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 JACQUELYN BAINBRIDGE, PHARM.D.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 8,399,514
`
`US_137978938v1_385667-00004
`
`Sawai (IPR2019-00789), Ex. 1057, p. 001
`
`

`

`TABLE OF CONTENTS
`
`Page
`
`I.
`
`QUALIFICATIONS AND BACKGROUND ...................................... 6
`A.
`Education and Experience .......................................................... 6
`B.
`Legal Standards and Materials Considered ................................ 9
`C.
`Retention and Compensation ................................................... 10
`PERSON OF ORDINARY SKILL IN THE ART ............................. 10
`II.
`III. BRIEF SUMMARY OF OPINIONS ................................................. 11
`IV. THE ’514 PATENT [EX. 1001] ......................................................... 13
`V.
`BACKGROUND ................................................................................ 15
`A.
`Treatment of Psoriasis and Multiple Sclerosis Using
`Fumaric Acid Esters, Including DMF as a Monotherapy,
`Was Well-Known Before the Priority Date ............................. 15
`1.
`Fumaric acid esters to treat psoriasis. ............................ 15
`2.
`DMF as a monotherapy to treat psoriasis. ..................... 17
`3.
`Fumaric acid esters to treat multiple sclerosis. .............. 19
`4.
`DMF as a monotherapy to treat multiple sclerosis. ....... 21
`VI. SCOPE AND CONTENT OF THE PRIOR ART
`REFERENCES ................................................................................... 25
`A.
`Fumaderm Label [Ex. 1020] .................................................... 25
`B.
`Nugteren-Huying 1990 [Ex. 1029] .......................................... 26
`C.
`Altmeyer 1994 [Ex. 1030] ........................................................ 27
`D. Mrowietz 1998 [Ex. 1028] ....................................................... 28
`E.
`Nibbering 1993 [Ex. 1024] ....................................................... 29
`F.
`de Jong 1996 [Ex. 1023] .......................................................... 30
`G. Ockenfels 1998 [Ex. 1021] ....................................................... 31
`H.
`Joshi ’999 [Ex. 1009] ............................................................... 32
`I.
`Nieboer 1989 [Ex. 1031] .......................................................... 33
`J.
`Nieboer 1990 [Ex. 1017] .......................................................... 35
`K.
`Schimrigk 2004 Abstract [Ex. 1006] ....................................... 36
`L.
`Brune 2004 Abstract [Ex. 1013] .............................................. 38
`
`US_137978938v1_385667-00004
`
`2
`
`Sawai (IPR2019-00789), Ex. 1057, p. 002
`
`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`
`b.
`
`Schimrigk 2004 Poster [Ex. 1012] ........................................... 39
`M.
`N. Kappos 2005 [Ex. 1015] ........................................................... 42
`O.
`Clinical Trials [Ex. 1010] ......................................................... 43
`P.
`January 2006 Biogen Press Release [Ex. 1005] ....................... 44
`Q. Kappos 2006 [Ex. 1007] ........................................................... 45
`R. May 2006 Biogen Press Release [Ex. 1016] ............................ 46
`S.
`Kappos 2006 Presentation [Ex. 1046] ...................................... 47
`T.
`ICH [Ex. 1011] ......................................................................... 49
`U. WO ’342 [Ex. 1008] ................................................................. 50
`VII. UNPATENTABILITY OF THE ’514 PATENT ............................... 52
`A. Ground 1: All Claims of the ’514 Patent Are Obvious
`Over the January 2006 Biogen Press Release In View of
`the Schimrigk 2004 Abstract .................................................... 52
`1.
`Independent Claims 1, 11, 15, and 20 Are Obvious
`Over the January 2006 Biogen Press Release in
`View of the Schimrigk 2004 Abstract. .......................... 52
`a.
`Teachings of the January 2006 Biogen Press
`Release and the Schimrigk 2004 Abstract ........... 54
`Skilled artisans would have been motivated
`to pursue, with a reasonable expectation of
`success, the treatment of MS patients with
`480 mg/day of DMF ............................................ 56
`Dependent Claims 2-10, 12-14, 16-19 Are Obvious
`Over the January 2006 Biogen Press Release in
