UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________________________
`
`SAWAI USA, INC. AND
`SAWAI PHARMACEUTICAL CO., LTD.
`Petitioners,
`
`v.
`
`BIOGEN MA, INC.
`Patent Owner.
`_______________________________
`
`Patent No. 8,399,514
`_______________________________
`
`Inter Partes Review IPR2019-00789
`_______________________________
`
`EXPERT DECLARATION OF ROBERT WALTER BAUMHEFNER, M.D.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 8,399,514
`
`137978264v1
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`Sawai (IPR2019-00789), Ex. 1056, p. 001
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`TABLE OF CONTENTS
`
`Page
`
`I.
`
`II.
`III.
`IV.
`V.
`
`QUALIFICATIONS AND BACKGROUND ................................................. 5
`A.
`Education and Experience; Prior Testimony......................................... 5
`B.
`Bases for Opinions and Materials Considered ...................................... 6
`C.
`Scope of Work ....................................................................................... 6
`SUMMARY OF OPINIONS ........................................................................... 7
`LEGAL STANDARDS .................................................................................10
`PERSON OF ORDINARY SKILL IN THE ART ........................................11
`THE ’514 PATENT (EX. 1001) ....................................................................12
`A.
`Claims of the ’514 Patent .................................................................... 12
`VI. CLAIM CONSTRUCTION ..........................................................................14
`VII. BACKGROUND ...........................................................................................15
`A. Multiple Sclerosis ................................................................................ 15
`B. Multiple Sclerosis Therapies ............................................................... 20
`VIII. SCOPE AND CONTENT OF THE PRIOR ART REFERENCES ..............22
`A.
`Schimrigk 2004 Abstract ..................................................................... 22
`B.
`Schimrigk 2004 Poster ........................................................................ 24
`C.
`Brune 2004 .......................................................................................... 25
`D.
`Schimrigk 2005 Abstract ..................................................................... 26
`E.
`Kappos 2005 ........................................................................................ 27
`F.
`January 2006 Biogen Press Release .................................................... 28
`G. May 2006 Biogen Press Release ......................................................... 29
`H.
`Kappos 2006 ........................................................................................ 30
`I.
`WO ’342 .............................................................................................. 31
`J.
`Nieboer 1990 ....................................................................................... 32
`K.
`Schimrigk 2006 ................................................................................... 34
`L. Mrowietz 2005 .................................................................................... 35
`M.
`Fumaderm® Label .............................................................................. 36
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`N. Ockenfels 1998 .................................................................................... 37
`O.
`de Jong 1996 ........................................................................................ 38
`P.
`Nibbering 1993 .................................................................................... 39
`Q.
`Clinical Trials ...................................................................................... 40
`R.
`ICH Guidelines .................................................................................... 40
`S.
`Joshi Patents ........................................................................................ 41
`T.
`Biogen 2005 Press Release ................................................................. 42
`U. Ormerod 2004 ...................................................................................... 43
`V. Mrowietz 1998 .................................................................................... 44
`W. Additional prior art references and knowledge ................................... 44
`IX. UNPATENTABILITY OF THE ’514 PATENT ..........................................45
`A.
`The Claims of the ’514 Patent are Obvious over the January
`2006 Biogen Press Release in view of the Schimrigk 2004
`Abstract................................................................................................ 45
`1.
`Independent Claims 1, 11, 15, and 20. ......................................45
`2.
`Dependent Claims .....................................................................62
`The Claims of the ’514 Patent are Obvious over Kappos 2006
`in view of the Schimrigk 2004 Abstract ............................................. 66
`1.
`Independent Claims 1, 11, 15, and 20. ......................................66
`2.
`Dependent claims ......................................................................74
`The Claims of the ’514 Patent are Obvious over Kappos 2006
`in view of WO ’342 ............................................................................. 74
`1.
`Independent Claims 1, 11, 15, and 20 .......................................74
`2.
`Dependent claims ......................................................................76
`The Claims of the ’514 Patent are Obvious over Kappos 2006,
`Clinical Trials, Joshi ’999, and ICH Guidelines ................................. 76
`1.
`Independent Claims 1, 11, 15, and 20 .......................................76
`2.
`Dependent claims ......................................................................82
`
`B.
`
`C.
`
`D.
