UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC.
`Petitioner,
`
`v.
`
`BIOGEN MA, INC.
`Patent Owner.
`
`Patent No. 8,399,514
`
`Inter Partes Review IPR2018-01403
`
`EXPERT DECLARATION OF JOHN R. CORBOY, M.D.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 8,399,514
`
`Sawai (IPR2019-00789), Ex. 1002, p. 001
`
`

`

`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..................................... 8
`C.
`Scope of Work...................................................................................... 9
`SUMMARY OF OPINIONS.......................................................................... 9
`LEGAL STANDARDS ................................................................................12
`PERSON OF ORDINARY SKILL IN THE ART .......................................14
`THE ’514 PATENT (EX. 1001).................................................................. 14
`A.
`Claims of the ’514 Patent...................................................................14
`VI. CLAIM CONSTRUCTION .........................................................................17
`VII. BACKGROUND ..........................................................................................17
`A. Multiple Sclerosis...............................................................................17
`B. Multiple Sclerosis Therapies..............................................................23
`VIII. SCOPE AND CONTENT OF THE PRIOR ART REFERENCES .............25
`A.
`Schimrigk 2004 Abstract....................................................................25
`B.
`Schimrigk 2004 Poster .......................................................................27
`C.
`Brune 2004 .........................................................................................28
`D.
`Schimrigk 2005 Abstract....................................................................29
`E.
`Kappos 2005.......................................................................................30
`F.
`January 2006 Biogen Press Release...................................................31
`G. May 2006 Biogen Press Release........................................................32
`H.
`Kappos 2006.......................................................................................33
`I.
`WO ’342.............................................................................................34
`J.
`Nieboer 1990 ......................................................................................36
`K.
`Schimrigk 2006 ..................................................................................37
`L. Mrowietz 2005 ...................................................................................39
`M.
`Fumaderm® Label .............................................................................39
`-2-
`
`Sawai (IPR2019-00789), Ex. 1002, p. 002
`
`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`
`Ockenfels 1998...................................................................................40
`N.
`de Jong 1996.......................................................................................41
`O.
`Nibbering 1993...................................................................................43
`P.
`Clinical Trials.....................................................................................43
`Q.
`ICH Guidelines...................................................................................44
`R.
`Joshi Patents .......................................................................................45
`S.
`Biogen 2005 Press Release ................................................................46
`T.
`Ormerod 2004.....................................................................................47
`U.
`V. Mrowietz 1998 ...................................................................................48
`W. Additional prior art references and knowledge..................................48
`IX. UNPATENTABILITY OF THE ’514 PATENT ......................................... 49
`A.
`The Claims of the ’514 Patent are Obvious over the January
`2006 Biogen Press Release in view of the Schimrigk 2004
`Abstract...............................................................................................49
`1.
`Independent Claims 1, 11, 15, and 20......................................49
`2.
`Dependent Claims....................................................................66
`The Claims of the ’514 Patent are Obvious over Kappos 2006
`in view of the Schimrigk 2004 Abstract ............................................71
`1.
`Independent Claims 1, 11, 15, and 20......................................71
`2.
`Dependent claims.....................................................................78
`The Claims of the ’514 Patent are Obvious over Kappos 2006
`in view of WO ’342............................................................................78
`1.
`Independent Claims 1, 11, 15, and 20......................................78
`2.
`Dependent claims.....................................................................81
`The Claims of the ’514 Patent are Obvious over Kappos 2006,
`Clinical Trials, Joshi ’999, and ICH Guidelines ................................81
`1.
`Independent Claims 1, 11, 15, and 20......................................81
`2.
`Dependent claims.....................................................................86
`
`B.
`
`C.
`
`D.
`
`-3-
`
`Sawai (IPR2019-00789), Ex. 1002, p. 003
`
`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`
`E.
`
`There Are No Secondary Considerations of Nonobviousness...........87
`1.
`The invention claimed in the ’514 patent did not achieve
`unexpected results....................................................................87
`The invention claimed in the ’514 patent did not fill a
`long-felt but unmet need. .........................................................95
`
`2.
`
`-4-
`
`Sawai (IPR2019-00789), Ex. 1002, p. 004
`
`