`View of the Schimrigk 2004 Abstract. .......................... 62
`Ground 2: All Claims of the ’514 Patent Are Obvious
`Over Kappos 2006 In View of The Schimrigk 2004
`Abstract..................................................................................... 67
`1.
`Independent claims 1, 11, 15, and 20 Are Obvious
`Over Kappos 2006 in View of the Schimrigk 2004
`Abstract. ......................................................................... 67
`
`2.
`
`B.
`
`US_137978938v1_385667-00004
`
`3
`
`Sawai (IPR2019-00789), Ex. 1057, p. 003
`
`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`
`a.
`
`b.
`
`b.
`
`C.
`
`2.
`
`2.
`
`Teachings of Kappos 2006 and the
`Schimrigk 2004 Abstract ..................................... 67
`Skilled artisans would have been motivated
`to pursue, with a reasonable expectation of
`success, the treatment of MS patients with
`480 mg/day of DMF ............................................ 69
`Dependent Claims 2-10, 12-14, 16-19 Are Obvious
`Over Kappos 2006 in View of the Schimrigk 2004
`Abstract .......................................................................... 79
`Ground 3: All Claims of the ’514 Patent Are Obvious
`Over Kappos 2006 In View of WO ’342 ................................. 79
`1.
`Independent claims 1, 11, 15, and 20 Are Obvious
`Over Kappos 2006 in View of WO ’342. ...................... 79
`a.
`Teachings of Kappos 2006 and WO ’342 ........... 80
`b.
`Skilled artisans would have been motivated
`to pursue, with a reasonable expectation of
`success, the treatment of MS patients with
`480 mg/day of DMF ............................................ 81
`Dependent Claims 2-10, 12-14, 16-19 Are Obvious
`Over Kappos 2006 in View of WO ’342 ....................... 82
`D. Ground 4: All Claims of the ’514 Patent Are Obvious
`Over Kappos 2006 in View of Clinical Trials, Joshi ’999,
`and ICH .................................................................................... 83
`1.
`Independent claims 1, 11, 15, and 20 Are Obvious
`Over Kappos 2006 in View of Clinical Trials,
`Joshi ’999, and ICH ....................................................... 83
`a.
`Teachings of Kappos 2006, Clinical Trials,
`Joshi ’999, and ICH ............................................. 83
`Skilled artisans would have been motivated
`to pursue, with a reasonable expectation of
`success, the treatment of MS patients with
`480 mg/day of DMF ............................................ 84
`
`US_137978938v1_385667-00004
`
`4
`
`Sawai (IPR2019-00789), Ex. 1057, p. 004
`
`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`
`2.
`
`2.
`
`Dependent Claims 2-10, 12-14, 16-19 Are Obvious
`Over Kappos 2006 in View of Clinical Trials,
`Joshi ’999, and ICH. ...................................................... 86
`VIII. THERE ARE NO UNEXPECTED RESULTS .................................. 87
`A.
`The DEFINE and CONFIRM Studies Do Not Support
`Unexpected Results .................................................................. 87
`1.
`The Kappos Phase II, DEFINE, and CONFIRM
`Studies ............................................................................ 88
`Skilled Artisans Would Immediately Recognize
`the Kappos Phase II Study’s Discrepancy in the
`Mean No. of Baseline Gd+ Lesions for the 360
`mg/day Treatment Group and Would Normalize
`the Data. ......................................................................... 90
`The Lead Principle Investigators of the DEFINE
`and CONFIRM Trials Confirm That the Results
`for 480 mg/day DMF Are Not Unexpected. .................. 95
`The EMA Report Further Confirms that the
`Results of the DEFINE and CONFIRM Studies for
`the 480 mg/day Dose of DMF Were Not
`Unexpected. .................................................................... 98
`It is Not Unexpected For Doses Close in Range To
`Produce Different Pharmacologic Responses. ....................... 100
`Efficacy of the 480 mg/day Dose Would Not Be
`Unexpected Because Fumaderm® Was Effective at
`Treating RRMS at 360 mg/day and 720 mg/day Doses of
`DMF ....................................................................................... 101
`IX. CONCLUSION ................................................................................. 102
`
`
`
`3.
`
`4.
`
`B.
`
`C.
`
`US_137978938v1_385667-00004
`
`5
`
`Sawai (IPR2019-00789), Ex. 1057, p. 005
`
`