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`Sawai (IPR2019-00789), Ex. 1056, p. 003
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`
`
`E.
`
`There Are No Secondary Considerations of Nonobviousness ............ 82
`1.
`The invention claimed in the ’514 patent did not achieve
`unexpected results .....................................................................82
`The invention claimed in the ’514 patent did not fill a long-felt
`but unmet need. .........................................................................89
`
`2.
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`Sawai (IPR2019-00789), Ex. 1056, p. 004
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`
`1. My name is Robert Walter Baumhefner, M.D. I have been retained by
`
`counsel for Sawai USA, Inc. and Sawai Pharmaceutical Co., Ltd. (“Sawai”). I
`
`understand that Sawai intends to petition for inter partes review (“IPR”) of U.S.
`
`Patent No. 8,399,514 (“the ’514 patent”), Ex. 1001, which is assigned to Biogen MA
`
`Inc. I also understand that Sawai will request that the United States Patent and
`
`Trademark Office cancel all claims of the ’514 patent as unpatentable in such IPR
`
`petition. I submit this expert declaration, which addresses and supports Sawai’s IPR
`
`petition for the ’514 patent.
`
`II. QUALIFICATIONS AND BACKGROUND
`
`A. Education and Experience; Prior Testimony
`
`2.
`
`I received my B.A. in Biochemistry from the University of California
`
`in 1970 and my M.D. from Northwestern University in 1974. I did a residency in
`
`Neurology at Harbor General Hospital from 1975-1978 and was a Research Fellow
`
`in Multiple Sclerosis from 1978-1980. In 1980, I became a Staff Physician at VA
`
`West Los Angeles Medical Center, where I am still employed today as an Instructor
`
`and Attending Neurologist.
`
`3.
`
`I served as Chairman of the Clinical Advisory Committee of the Los
`
`Angeles Chapter of the National Multiple Sclerosis Society from 1995-1999, Co-
`
`director of the National Neurological Research Specimen Bank at the VA West Los
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`Angeles Healthcare from 2002 to today and Chairman of the Veteran’s
`
`Administration Special Interest Group Research Committee from 1998-2005.
`
`4.
`
`I also teach a clinical elective in neurology at UCLA Medical School
`
`and a neurology lecture for rehabilitation at VA West Los Angeles Medical Center.
`
`5.
`
`I have received numerous fellowships and funding as shown in Exhibit
`
`A.
`
`6.
`
`I am author of various articles and have presented at numerous
`
`conferences which can be seen in Exhibit A.
`
`7.
`
`In all, I have almost 30 post-residency years of practical and research
`
`experience specializing in the treatment of patients with MS and other neurological
`
`diseases, and in the field of neurology.
`
`8. My curriculum vitae is attached hereto as Exhibit A.
`
`B.
`
`9.
`
`Bases for Opinions and Materials Considered
`
`Exhibit B includes a list of the materials I considered, in addition to my
`
`experience, education, and training, in providing the opinions contained herein.
`
`C.
`
`Scope of Work
`
`10.
`
`I have been retained by Sawai as a technical expert in this matter to
`
`provide various opinions regarding the ’514 patent. I receive $500 per hour for my
`
`services and $250 per hour for travel time. No part of my compensation is dependent
`
`upon my opinions given or the outcome of this case. I do not have any affiliations
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`with Biogen MA Inc., or any affiliates presently known to me, or the named
`
`inventors on the ’514 patent.
`
`III. SUMMARY OF OPINIONS
`
`11.
`
`In my view, all of the claims of the ’514 patent are obvious over the
`
`Schimrigk 2004 Abstract and the January 2006 Biogen Press Release. The
`
`Schimrigk 2004 Abstract discloses that 360 mg/day and 720 mg/day of DMF dosed
`
`as Fumaderm® are efficacious doses of DMF for the treatment of MS. The claimed
`
`dosage (480 mg/day) falls squarely within the dose ranges disclosed in Schimrigk.