`

`1. My name is John R. Corboy, M.D. I have been retained by counsel
`
`for Mylan Pharmaceuticals Inc. (“Mylan”). I understand that Mylan 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
`
`Mylan 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 Mylan’s IPR petition for the ’514
`
`patent.
`
`I.
`
`QUALIFICATIONS AND BACKGROUND
`A.
`Education and Experience; Prior Testimony
`2.
`I received an M.D. in 1985 from the University of Pennsylvania. In
`
`1989 I completed a residency in Neurology at the University of Pennsylvania.
`
`From 1989 to 1992 I was a postdoctoral fellow in Neurovirology at The Johns
`
`Hopkins University. I attended in the Multiple Sclerosis (“MS”) clinic for the
`
`three years of my fellowship. I have been Board Certified in Psychiatry and
`
`Neurology since 1990.
`
`3.
`
`From 1992 to 1994 I was employed at the University of Minnesota
`
`both as an Assistant Professor and as a Staff Neurologist at the University’s
`
`hospital and at the Minneapolis Veteran’s Affairs hospital. While there, I saw
`
`MS and HIV patients. I have been employed at the University of Colorado since
`
`-5-
`
`Sawai (IPR2019-00789), Ex. 1002, p. 005
`
`

`

`1994. From 1994 until 2000 I was an Assistant Professor in the Department of
`
`Neurology. From 2000 to 2006 I was an Associate Professor in the Department of
`
`Neurology. From 2006 to present I have been a Professor in the Department of
`
`Neurology. Since 1997 I have also been the Director and Organizer of the
`
`University of Colorado Multiple Sclerosis Center. In 2009, this transitioned into
`
`the Rocky Mountain MS Center at the University of Colorado, of which I am the
`
`Co-Director. I am also the Director of the Rocky Mountain MS Center Tissue
`
`Bank, which supplies samples throughout the world to advance research into the
`
`causes of and cure for MS. In addition to my academic appointments, since 1994,
`
`I have held hospital positions on staff at the University of Colorado Hospital
`
`(1994-continues), at the Denver Health Medical Center (1995-2013, where I
`
`started a MS clinic), and at the Denver Veteran’s Affairs Medical Center (2000-
`
`2017). Presently, all of my energies are spent at the University of Colorado
`
`School of Medicine and Hospital. In total, I have been seeing substantial numbers
`
`of MS patients since starting my fellowship in 1989 in Baltimore.
`
`4. My duties at the University of Colorado include teaching medical
`
`students and residents. At numerous points in my career I have served as a
`
`lecturer in neurology courses and have mentored and supervised many medical
`
`students pursuing neurology.
`
` My early research was directed
`
`toward
`
`understanding the nature of viruses interacting with the nervous system, but since
`
`-6-
`
`Sawai (IPR2019-00789), Ex. 1002, p. 006
`
`

`

`about 2000 all my research has been about MS, and has focused on diagnosis and
`
`misdiagnosis of MS, viruses in MS, clinical trials with novel or repurposed
`
`medications, magnetic resonance imaging (MRI) in MS, pharmacoeconomics, and
`
`physical therapy aspects of MS. Most recently, I wrote the grant for and we are
`
`the coordinating center for a randomized, controlled 15-center trial looking at the
`
`discontinuation of disease modifying therapies (DMTs) in MS (funded by the
`
`Patient Centered Outcomes Research Institute, PCORI, and the National MS
`
`Society, NMSS). We are at the beginning stages of studying risk factors in the
`
`earliest aspects of MS. I continue to be very active clinically, seeing about 1000
`
`clinic visits each year, and have personally seen over 6000 patients with possible
`
`MS, MS, or related neuroimmunological conditions during my career. I have
`
`received numerous research grants, including from the National Institute of
`
`Health, the National Multiple Sclerosis Society, the Patient-Centered Outcomes
`
`Research Institute, and others for my research.
`
`5.
`
`I am the founder and currently editor for the Neurology Clinical
`
`Practice (NCP) journal, and have been an ad hoc reviewer for numerous journals,
`
`such as JAMA, Clinical Pharmacology and Therapeutics, Neurology, and Annals
`
`of Neurology. I also have been very active in the American Academy of
`
`Neurology, serving on several committees over more than 20 years, including
`
`being the chair of the graduate education subcommittee and presently on the
`
`-7-
`
`Sawai (IPR2019-00789), Ex. 1002, p. 007
`
`