`

`
`
`1. My name is Jacquelyn Bainbridge, Pharm.D. I have been retained by
`
`counsel for Petitioners Sawai USA, Inc. and Sawai Pharmaceutical Co., Ltd.
`
`(“Sawai”). I understand that Sawai is submitting a petition for inter partes review
`
`(“IPR”) of U.S. Patent No. 8,399,514 to Lukashev et al. (“the ’514 patent,” attached
`
`as Ex. 1001), which is assigned to Biogen MA Inc., requesting the United States
`
`Patent and Trademark Office to cancel all claims of the ’514 patent as unpatentable.
`
`I submit this expert declaration in support of Sawai’s IPR petition for the ’514 patent.
`
`I.
`
`QUALIFICATIONS AND BACKGROUND
`
`A. EDUCATION AND EXPERIENCE
`
`2.
`
`I am currently a Professor at University of Colorado Skaggs School of
`
`Pharmacy and Pharmaceutical Sciences Department of Clinical Pharmacy and
`
`Department of Neurology.
`
`3.
`
`I received my Bachelor of Science in Pharmacy in 1988 and my Doctor
`
`of Pharmacy from the University of Colorodo in 1995. I also undertook a Specialty
`
`Residency in Neurology from 1995-1996. I am licensed in Colorado and I am a
`
`Multiple Sclerosis Certified Specialist.
`
`4.
`
`In 1995 I was a Visiting Assistant Professor at the University of
`
`Californial San Francisco. In 1996 I was an Assistant Professor at the University of
`
`Colorado School of Pharmacy and Department of Neurology. I was promoted to
`
`Associate Professor in 2003 and Professor at the University of Colorado Skaggs
`
`US_137978938v1_385667-00004
`
`6
`
`Sawai (IPR2019-00789), Ex. 1057, p. 006
`
`

`

`
`
`School of Pharmacy and Pharmaceutical Sciences Department of Clinical Pharmacy
`
`and Department of Neurology in 2009.
`
`5. My areas of specialization over the course of my career include
`
`neurological disorders including multiple sclerosis.
`
`6.
`
`In addition to my teaching responsibilities, I have held leadership
`
`positions in a number of organizations in my field of study, including: serving as
`
`Vice President and Chair of the National Restless Leg Syndrome Board of Directors,
`
`Member and Chair of Programming Committee for the Consortium of Multiple
`
`Sclerosis Centers, member of the Epilepsy Foundation of America, President of the
`
`Epilepsy Foundation of Colorado Board of Directors, member and chair of the
`
`American College of Clinical Pharmacy and Chair of the Americal Epilpsy Society.
`
`7.
`
`I have been awarded numerous awards, prizes and honors for work I
`
`have conducted in my field, including:
`
`a.
`
`“Excellence in Precepting Award” nomination. University of
`
`Colorado Skaggs School of Pharmacy. Aurora, CO. May 15, 2015.
`
`b.
`
`Outstanding service Colorado Multiple Institutional Review
`
`Board 2001.
`
`c.
`
`d.
`
`e.
`
`Outstanding recruitment VA Study # 428 1998.
`
`Outstanding recruitment VA Study # 428 1999.
`
`Outstanding recruitment VA Study # 428 2001.
`
`US_137978938v1_385667-00004
`
`7
`
`Sawai (IPR2019-00789), Ex. 1057, p. 007
`
`