`
`The January 2006 Biogen Press Release reported on a study that tested 120 mg/day,
`
`360 mg/day, and 720 mg/day of DMF, and confirmed that DMF monotherapy is
`
`efficacious to treat MS. The claimed dosage of 480 mg/day is well within the range
`
`of doses that skilled artisans would have expected to be efficacious based on the
`
`prior art. Moreover, skilled artisans would have been motivated to optimize the
`
`dosing of DMF considering its well-known side effects (including flushing and
`
`gastrointestinal issues), and would have been motivated to seek a dose that would
`
`have easily allowed for twice daily dosing, such as 480 mg/day, to improve patient
`
`adherence. Additionally, considering background art that demonstrates that DMF
`
`was a well-known efficacious treatment for MS with a range of expected efficacious
`
`doses, optimizing the dose to 480 mg/day was obvious.
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`12. All of the claims of the ’514 patent are likewise obvious over the
`
`Schimrigk 2004 Abstract in view of Kappos 2006, for the reasons explained in detail
`
`below. Kappos 2006 confirms what skilled artisans already expected, that
`
`720 mg/day was an effective dose of DMF. The Kappos results provided additional
`
`motivation for skilled artisans to seek to optimize the dose, as well as additional data
`
`confirming a skilled artisan’s reasonable expectation of success.
`
`13. Additionally, the claims of the ’514 patent are obvious over Kappos
`
`2006 in view of WO ’342. As detailed above, Kappos 2006 discloses the elements
`
`of the claimed MS treatment method using DMF, but for the use of 480 mg/day of
`
`DMF. WO ’342 is a patent application that discloses just that: WO ’342 claims
`
`certain pharmaceutical compositions and details in its specification treating
`
`autoimmune diseases, including MS, with a variety of doses, including 480 mg/day
`
`of DMF. Kappos 2006 in view of WO ’342, considering the background art
`
`available to skilled artisans, confirms the obviousness of the ’514 patent claims.
`
`14.
`
`In my opinion, the claims are also obvious over Kappos 2006,
`
`Joshi ‘999, Clinical Trials and the ICH Guidelines. I understand the Patent Trial and
`
`Appeal Board (“PTAB”) has already found based on those references that “one
`
`having ordinary skill in the art would have had ample reason to use routine
`
`experimentation, including appropriate clinical trials, to determine the optimum
`
`doses for MS treatment.” Coalition for Affordable Drugs V LLC et al v. Biogen MA
`
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`Sawai (IPR2019-00789), Ex. 1056, p. 008
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`Inc., IPR2015-0119, Final Written Decision, Paper 63 at 26 (“Final Written
`
`Decision”). Moreover, the PTAB stated that “those working the field would have
`
`had sufficient reason to investigate doses between 720 mg/day and 360 mg/day in
`
`hopes of identifying [an] effective dose with fewer side effects.” Id. And finally, the
`
`PTAB found that “[t]hose working the art would have had a reasonable expectation
`
`of success in determining additional therapeutically effective doses.” Id. Based on
`
`my review of Kappos 2006, Joshi ’999, Clinical Trials, and the ICH Guidelines, and
`
`the materials from those proceedings, I agree with the PTAB’s findings related to
`
`motivation and a reasonable expectation of success and believe that the claims of the
`
`‘514 patent are obvious over Kappos 2006, Joshi ’999, Clinical Trials, and the ICH
`
`Guidelines. I understand that the PTAB ultimately did not find the claims
`
`unpatentable based on “unexpected results.” As detailed herein, there is scientific
`
`literature that was not in front of the PTAB previously that demonstrates that any
`
`similarity in efficacy between 480 mg/day of DMF and 720 mg/day of DMF was not
`
`unexpected. To the contrary, the literature confirms that a skilled artisan would have
`
`expected DMF doses of 480 mg/day and 720 mg/day to be similarly efficacious in
`
`treating MS.
`
`15. Finally, in my view, Patent Owner cannot demonstrate unexpected
`
`results. I understand that experts on behalf of Patent Owner have opined, for
`
`example, that it would have been unexpected that a 480 mg/day dose of DMF would
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`be similarly efficacious to a 720 mg/day dose of DMF. I disagree with that position
`
`because, as explained in detail below, it misreads the prior art and ignores other
`
`literature which makes clear that, it would be entirely expected that 480 mg/day
`
`would be similarly efficacious as 720 mg/day in treating MS. In sum, it is my
`
`opinion that all of the claims of the ’514 patent are obvious.
`
`IV. LEGAL STANDARDS
`
`16.