`

`science committee. Finally, I have been an active supporter of the NMSS, sitting
`
`on the national committee for graduate education, and for over 13 years I was a
`
`board member of the local Colorado-Wyoming chapter.
`
`6.
`
`As of July 2018, my research has resulted in more than 68 peer-
`
`reviewed journal publications, 10 peer-reviewed publications as a contributing
`
`investigator, 12 invited publications, 13 book chapters and a host of other
`
`appearances on radio, TV or other distributed media. Moreover, I have been
`
`invited
`
`to present my clinical and research work both nationally and
`
`internationally on more than 80 occasions, to colleagues and other researchers, as
`
`well as to patients and their families.
`
`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.
`
`-8-
`
`Sawai (IPR2019-00789), Ex. 1002, p. 008
`
`

`

`C.
`10.
`
`Scope of Work
`I have been retained by Mylan as a technical expert in this matter to
`
`provide various opinions regarding the ’514 patent. I receive $650 per hour for
`
`my services. No part of my compensation is dependent upon my opinions given
`
`or the outcome of this case. I do not have any affiliations with Biogen MA Inc.,
`
`or any affiliates presently known to me, or the named inventors on the ’514 patent.
`
`I have received grant support in the past from Biogen, but never from Mylan. I
`
`have been a consultant to several pharmaceutical companies in the past, including
`
`Biogen, but never Mylan. I essentially discontinued consulting activity after
`
`starting the journal NCP.
`
`II.
`
`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
`
`-9-
`
`Sawai (IPR2019-00789), Ex. 1002, p. 009
`
`

`

`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.
`
`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
`
`-10-
`
`Sawai (IPR2019-00789), Ex. 1002, p. 010
`
`

`

`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 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
`
`-11-
`
`Sawai (IPR2019-00789), Ex. 1002, p. 011
`
`

`

`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 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.
`
`III.
`
`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.
`
`-12-
`
`Sawai (IPR2019-00789), Ex. 1002, p. 012
`
`

`

`17.
`
`I have been
`
`told
`
`that Mylan bears
`
`the burden of proving
`
`unpatentability by a preponderance of the evidence. I am informed that this
`
`“preponderance-of-the-evidence” standard means that Mylan 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
`
`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.
`
`-13-
`
`Sawai (IPR2019-00789), Ex. 1002, p. 013
`
`

`

`IV.
`
`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.
`
`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.
`
`V.
`
`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
`-14-
`
`Sawai (IPR2019-00789), Ex. 1002, p. 014
`
`

`

`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 Mylan 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
`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.
`
`-15-
`
`Sawai (IPR2019-00789), Ex. 1002, p. 015
`
`

`

`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:
`
`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.
`
`-16-
`
`Sawai (IPR2019-00789), Ex. 1002, p. 016
`
`

`

`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.
`
`VI. 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 reasonable construction in light of the specification of the patent in which
`
`they appear.
`
`VII. 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
`
`-17-
`
`Sawai (IPR2019-00789), Ex. 1002, p. 017
`
`

`

`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
`
`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
`
`-18-
`
`Sawai (IPR2019-00789), Ex. 1002, p. 018
`
`

`

`(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
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`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
`
`to years, with or without superimposed relapses. In addition, there may be clinical
`
`quiescence, either between relapses, or with no relapses and no progression,
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`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
`
`-19-
`
`Sawai (IPR2019-00789), Ex. 1002, p. 019
`
`