`

`
`
`f.
`
`g.
`
`h.
`
`i.
`
`Outstanding recruitment VA Study # 428 2002.
`
`Pharmacist of Year, University of Colorado Hospital, 1992.
`
`Rho Chi National Pharmaceutical Honor Society, 1995.
`
`Preceptor of the Year, School of Pharmacy. University of
`
`Colorado Health Sciences Center, 2003.
`
`j.
`
`k.
`
`Preceptor.
`
`Fellow American College of Clinical Pharmacy, 2004.
`
`Skaggs School of Pharmacy and Pharmaceutical Science Valued
`
`l.
`
`Preceptor of the Year, School of Pharmacy. University of
`
`Colorado Health Sciences Center, 2005.
`
`m.
`
`University of Colorado Denver, School of Pharmacy P2
`
`Professor of the Year, 2008.
`
`n.
`
`Skaggs School of Pharmacy and Pharmaceutical Sciences P2
`
`Professor of the Year. 2010, 2011, 2012, 2013.
`
`o.
`
`Multiple Sclerosis Certified Specialist (MSCS). May 2017
`
`8.
`
`I have published more than 75 articles, and more than 40 book chapters,
`
`and in the areas of neurological disorders including multiple sclerosis and epilepsy.
`
`9.
`
`Based on my expertise in the field of pharmacology, pharmacokinetics,
`
`drug delivery and drug metabolism, I have been invited to serve (and currently serve)
`
`on review panels, including the RLS Foundation Quality Care Center Program.
`
`US_137978938v1_385667-00004
`
`8
`
`Sawai (IPR2019-00789), Ex. 1057, p. 008
`
`

`

`
`
`10.
`
`I have received numerous grants including several in the areas of
`
`multiple sclerosis and epilepsy.
`
`11. During my career I have presented at numerous conferences including
`
`at the Movement Disorders Society (MDS) International Conference.
`
`12. A copy of my curriculum vitae providing a more comprehensive review
`
`of my work is attached as Exhibit A.
`
`B.
`
`LEGAL STANDARDS AND MATERIALS CONSIDERED
`
`13.
`
`In preparing and forming my opinions set forth in this declaration, I
`
`have been informed of the relevant legal principles. I have applied my understanding
`
`of those principles in forming my opinions. My understanding of those principles is
`
`summarized below.1
`
`14.
`
`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-
`
`
`1
`In performing my analysis and reaching my opinions and conclusions, I have
`
`been informed of and been advised to apply various legal principles relating to
`
`patentability, which I set forth herein. In setting forth these legal standards, it is not
`
`my intention to testify about the law. I only provide my understanding of the law,
`
`as explained to me by counsel, as a context for the opinions and conclusions I am
`
`providing in this case.
`
`US_137978938v1_385667-00004
`
`9
`
`Sawai (IPR2019-00789), Ex. 1057, p. 009
`
`

`

`
`
`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.
`
`15.
`
`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.
`
`16.
`
`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.
`
`17. A list of the materials I considered, in addition to my experience,
`
`education, and training, in providing the opinions contained herein is attached as
`
`Exhibit B.
`
`C. RETENTION AND COMPENSATION
`
`18.
`
`I have been retained by Sawai as a technical expert in this matter to
`
`provide certain of my opinions regarding the ’514 patent. I receive $600 per hour
`
`for consulting, including preparation of this declaration and $800 for depositions and
`
`related preparatory work. No part of my compensation is dependent upon my
`
`opinions given or the outcome of this case.
`
`II.
`
`PERSON OF ORDINARY SKILL IN THE ART
`
`US_137978938v1_385667-00004
`
`10
`
`Sawai (IPR2019-00789), Ex. 1057, p. 010
`
`

`

`
`
`19. As stated above, 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. 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.
`
`20.
`
`In my opinion, a person having ordinary skill in the art here would have
`
`had (1) several years’ experience in designing clinical studies to meet regulatory
`
`expectations and/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.
`
`III. BRIEF SUMMARY OF OPINIONS
`
`21.
`
`It is my opinion for the reasons below that claims 1-20 of the
`
`’514 patent would have been obvious to skilled artisans based on Biogen’s
`
`January 9, 2006 press release entitled “Phase II Study of Oral Compound BG-12
`
`Meets Primary Endpoint in Multiple Sclerosis” (“January 2006 Biogen Press
`
`Release”) in view of an abstract published in 2004 by Schimrigk et al. titled “A
`
`US_137978938v1_385667-00004
`
`11
`
`Sawai (IPR2019-00789), Ex. 1057, p. 011
`
`