`
`In preparing and forming my opinions set forth in this declaration, I
`
`have been informed regarding the relevant legal principles. I have used my
`
`understanding of those principles in forming my opinions. My understanding of
`
`those principles is summarized below.
`
`17.
`
`I have been told that Sawai bears the burden of proving unpatentability
`
`by a preponderance of
`
`the evidence.
`
`
`
`I am
`
`informed
`
`that
`
`this
`
`“preponderance- of- the- evidence” standard means that Sawai must show that
`
`unpatentability is more probable than not. I have taken these principles into account
`
`when forming my opinions in this case.
`
`18.
`
`I have also been told that claims should be given their broadest
`
`reasonable interpretation in light of the specification from the perspective of a person
`
`of ordinary skill in the art.
`
`19.
`
`I am told that the concept of patent obviousness involves four factual
`
`inquiries: (1) the scope and content of the prior art; (2) the differences between the
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`claimed invention and the prior art; (3) the level of ordinary skill in the art; and
`
`(4) secondary considerations of non-obviousness.
`
`20.
`
`I am also informed that when there is some recognized reason to solve
`
`a problem, and there are a finite number of identified, predictable and known
`
`solutions, a person of ordinary skill in the art has good reason to pursue the known
`
`options within his or her technical grasp. If such an approach leads to the expected
`
`success, it is likely not the product of innovation but of ordinary skill and common
`
`sense. In such a circumstance, when a patent simply arranges old elements with each
`
`performing its known function and yields no more than what one would expect from
`
`such an arrangement, the combination is obvious.
`
`V.
`
`PERSON OF ORDINARY SKILL IN THE ART
`
`21.
`
`I have been informed by counsel that the obviousness analysis is to be
`
`conducted from the perspective of a person of ordinary skill in the art (a “person of
`
`ordinary skill” or “skilled artisan”) at the time of the invention.
`
`22.
`
`I have also been informed by counsel that in defining a person of
`
`ordinary skill the following factors may be considered: (1) the educational level of
`
`the inventor; (2) the type of problems encountered in the art; (3) prior art solutions
`
`to
`
`those problems; (4) rapidity with which
`
`innovations are made; and
`
`(5) sophistication of the technology and educational level of active workers in the
`
`field.
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`23. Here, a person having ordinary skill in the art would have had
`
`(1) several years’ experience in designing clinical studies to meet regulatory
`
`expectations or analyzing data from such studies; (2) an advanced degree (PhD, MD,
`
`PharmD) and training in clinical pharmacology or experience treating MS; and
`
`(3) experience with the administration or formulation of therapeutic agents, their
`
`dosing, and the literature concerning drug developmental study and design.
`
`VI. THE ’514 PATENT (EX. 1001)
`
`A. Claims of the ’514 Patent
`
`24.
`
`I have read the ’514 patent, entitled “Treatment for Multiple Sclerosis.”
`
`The ’514 patent was filed on Feb. 13, 2012, as application No. 13/372,426, claims
`
`priority to provisional application No. 60/888,921, filed on Feb. 8, 2007, and is a
`
`continuation
`
`of
`
`application No.
`
`12/526,296,
`
`filed
`
`as
`
`application
`
`No. PCT/US2008/0016012 on Feb. 7, 2008, now abandoned. I understand that the
`
`’514 patent claims a priority date of Feb. 8, 2007.
`
`25.
`
`I understand that Sawai is challenging claims 1-20. The ’514 patent
`
`includes 4 independent claims: claims 1, 11, 15, and 20.
`
`26.
`
`Independent claim 1 recites:
`
`A method of treating a subject in need of treatment for
`
`multiple sclerosis comprising orally administering to the
`
`subject in need thereof a pharmaceutical composition
`
`consisting essentially of (a) a therapeutically effective
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`amount of dimethyl fumarate, monomethyl fumarate, or a
`
`combination
`
`thereof,
`
`and
`
`(b)
`
`one
`
`or more
`
`pharmaceutically acceptable excipients, wherein
`
`the
`
`therapeutically effective amount of dimethyl fumarate,
`
`monomethyl fumarate, or a combination thereof is about
`
`480 mg per day.
