains of MS patients. That work
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`produced Tysabri, which the Academy characterized as “the most effective approved
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`therapy for MS.”
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`22.
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`I was first retained in this matter in July 30, 2016. In preparing my
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`testimony in this declaration, I have worked approximately 100 hours, including
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`many hours conducting my own research into the prior art. I also attended counsels’
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`deposition of Dr. Giesser on October 2, 2017. I have spoken with counsel and
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`reviewed and commented upon drafts they prepared based on our discussions. I have
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`thoroughly reviewed the contents of my final declaration and believe this document
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`accurately sets forth my views. I reserve the right to amend any part of my testimony
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`in the event of new information brought to my attention.
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` The June 2006 State of the Art and the Invention
`23.
`In June 2006, the medical community needed new medicines for MS, a
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`terrible affliction that strikes patients in the prime of life with debilitating, sometimes
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`disabling symptoms. Fingolimod was a promising immunosuppressant discovered
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`in the early 1990s that had been researched for a variety of conditions, including MS.
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`A. Multiple Sclerosis
`24. The Thomson reference Dr. Giesser cites summarizes general facts
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`about MS. (Ex. 1005, cited in, Giesser Dec., Ex. 1002 ¶¶ 81-88.) As of June 2006,
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`“[t]here [we]re about 2.5 million individuals with multiple sclerosis in the world,
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`and in the USA alone there [we]re about 350,000 affected patients. Multiple
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`sclerosis develops in twice as many women as men and age at onset of the disease
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`is usually 20-30 years.” (Ex. 1005 at 158 (citation omitted).) As Thomson describes,
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`“[t]he symptoms of multiple sclerosis are diverse and can include tremor, paralysis,
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`loss of bladder or bowel control, fatigue, pain, loss of cognitive function,
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`disturbances in vision and speech, emotional changes, and nystagmus.” (Id.) I agree
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`with Thomson that “[t]hese symptoms can have a profound effect on patients’
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`quality of life and can also lead to significant reliance on their family, dependents,
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`and carers [sic].” (Id.; see also Virley, Ex. 1016 at 638 (“Functional impairment,
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`disability, and handicap are expressed as paralysis, sensory and cognitive
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`disturbances, spasticity, tremor, lack of coordination, and visual impairment. All
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`these symptoms significantly impact on the quality of life of the individual.”).)
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`25. Scientists in June 2006 recognized four forms of MS: RRMS;
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`Secondary Progressive MS; Primary Progressive MS; and Progressive Relapsing
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`MS. The Patent describes each (Ex. 1001 at 9:64-10:16), as does Thomson (Ex.
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`1005 at 159). (See also Giesser Dec., Ex. 1002 ¶ 49 (“There are four types of
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`multiple sclerosis, relapsing remitting, secondary progressive, primary progressive,
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`and progressive relapsing[.]”) (parenthetical abbreviations omitted).) RRMS is by
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`far the most common, accounting for 85% of MS cases. (Thomson, Ex. 1005 at 159;
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`Giesser Dec., Ex. 1002 ¶ 49.) Although disease classifications have changed
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`somewhat since 2006, RRMS is still recognized as a separate disease course today.
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`26.
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`In June 2006, researchers did not know what initially causes MS, and
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`we still do not. The disease involves two of the most complex systems in the human
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`body, the immune and central nervous systems. Thomson observes that “[p]ossible
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`triggers for the initial inflammatory insult include an autoimmune response (initiated
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`by autoreactive T lymphocytes) or a structural alteration in the white matter as a
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`result of microbial infection.” (Thomson, Ex. 1005 at 159.)