`

`
`
`Prospective, Open-Label, Phase II Study of Oral Fumarate Therapy for the
`
`Treatment of Relapsing-Remitting Multiple Sclerosis”
`
`(“Schimrigk 2004
`
`Abstract”).
`
`22. Furthermore, it is my opinion that claims 1-20 of the ’514 patent would
`
`have been obvious to skilled artisans over an abstract published in May 2006 by
`
`Kappos et al. titled “Efficacy of a Novel Oral Single-Agent Fumarate, BG-12, in
`
`Patients with Relapsing-Remitting Multiple Sclerosis: Results of a Phase 2 Study”
`
`(“Kappos 2006”) in view of the Schimrigk 2004 Abstract.
`
`23.
`
`It is my opinion that claims 1-20 would have also been obvious to
`
`skilled artisans based on Kappos 2006 and International Publication No. WO
`
`2006/037342 titled “Controlled Release Pharmaceutical Compositions Comprising
`
`a Fumaric Acid Ester,” which was published on April 13, 2006 (“WO ’342”).
`
`24.
`
`It is my opinion that claims 1-20 would have also been obvious to
`
`skilled artisans based on Kappos 2006, a printout from the ClinicalTrials.gov archive
`
`website, which was publicly available on September 14, 2005 (“Clinical Trials”), a
`
`document titled “Dose-Response Information to Support Drug Registration E4,”
`
`issued by the International Conference on Harmonisation of Technical Requirements
`
`for Registration of Pharmaceuticals for Human Use and published in 1994 (“ICH”),
`
`and U.S. Patent 7,320,999, which issued as a patent on January 22, 2008 (“Joshi
`
`’999”).
`
`US_137978938v1_385667-00004
`
`12
`
`Sawai (IPR2019-00789), Ex. 1057, p. 012
`
`

`

`
`
`25.
`
`It is also my opinion that it is not unexpected that a dose of 480 mg/day
`
`of DMF would have similar efficacy to a dose of 720 mg/day of DMF in treating
`
`patients with MS.
`
`26. The particular citations listed are intended to be illustrative, not
`
`exhaustive. A detailed discussion of the rationale to modify follows the discussion
`
`of each individual claim analyzed below in view of the disclosures in the prior art
`
`references.
`
`IV. THE ’514 PATENT [EX. 1001]
`
`27.
`
`I have read the ’514 patent and the issued claims, entitled “Treatment
`
`for Multiple Sclerosis.” The ’514 patent claims priority as a continuation application
`
`to U.S. App. No. 12/526,296, filed January 13, 2011, which in turn claims priority
`
`to PCT App. No. PCT/US2008/001602, filed February 7, 2008. That PCT
`
`application claims priority to U.S. Provisional Application No. 60/888,921, filed on
`
`February 8, 2007, which is the earliest possible priority date for the ’514 patent. The
`
`’514 patent issued March 19, 2013, and names Matvey E. Lukashev and Gilmore
`
`O’Neill as the inventors. The patent is assigned to Biogen MA, Inc.
`
`28.
`
`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
`
`US_137978938v1_385667-00004
`
`13
`
`Sawai (IPR2019-00789), Ex. 1057, p. 013
`
`

`

`
`
`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.”
`
`29.
`
`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 per day of dimethyl fumarate, monomethyl fumarate, or a
`
`combination thereof.”
`
`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.
`
`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.”
`
`32. The dependent claims recite that “the pharmaceutical composition is
`
`administered in the form of a tablet, a suspension, or a capsule” (claim 2); “the
`
`US_137978938v1_385667-00004
`
`14
`
`Sawai (IPR2019-00789), Ex. 1057, p. 014
`
`