`
`27. Dependent claims 2-10, and 17 depend from claim 1. Dependent
`
`claim 2 relates to the form of the pharmaceutical preparation. Dependent claims 3-5,
`
`and 8-10 relate to dosing schedules. Dependent claims 6-7 are limited to dimethyl
`
`fumarate or monomethyl fumarate respectively. Dependent claim 17 recites a
`
`limitation related to expression levels of NQO1.
`
`28.
`
`Independent claim 11 recites:
`
`A method of treating a subject in need of treatment for
`
`multiple sclerosis consisting essentially of orally
`
`administering to the subject about 480 mg of dimethyl
`
`fumarate, monomethyl fumarate, or a combination
`
`thereof.
`
`29. Dependent claims 12-14, and 18 depend from claim 11. Dependent
`
`claim 12 recites administering 480 mg of dimethyl fumarate to a subject. Dependent
`
`claims 13-14 claim dosing schedules. Dependent claim 18 recites a limitation
`
`related to expression levels of NQO1.
`
`30.
`
`Independent claim 15 recites:
`
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`A method of treating a subject in need of treatment for
`
`multiple sclerosis comprising orally administering to the
`
`subject pharmaceutical composition consisting essentially
`
`of (a) a therapeutically effective amount of dimethyl
`
`fumarate and (b) one or more pharmaceutically acceptable
`
`excipients, wherein the therapeutically effective amount of
`
`dimethyl fumarate is about 480 mg per day.
`
`31. Dependent claims 16 and 19 depend from claim 15. Dependent
`
`claim 16 recites a dosing schedule. Dependent claim 19 recites a limitation related
`
`to expression levels of NQO1.
`
`32.
`
`Independent claim 20 recites:
`
`A method of treating a subject in need of treatment for
`
`multiple sclerosis comprising treating the subject in need
`
`thereof with a therapeutically effective amount of
`
`dimethyl
`
`fumarate, monomethyl
`
`fumarate, or a
`
`combination thereof, wherein the therapeutically effective
`
`amount of dimethyl fumarate, monomethyl fumarate, or a
`
`combination thereof is about 480 mg per day.
`
`33. There are no dependent claims that depend from claim 20.
`
`VII. CLAIM CONSTRUCTION
`
`34.
`
`I understand that the claim terms used in the ’514 patent are to be
`
`understood according to their ordinary and customary meaning based on the broadest
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`reasonable construction in light of the specification of the patent in which they
`
`appear.
`
`VIII. BACKGROUND
`
`A. Multiple Sclerosis
`
`35. MS is a chronic, often debilitating inflammatory and neurodegenerative
`
`disease of the central nervous system (CNS). See, e.g., E. Frohman et al., “Multiple
`
`Sclerosis — The Plaque and its Pathogenesis” 354 New Eng. J. Med. 942-55 (2006)
`
`Ex. 1040. The average onset for MS is estimated to be 30 years of age, and the
`
`disease was previously estimated to affect approximately 400,000 individuals in the
`
`United States, although more recent estimates place the prevalence closer to one
`
`million. J. Miller, “The Importance of Early Diagnosis in Multiple Sclerosis” J.
`
`Manag.
`
`Care
`
`Pharm.
`
`S4-S11
`
`(2004)
`
`Ex.
`
`1041;
`
`https://www.nationalmssociety.org/About-the-Society/MS-Prevalence Ex. 1042.
`
`36. The CNS is composed of the brain, optic nerves, and the spinal cord,
`
`and it operates to transmit information between the brain and the body and within
`
`the brain and spine. Information is communicated throughout the nervous system
`
`via electrical and chemical signals sent and received by nerve cells, known as
`
`neurons. Neurons are composed of three parts: (1) a cell body—the location for
`
`most of the main systems within the cell; (2) an axon—a cable-like structure that
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`may be short or long, but leads to connections with other nerves; and (3) dendrites—
`
`the actual connections to other neurons and related supportive cells.
`
`37. Many CNS axons are enclosed in myelin sheaths, the main function of
`
`which is to enhance the speed of neural transmission. For the CNS to function
`
`properly, myelin must be present.