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`27. Whatever the initial cause, it is clear the disease progresses when
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`lymphocytes, including T-cell lymphocytes, are activated to attack central nervous
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`system tissue, especially the myelin coating surrounding axon nerve cells. (See
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`Katoaka, Ex. 1029 at 440 (“The etiology of MS remains unknown, but is widely
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`considered to involve the organ specific autoimmune destruction of CNS myelin
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`mediated by myelin-specific T cells.”).) I agree with Dr. Giesser (Ex. 1002 ¶ 50)
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`that inflammation from this process triggers MS symptoms. That ultimately results
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`in “demyelination” and axon loss. (Thomson, Ex. 1005 at 159.) In turn, “[t]his leads
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`to the presence of characteristic multifocal sclerotic plaques in the white matter of
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`the central nervous system. These lesions are particularly common in the optic
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`nerves, and white matter tracts of the periventricular regions, brain stem, and spinal
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`cord[.]” (Id.)
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`28. The “Virley” reference (Ex. 1016), cited in Dr. Giesser’s declaration
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`(Ex. 1002 ¶ 19), includes a schematic that depicts the process:
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`(Ex. 1016 at 639.)
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`29. As Thomson describes, RRMS manifests via “clearly defined disease
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`relapses with full recovery or with sequelae and residual deficit upon recovery. On
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`average, about 1.5 attacks occur each year and approximately 10 new lesions are
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`detected annually on MRI scan[s.]” (Ex. 1005 at 159.) Moreover, “[a]lthough
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`RRMS is not classified as a progressive form of multiple sclerosis, residual deficits
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`may occur after each exacerbation.” (Id.) Thomson depicts this progression in this
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`chart:
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`12
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`(Id.)
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`30. While attacks average 1.5 per year, wide differences exist among
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`individuals in attack frequency, duration, symptoms, severity, and residual effects.
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`Dr. Giesser agreed in her deposition that the disease manifests in individual patients
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`in widely different ways. (Ex. 2039 at 32:12-18; 37:14-38:3.) That poses a
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`challenge in assessing any therapeutic intervention for an individual patient. An
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`apparent positive turn could simply be the result of natural variation in disease
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`progression, rather than due to the therapy.
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`31. A reference Dr. Giesser cites summarizes this issue well: “Everyone
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`working in any area of multiple sclerosis research is confronted by the profound
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`variability of the disease. Clinically the manifestations are unpredictable, as is the
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`course and response to treatment.” (McAlpine’s, Ex. 2047 at 667.)2 As a result,
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`“[m]ajor differences are seen between patients” in various aspects of the disease.
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`(Id.) Virley says a version of the same thing: “Due to the fluctuating nature and
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`breadth of symptoms, robust measurement of the clinical manifestations of MS is
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`problematic.” (Ex. 1016 at 639.)
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`32.
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`In clinical practice, medical doctors typically see a patient only after
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`the disease has begun. MS generally cannot be predicted and addressed
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`prophylactically. Therapy thus starts only after the disease has progressed. Dr.
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`Giesser agreed in her deposition that patients usually begin therapy after the disease
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`has manifested symptoms. (Ex. 2039 at 35:18-36:20.) Patients thus will already
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`have multiple CNS lesions, and likely have had one or more symptomatic episodes.
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`B.
`Existing MS Therapies in June 2006
`33. Virley describes that, in 2005, “[t]he treatment of MS [was] still in its
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`infancy with limited therapeutic options, where the main-stay therapies involve the
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`utility of corticosteroid and immunosuppressive interventions.” (Ex. 1016 at 641.)
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`So, too, in June 2006.
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` 2 Dr. Giesser submitted only selections from McAlpine’s. The passage I cite above
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`is from a section she did not submit. It thus has a new Exhibit number.
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`34. Available RRMS drugs fell into two broad categories—those that
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`treated disease symptoms, and “disease modifying therapies” or “DMTs.” Symptom
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`treatments included steroids that could reduce the severity of a relapse. These
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`therapies generally are not thought to affect relapse rates or disease progression.
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`DMTs, in contrast, included drugs like interferon beta and glatiramer acetate. Some
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`of these drugs had been shown to reduce relapse rates, while others had been shown
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`also to reduce various measures of disease progression.
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`35.