`

`
`
`therapeutically effective amount is administered in separate administrations of 2, 3,
`
`4, or 6 equal doses” (claim 3), or “2 equal doses” (claims 4, 9, 13, and 16), or
`
`“3 equal doses” (claims 5, 14); the composition “consists essentially of” dimethyl
`
`fumarate (claim 6), monomethyl fumarate (claim 7), or 480 mg of dimethyl fumarate
`
`per day (claim 12); that the treatment is for at least 12 weeks (claims 8 and 10); and
`
`that the subject’s NQO1 level is elevated after administration (claims 17-19).
`
`V. BACKGROUND
`
`A. TREATMENT OF PSORIASIS AND MULTIPLE SCLEROSIS USING
`FUMARIC ACID ESTERS, INCLUDING DMF AS A MONOTHERAPY, WAS
`WELL-KNOWN BEFORE THE PRIORITY DATE
`
`33. Orally administered fumaric acid esters (FAEs), including DMF as a
`
`monotherapy, were well-known before the earliest priority date of the ’514 patent to
`
`be effective in treating autoimmune diseases, such as psoriasis and multiple
`
`sclerosis.
`
`1.
`
`Fumaric acid esters to treat psoriasis.
`
`34.
`
`In 1959, a German chemist first reported that FAEs composed of
`
`monoethyl and dimethyl esters could be used to treat psoriasis by successfully
`
`treating his own psoriatic lesions with FAEs. Ex. 1019 (Mroweitz 2005) at 1. In the
`
`1980s and 90s, various clinical trials established the safety and efficacy of a
`
`combination of oral FAEs comprised of dimethylfumarate (DMF) and
`
`monoethylfumarate (MEF) to treat psoriasis. See, e.g., Ex. 1029 (Nugteren-Huying
`
`US_137978938v1_385667-00004
`
`15
`
`Sawai (IPR2019-00789), Ex. 1057, p. 015
`
`

`

`
`
`1990) at 1; Ex. 1030 (Altmeyer 1994) at 4; Ex. 1028 (Mroweitz 1998) at 4. Doses
`
`of FAEs including up to 720 mg/day of DMF were shown to be effective in treating
`
`psoriasis. See, e.g., Ex. 1029 (Nugteren-Huying 1990) at 1; Ex. 1030 (Altmeyer
`
`1994) at 2, 4; Ex. 1028 (Mroweitz 1998) at 4. One of the well-known reported
`
`drawbacks of FAEs were its side effects, the main effects being flushing, diarrhea,
`
`fatigue and nausea. See, e.g., Ex. 1029 (Nugteren-Huying 1990) at 1; Ex. 1030
`
`(Altmeyer 1994) at 4; Ex. 1028 (Mroweitz 1998) at 4. Adverse effects were reported
`
`to be related to the dose of FAEs. Ex. 1028 (Mroweitz 1998) at Abstract, 4. A slow
`
`increase in dosage or lower dose regimens were suggested to overcome the problem
`
`with side effects. Ex. 1029 (Nugteren-Huying 1990) at1; Ex. 1030 (Altmeyer 1994)
`
`at 4; Ex. 1028 (Mroweitz 1998) at 4.
`
`35. By 1994, a combination of FAEs marketed as Fumaderm® was
`
`approved in Germany for the treatment of psoriasis. In at least 2004, two different
`
`enteric coated Fumaderm® tablets were available that included 30 mg of DMF
`
`(Fumaderm® initial) or 120 mg of DMF (Fumaderm®) and three salts of monoethyl
`
`fumarate (MEF). Ex. 1020 (Fumaderm Label) at 2. The dosage schedule for treating
`
`psoriasis with Fumaderm® consisted of an escalating dose for three weeks of up to
`
`three Fumaderm® initial tablets/day (DMF 90 mg/day) followed by an escalating
`
`dose of up to six Fumaderm® tablets/day (DMF 720 mg/day). Id. at 3. The
`
`Fumaderm® dosage schedule included daily doses of Fumaderm® containing DMF
`
`US_137978938v1_385667-00004
`
`16
`
`Sawai (IPR2019-00789), Ex. 1057, p. 016
`
`