`
`38. While, as of February 2007, when the provisional application to the
`
`’514 patent was filed, the cause of MS was under investigation, the best conclusion
`
`was that MS lesions in the CNS resulted from an inflammatory attack by a
`
`misdirected immune system against CNS structures and cells. Ex. 1040 (Frohman)
`
`at 942-3. This includes significant damage to the myelin wrapping, resulting in
`
`demyelination, and dropout of neurons and supportive cells. Moreover, this damage
`
`leads to numerous ongoing, and often permanent neurological symptoms such as
`
`numbness, incoordination, weakness, fatigue, loss of balance, walking difficulty,
`
`paralysis, blurred vision, sexual dysfunction, and loss of bowel and bladder control.
`
`Symptoms can be unpredictable and vary in both type and severity in the same
`
`patient over time, and from one person to another.
`
`39. As of February 2007, patients with MS generally experienced MS in
`
`two broad ways: (1) new relapses, or worsened symptoms that arise over hours to
`
`days and are followed by complete or incomplete remissions of symptoms over
`
`weeks to months; or, (2) slow progression or worsening of symptoms over months
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`to years, with or without superimposed relapses. In addition, there may be clinical
`
`quiescence, either between relapses, or with no relapses and no progression,
`
`especially as individuals age. In general, MS may be thought of as developing
`
`through different phases, with relapses being most prominent when patients are
`
`young, and slow progression of symptoms most commonly as people age. Most
`
`typically, the first relapse or attack of symptoms, the clinically-isolated syndrome
`
`(CIS), occurs when people are in their 20’s or 30’s. This heralds recurrent, typically
`
`different relapses and remissions, the relapsing-remitting multiple sclerosis (RRMS)
`
`phase. As patients age, and with a mean onset around 40-45 years, the majority of
`
`RRMS patients enter a period of slow progressive MS symptoms, with or without
`
`superimposed relapses. For those with prior relapses, the progressive phase is
`
`referred to as secondary progressive multiple sclerosis (SPMS). A small minority
`
`of patients, however, have onset of slowly progressive symptoms without prior
`
`relapses, typically in their 40’s, and this is referred to as primary progressive (PPMS)
`
`or progressive-onset MS.
`
`40.
`
`In February 2007, and still today, diagnosing and monitoring MS
`
`included subjective as well as objective analyses. Objective methods for diagnosing
`
`and monitoring MS included: the neurological examination, magnetic resonance
`
`imaging (MRI), analysis of cerebrospinal fluid for evidence of immune systems
`
`dysfunction, and use of electrical studies such as visual evoked potentials.
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`Subjective measures would include: the detailed history of relapses and progression
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`of symptoms noted by the patient. Other potential conditions would be ruled out by
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`an analysis of history, neurological examination and use of other blood and
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`radiographic tests. For research purposes, objective evaluations would include:
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`assessing frequency of relapses, the degree and rate of disability progression using
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`the Expanded Disability Status Scale (EDSS) or ambulation index (AI). See, e.g., S.
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`Rich et al., Stepped-Care Approach to Treating MS: A Managed Care Treatment
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`Algorithm,” 10(3) J. Manag. Care Pharm. S26-S32 (2004) Ex. 1043. These
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`objective assessment methods were often combined with a patient’s subjective
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`assessment of possible new relapses or progression of symptoms. Id.
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`41. MRI scans have enhanced the early diagnosis of MS and revolutionized
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`our understanding of the basic pathophysiology of the disease. MS lesions are
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`detected via MRI using T1 and T2 weighted sequences to produce variable images,
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`and are seen in a pattern of locations which distinguish these lesions from those that
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`are produced by other conditions or are simply nonspecific. T2 weighted MRI scans
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`show the total number of lesions. The MS lesions show up as hyperintense
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`abnormalities or “bright spots.” Hyperintense T2 lesions can be caused by a number
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`of conditions, including, for example, damage to small blood vessels as with
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`vascular disease or migraine; loss or damage to myelin due to toxins, inflammation
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`or metabolic deficiencies; and breaches of the blood-brain barrier (BBB) between
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`the brain and the circulation system. T2 lesions evolve over time, first being
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`relatively large and then shrinking, and can rarely “disappear.”
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`42.
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`In comparison, an MRI scan using T1 weighted sequences produces
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`images appearing hypointense, as so-called “black holes,” reflecting areas of severe
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`damage to the CNS. Only a subset of T2 lesions will become T1 black holes, which
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`represent areas of permanent myelin and axonal damage or loss.