`

`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
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`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.
`
`Subjective measures would include: the detailed history of relapses and
`
`progression of symptoms noted by the patient. Other potential conditions would
`
`be ruled out by an analysis of history, neurological examination and use of other
`
`blood and radiographic tests. For research purposes, objective evaluations would
`
`include: assessing frequency of relapses, the degree and rate of disability
`
`progression using the Expanded Disability Status Scale (EDSS) or ambulation
`
`index (AI). See, e.g., S. Rich et al., Stepped-Care Approach to Treating MS: A
`
`Managed Care Treatment Algorithm,” 10(3) J. Manag. Care Pharm. S26-S32
`
`-20-
`
`Sawai (IPR2019-00789), Ex. 1002, p. 020
`
`

`

`(2004) Ex. 1043. These objective assessment methods were often combined with
`
`a patient’s subjective assessment of possible new relapses or progression of
`
`symptoms. Id.
`
`41. MRI scans have enhanced
`
`the early diagnosis of MS and
`
`revolutionized our understanding of the basic pathophysiology of the disease. MS
`
`lesions are detected via MRI using T1 and T2 weighted sequences to produce
`
`variable images, and are seen in a pattern of locations which distinguish these
`
`lesions from those that are produced by other conditions or are simply non-
`
`specific. T2 weighted MRI scans show the total number of lesions. The MS
`
`lesions show up as hyperintense abnormalities or “bright spots.” Hyperintense T2
`
`lesions can be caused by a number of conditions, including, for example, damage
`
`to small blood vessels as with vascular disease or migraine; loss or damage to
`
`myelin due to toxins, inflammation or metabolic deficiencies; and breaches of the
`
`blood-brain barrier (BBB) between the brain and the circulation system. T2
`
`lesions evolve over time, first being relatively large and then shrinking, and can
`
`rarely “disappear.”
`
`42.
`
`In comparison, an MRI scan using T1 weighted sequences produces
`
`images appearing hypointense, as so-called “black holes,” reflecting areas of
`
`severe damage to the CNS. Only a subset of T2 lesions will become T1 black
`
`holes, which represent areas of permanent myelin and axonal damage or loss.
`
`-21-
`
`Sawai (IPR2019-00789), Ex. 1002, p. 021
`
`

`

`43. As with many other radiographic images in medicine, the use of
`
`contrast agents enhances the utility of brain and spine scans in the diagnosis and
`
`monitoring of MS. Gadolinium is a rare earth metal with paramagnetic qualities
`
`which allow it to be seen in the CNS and other organs after IV injection and under
`
`the conditions of a T1 set of MRI sequences. Normally, however, in the CNS its
`
`size precludes entrance past the BBB. Thus, unless there is damage to the BBB,
`
`the contrast is simply processed and removed from the body. If, however, there is
`
`damage to the BBB, the contrast may leak into the brain or spine and be seen as a
`
`bright area in and around the lesion. This is referred to as enhancement, or being
`
`Gd+. Gd+ lesions are most prominent early in the evolution of a lesion, and are
`
`felt to reflect acute inflammation. Only a subset of T2 lesions in MS will also be
`
`seen as Gd+ on the T1 images, and the enhancement typically resolves by 2-8
`
`weeks, as the BBB re-closes.
`
`44.
`
`This does not mean the lesion is gone, simply that it does not appear
`
`as a Gd+ lesion due to the changing pathology of the lesion. Of note, 80-90% of
`
`all Gd+ lesions in the brain are not associated with overt new MS symptoms, but
`
`their presence and number are predictive of new clinical disease activity over
`
`time. Thus, Gd+ lesions have significant clinical and pathological importance in
`
`our understanding of the disease process in MS. In addition, mirroring the
`
`reduction in relapses with aging, the production of new MRI lesions, especially
`
`-22-
`
`Sawai (IPR2019-00789), Ex. 1002, p. 022
`
`

`

`Gd+ lesions, diminishes substantially i