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`In her deposition testimony, Dr. Giesser agreed that these aspects of the
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`disease are different, i.e., symptom management differs from reducing relapses
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`which differs from slowing disease progression. As she explained, some therapies
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`will work for one of these aspects of the disease but not others. (Ex. 2039 at 32:22-
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`33:19 (exercise therapy effect “primarily on symptom management[,]” but “[t]here
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`are no studies to date that show exercise has an effect on relapses”; a “disease
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`modifying therapy” can “affect the occurrence of relapses[,]” while “[s]ome disease
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`modifying therapies have been shown to impact some metrices of progression”).)
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`36. One of Dr. Giesser’s references, McAlpine’s, similarly separates
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`therapies into those that treat symptoms and those that modify the disease’s course.
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`Within the class of DMTs, some have “[t]he immediate aim … to inhibit disease
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`activity,” i.e., relapses, but some also may “limit the accumulation of disability and
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`prevent the onset of disease progression.” (Ex. 2047 at 805.)
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`37. Thomson, too, distinguishes among these various aspects of MS drug
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`therapies: “The aim of treatment of multiple sclerosis is to reduce the frequency
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`(and limit the lasting effects) of relapses, relieve symptoms, [and] prevent disability
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`arising from disease progression[,]” among other goals. (Ex. 1005 at 160.) As
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`Thomson describes, “[t]he management of multiple sclerosis has greatly benefited
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`from the availability of five [approved] disease-modifying agents[.]” (Id.) In
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`addition to those therapies, “[o]ther therapies may be used to alleviate some of the
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`chronic symptoms of the disease[.]” (Id.) As for the difference between reducing
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`relapses and slowing progression, Thomson explains that “[a]ll of the [DMTs] for
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`the treatment of RRMS have been shown to reduce relapse rates[.]” (Id.) In
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`addition, some had “achieved reductions in sustained disability progression[.]” (Id.)
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`38. Virley describes a similar pattern. Steroids are “extensively used in MS
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`for promoting a hastened recovery following a period of an acute attack[,]” i.e., to
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`treat symptoms. (Ex. 1016 at 641.) In contrast, interferon-beta is a DMT that has
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`been shown to cause a “one third reduction in relapse rate” but only “a tendency for
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`a reduction in the number of patients with observed progression of disability.” (Id.
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`at 642.)
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`C.
`Fingolimod
`39. Scientists discovered fingolimod in the early 1990s while researching
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`compounds derived from myriocin, an immunosuppressive substance in certain
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`fungi. Fingolimod is also called “FTY720,” or sometimes just “FTY.”3 The patent
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`for fingolimod and related myriocin derivatives describes how these compounds
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`could suppress transplant rejection and autoimmune disease in animal models. (Ex.
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`2007, U.S. Patent No. 5,604,229.)
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`40. Members of the research team that discovered fingolimod would later
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`identify one way the drug suppresses the immune system: “In experimental animals,
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`FTY rapidly and transiently reduces circulating mature lymphocytes in peripheral
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`blood[.]” (Budde, Ex. 1008 at 1073.) Dr. Kenji Chiba received a patent for this
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`discovery in 1998, the “Chiba” patent at issue in this proceeding. That patent
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`describes how fingolimod “directs lymphocytes to the peripheral lymph nodes,
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` 3 In her declaration, Dr. Giesser says the literature uses “FTY720” and “FTY” to
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`describe only the drug’s hydrochloride form. (Ex. 1002 ¶ 56.) That is different
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`than her deposition testimony, in which is said those terms are used to describe
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`fingolimod alone. (Giesser Dep., Ex. 2039 at 17:10-17 (“Q: And do you also
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`understand that fingolimod had a prior name in literature, which was FTY720?
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`A: I understand that their use is pretty synonymous. FTY20 [sic] means
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`fingolimod. Q: And do you understand sometimes researchers in the literature
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`have referred to FTY720 as simply ‘FTY’? A: Yes.”).) I agree with Dr.
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`Giesser’s deposition testimony on this point.
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`mesenteric lymph nodes, and Peyer’s patches. By reversibly sequestering
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`lymphocytes in these tissues, the compounds can inhibit an immune response[.]”
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`(Chiba, Ex. 1006, Abstract.)