`

`
`
`120 mg/day (week 1), DMF 240 mg/day (week 2), DMF 360 mg/day (week 3), DMF
`
`480 mg/day (week 4), DMF 600 mg/day (week 5), DMF 720 mg/day (week 6). Id.
`
`at 3. The Fumaderm Label lists various side effects reported with Fumaderm®
`
`treatment, such as flushing, gastrointestinal disorders, lymphopenia, and leukopenia.
`
`Id. at 4-5.
`
`2.
`
`DMF as a monotherapy to treat psoriasis.
`
`36.
`
`In the early 1990s, researchers investigated the in vitro activity of the
`
`different FAEs comprising Fumaderm® and reported that DMF is the most active
`
`component in Fumaderm®. For example, Nibbering 1993 reported that “[MMF] is
`
`the most active metabolite of the new antipsoriasis drug Fumaderm.” Ex. 1024 at
`
`Abstract. Another study stated that “[t]he most effective fumarate metabolite of
`
`[Fumaderm] is monomethylfumarate (MMF), which is formed in the circulation by
`
`hydrolysis of DMF.” Ex. 1023 (de Jong 1996) at 1. Another in vitro investigation
`
`“confirm[ed]
`
`the conclusion
`
`.
`
`.
`
`.
`
`that DMF, which
`
`is metabolized
`
`to
`
`monomethylfumarate (MMF), is apparently the most potent antipsoriatic substance
`
`in [Fumaderm].” Ex. 1021 (Ockenfels 1998) at 4. And in 2004, Ormerod concluded
`
`that “there is cumulating evidence that dimethylfumarate (DMF), the main
`
`ingredient of [Fumaderm®], is the active compound.” Ex. 1027 (Ormerod) at 1.
`
`37. Clinical trials also explored the differences in therapeutic effectiveness
`
`between DMF and MEF to treat psoriasis and reported that DMF is the most active
`
`US_137978938v1_385667-00004
`
`17
`
`Sawai (IPR2019-00789), Ex. 1057, p. 017
`
`

`

`
`
`of the FAEs and that DMF as a monotherapy was successful in treating psoriasis.
`
`See, e.g., Ex. 1031 (Nieboer 1989); Ex. 1017 (Nieboer 1990). For example, in a
`
`study administering DMF as a monotherapy to treat psoriasis patients, 240 mg/day
`
`of DMF was reported to produce “significant amelioration and prevented extension.”
`
`Ex. 1031 (Nieboer 1989) at Abstract. See also id. at 5. Whereas, another study
`
`reported that treatment with 240 and 720 mg/day of MEF alone found that
`
`240 mg/day was ineffective in treating psoriasis, but that 720 mg/day was beneficial.
`
`Id. at Abstract, 8; see also Ex. 1019 (Mrowietz 2005) at 2 (discussing the results in
`
`Nieboer 1989 and stating “[i]t was concluded that the main active ingredient of
`
`Fumaderm® is DMF”).
`
`38. Another study compared the therapeutic effects of 480 mg/day of DMF
`
`and a combination of FAEs (480 mg/day DMF and salts of MEFs) to determine
`
`whether DMF could be used as a monotherapy for the treatment of psoriasis.
`
`Ex. 1017 (Nieboer 1990) at 2-3. Patients were treated with tablets containing only
`
`DMF (120 mg DMF) or FAE (120 mg DMF plus 87 mg calcium-MEF, 5 mg
`
`magnesium-MEF, 3 mg zinc-MEF). Id. at 3. A gradually increasing dose was
`
`administered up to a maximum of 4 tablets a day (DMF 480 mg/day), handed out in
`
`two administrations daily. Id. Results demonstrated that both groups (480 mg/day
`
`DMF plus salts of MEFs vs. 480 mg/day DMF alone) showed considerable
`
`improvement, and therapeutic effects showed no significant difference in both
`
`US_137978938v1_385667-00004
`
`18
`
`Sawai (IPR2019-00789), Ex. 1057, p. 018
`
`