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`43. As with many other radiographic images in medicine, the use of
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`contrast agents enhances the utility of brain and spine scans in the diagnosis and
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`monitoring of MS. Gadolinium is a rare earth metal with paramagnetic qualities
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`which allow it to be seen in the CNS and other organs after IV injection and under
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`the conditions of a T1 set of MRI sequences. Normally, however, in the CNS its
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`size precludes entrance past the BBB. Thus, unless there is damage to the BBB, the
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`contrast is simply processed and removed from the body. If, however, there is
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`damage to the BBB, the contrast may leak into the brain or spine and be seen as a
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`bright area in and around the lesion. This is referred to as enhancement, or being
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`Gd+. Gd+ lesions are most prominent early in the evolution of a lesion, and are felt
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`to reflect acute inflammation. Only a subset of T2 lesions in MS will also be seen
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`as Gd+ on the T1 images, and the enhancement typically resolves by 2-8 weeks, as
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`the BBB re-closes.
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`44. This does not mean the lesion is gone, simply that it does not appear as
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`a Gd+ lesion due to the changing pathology of the lesion. Of note, 80-90% of all
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`Gd+ lesions in the brain are not associated with overt new MS symptoms, but their
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`presence and number are predictive of new clinical disease activity over time. Thus,
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`Gd+ lesions have significant clinical and pathological importance in our
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`understanding of the disease process in MS. In addition, mirroring the reduction in
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`relapses with aging, the production of new MRI lesions, especially Gd+ lesions,
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`diminishes substantially in the aging MS patient. Finally, the analysis of MRI lesion
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`formation and evolution has become a surrogate marker of MS disease activity,
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`especially replacing clinical outcomes in Phase II trials during the progression of a
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`drug towards approval by regulatory agencies, as the greater number of events and
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`high reliability of interpretation have improved the statistical power to define
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`differences between different drugs or between a drug and placebo.
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`B. Multiple Sclerosis Therapies
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`45. Currently there are no known cures for MS. However, as of February
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`2007, the most prominent treatments for MS were the use of several injectable
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`disease modifying therapeutics (DMTs). While DMTs do not stop or cure MS, they
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`work to modify the underlying immune dysfunction, therefore decreasing the
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`incidence of relapses and new MRI lesions, reducing brain inflammation, and
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`slowing disease progression. Common disease markers used to determine efficacy
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`of DMTs include: annual relapse rates, progression of disability using EDSS and
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`other clinical markers, number and volume of Gd+ enhancing lesions, number and
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`volume of T2 lesions, number of new or enlarging T2 lesions, and volume of T1
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`lesions.
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`46. As of February 2007, there were a number of DMTs that had been FDA
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`approved to treat MS. Those treatments included:
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`(a) Interferon beta-1b (Betaseron®): FDA approved in 1993,
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`indicated for treatment of patients with RRMS, administered
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`subcutaneously every-other-day
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`(b) Interferon beta-1a (Avonex®): FDA approved in 1996,
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`indicated for treatment of patients with RRMS (including CIS
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`patients who had experienced a first clinical episode and have
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`MRI
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`features
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`consistent with MS),
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`administered
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`intramuscularly on a weekly basis
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`(c) Glatiramer acetate (Copaxone®): FDA approved in 1996,
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`indicated for treatment of patients with RRMS (including CIS
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`patients who had experienced a first clinical episode and have
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`MRI
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`features
`
`consistent with MS),
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`administered
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`subcutaneously every day
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`(d) Interferon beta-1a (Rebif®): FDA approved in 2002,
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`indicated for treatment of patients with RRMS, administered
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`subcutaneously three times a week, and with each dose at
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`least 48 hours apart.
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`(e) Natalizumab (Tysabri®): FDA approved in 2004, indicated
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`for treatment of patients with RRMS and patients with
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`Crohn’s disease, administered intravenously every four
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`weeks
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`IX. SCOPE AND CONTENT OF THE PRIOR ART REFERENCES
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`A.
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`Schimrigk 2004 Abstract
`
`47. The Schimrigk 2004 Abstract is titled “A Prospective, Open-Label,
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`Phase II Study of Oral Fumarate Therapy for the Treatment of Relapsing-Remitting
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`Multiple Sclerosis.” Ex. 1006. The Schimrigk 2004 Abstract was publicly av