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`41. Researchers thereafter consistently identified this mechanism as central
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`to fingolimod’s effects. Thomson said that “[r]esults from a number of clinical
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`studies have
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`shown
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`that FTY720 produces profound and
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`reversible
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`immunomodulation following oral administration. The mechanism of action of
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`FTY720 leads to a reversible redistribution of lymphocytes from the circulation to
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`secondary lymphatic tissue.” (Ex. 1005 at 162.) The “Dumont” reference similarly
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`says “[a] striking feature of the in vivo action of fingolimod, invariably observed in
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`the aforementioned studies, was the induction (at immunosuppressive doses) of a
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`marked decrease in the number of peripheral blood lymphocytes (PBLs).” (Ex. 1018
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`at 238.) Given this effect, many scientists believed that “[t]he resulting lymphocyte
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`sequestration is a convenient surrogate marker of the pharmacodynamic effect of
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`FTY720 and may be a useful parameter for monitoring the immunomodulatory
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`effect of the drug in the clinic.” (Thomson, Ex. 1005 at 162.)
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`42. Early data showed that higher amounts of fingolimod tended to yield
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`more lymphocyte suppression and better therapeutic results. For instance, Chiba
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`Figure 11 shows lymphocyte blood counts in rats for doses of 0.1 mg/kg, 1.0 mg/kg,
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`and 10 mg/kg. (Ex. 1006 at Sheet 8 of 11; id. at col. 10 l. 1-8.) Lymphocyte counts
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`were consistently lower at higher doses:
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`43. The following chart from the “Xie” paper (Ex. 2053) similarly shows
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`greater suppression in rats as doses escalate from 0.01 mg/kg; 0.03 mg/kg; 0.1
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`mg/kg; and 0.3 mg/kg:
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`(Id. at 3664.)
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`44. With respect to therapeutic benefit, Dr. Chiba published a 1998 paper
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`reporting on animal organ rejection experiments. (Ex. 2034.) The data show higher
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`fingolimod doses delayed organ rejection longer than lower doses:
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`(Id. at 5038.)
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`45. Similar data is in the Chiba patent (Ex. 1006). For instance, the
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`following figure shows increasing transplant graft survival with escalating doses:
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`(Id. at Sheet 1 of 11.)
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`46. The early research thus pointed toward using higher doses to suppress
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`more lymphocytes to produce better therapy. Subsequent research fleshed out how
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`fingolimod might achieve these results. Papers in 2002 showed fingolimod is a “pro-
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`drug” that becomes active only after being phosphorylated in the body into FTY-P.
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`(Brinkman 2002, Ex. 2008 at 21454-56; Fujino, Ex. 1028 at 76.) That metabolite
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`then can interfere with cellular signaling systems involving sphingosine-1
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`phosphate. (Id.) Among other things, these systems help signal lymphocytes to exit
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`lymphatic tissue and enter the blood stream. (Brinkman 2002, Ex. 2008 at 21454-
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`56; Dumont, Ex. 1018 at 239 (“S1P1 receptors, which are expressed on lymphocytes
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`and endothelial cells, appear to be the most important S1P receptors with regard to
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`the immunosuppressive action of fingolimod.”).)
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`D. Research into Fingolimod Dosing as of June 2006
`47. Multiple teams ultimately investigated fingolimod as a potential human
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`therapy, first in transplant rejection studies and then in MS models. These
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`researchers often used lymphocyte suppression as a biomarker for the drug’s
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`pharmacological effects. These studies confirmed the earlier research that higher
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`doses would suppress lymphocytes to a greater degree. But the studies showed also
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`that only substantial lymphocyte suppression—70-80% or more—correlated with
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`therapeutic benefit.
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`i.
`Transplant Studies
`48. Researchers first studied fingolimod as a renal transplant rejection drug.
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`Those studies produced voluminous human pharmacokinetics
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`(PK) and
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`pharmacodynamics (PD) data about the drug’s behavior. PK measures how the body
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`processes a drug, and PD measures how the drug affects the body. (See also Giesser
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`Dep., Ex. 2039 at 27:13-24 (“Pharmacokinetics is basically what your body does to
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`the drug [and] … pharmacodynamics is what the drug do
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