`

`
`
`groups with respect to psoriasis scores. Id. The study concluded that “treatment of
`
`psoriasis with FAC-EC does not result in a better therapeutic result compared to
`
`DMFAE-EC monotherapy.” Id. at 6.
`
`39. The use of DMF as a monotherapy to treat psoriasis was further
`
`evaluated in the early 2000s. In 2005, Biogen Idec and Fumapharm announced in a
`
`press release that a phase III study “designed to evaluate the efficacy and safety of
`
`BG-12, an oral fumarate, in the treatment of moderate to severe psoriasis” was
`
`successful. Ex. 1026 (Biogen 2005 Press Release). Skilled artisans were aware that
`
`the active component in BG-12 was DMF. Ex. 1034 (Kappos 2005 Poster). Patients
`
`in the study were randomized to receive placebo or 720 mg/day for 16 weeks.
`
`Ex. 1026. The press release reported that “[t]he trial met the primary endpoint and
`
`patients receiving BG-12 demonstrated a statistically significant clinical
`
`improvement as measured by a lower median psoriasis severity score after 16 weeks
`
`of treatment than patients receiving placebo.” Id. During the study, “the most
`
`commonly reported adverse events were flushing and diarrhea.” Id.
`
`3.
`
`Fumaric acid esters to treat multiple sclerosis.
`
`40. Beginning in at least the late 1990s, researchers were investigating
`
`whether FAE therapy was effective in patients with MS owing to the similarity in
`
`immunological pathways between the Th-1 mediated autoimmune diseases,
`
`psoriasis and MS. See Ex. 1012 (Schimrigk 2004 Poster) at 4 (“Given the
`
`US_137978938v1_385667-00004
`
`19
`
`Sawai (IPR2019-00789), Ex. 1057, p. 019
`
`

`

`
`
`involvement of immune-mediated responses and predominance of the Th1 cytokine
`
`profile in both psoriasis and MS, the objective of this study was to determine if oral
`
`fumarate therapy is effective in patients suffering from relapsing-remitting MS
`
`(RRMS).”); Ex. 1006 (Schimrigk 2004 Abstract) at 4-5; see also Ex. 1032 at 7;
`
`Ex. 1033 at 4; Ex. 1044 at 7; Ex. 1045 at 5. A series of abstracts were published that
`
`reported on the beneficial effects of using FAEs (Fumaderm®) to treat small
`
`populations of MS patients. See, e.g., Ex. 1006 at 4-5; Ex. 1013 at 5; Ex. 1014 at 3;
`
`Ex. 1032 at 7; Ex. 1033 at 4; Ex. 1044 at 7; Ex. 1045 at 5.
`
`41. For example, in 2004, the Schimrigk 2004 Abstract disclosed results
`
`from an exploratory, prospective, open-label study investigating the use of
`
`Fumaderm® for the treatment of patients with RRMS. Ex. 1006 at 4-5. The four
`
`phases of the study included a 6-week baseline, an 18-week treatment, a 4-week
`
`wash-out, and a second 70-week treatment phase. Id. at 5. As explained in the
`
`Schimrigk 2004 Abstract, “[a]ll patients were treated with oral fumarate therapy,
`
`with the dosage slowly titrated up to a maximum of 6 tablets per day (720 mg [DMF]
`
`daily) in the first treatment period and up to 3 tablets per day (360 mg [DMF] daily)
`
`in the second treatment period.” Id. Results indicated that “[s]ignificant reductions
`
`from baseline in the number of Gd + lesions were observed starting after week 12 of
`
`treatment with fumarate (p < 0.05).” Id. There were also “significant reductions
`
`from baseline in Gd + lesion volume starting after week 12 (p < 0.01).” Id. The
`
`US_137978938v1_385667-00004
`
`20
`
`Sawai (IPR2019-00789), Ex. 1057, p. 020
`
`

`

`
`
`Schimrigk 2004 Abstract concluded that “[o]ral fumarate therapy significantly
`
`reduced the number and volume of Gd + lesions over 70 weeks of treatment.” Id.
`
`“These findings indicate that oral fumarates may be a promising new treatment for
`
`RRMS.” Id. The results of this study were also presented in a poster presentation
`
`available on Fumapharm’s website in 2004. Ex. 1012 (Schimrigk 2004 Poster); see
`
`also Ex. 1014 (Schimrigk 2005) at 3; Ex. 1018 (Schimrigk 2006).
`
`42. The Brune 2004 Abstract, published in the same journal as the
`
`Schimrigk 2004 Abstract, reported that “[o