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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`MYLAN PHARMACEUTICALS INC.
`Petitioner,
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`v.
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`BIOGEN MA, INC.
`Patent Owner.
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`
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`Patent No. 8,399,514
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`Inter Partes Review IPR2018-01403
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`
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`REPLY DECLARATION OF BENJAMIN M. GREENBERG, M.D.
`IN SUPPORT OF PETITIONER’S REPLY TO PATENT OWNER’S
`RESPONSE
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`TABLE OF CONTENTS
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`Page
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`I.
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`QUALIFICATIONS AND BACKGROUND ................................................ 5
`A.
`Education and Experience; Prior Testimony........................................ 5
`B.
`Bases for Opinions and Materials Considered ..................................... 8
`C.
`Scope of Work ...................................................................................... 8
`SUMMARY OF OPINIONS .......................................................................... 8
`II.
`III. LEGAL STANDARDS .................................................................................. 9
`IV. PERSON OF ORDINARY SKILL IN THE ART ....................................... 10
`V.
`THE ’514 PATENT [EX. 1001] .................................................................. 11
`A.
`Claims of the ’514 Patent ................................................................... 11
`VI. CLAIM CONSTRUCTION ......................................................................... 14
`VII. BACKGROUND .......................................................................................... 14
`A. Multiple Sclerosis ............................................................................... 14
`B. Underlying Causes of MS .................................................................. 15
`C. Multiple Sclerosis Therapies .............................................................. 16
`VIII. SCOPE AND CONTENT OF THE PRIOR ART REFERENCES ............. 19
`A.
`Schimrigk 2004 Abstract [Ex. 1006] ................................................. 19
`B.
`Schimrigk 2004 Poster [Ex. 1012] ..................................................... 20
`C.
`Brune 2004 [Ex. 1013] ....................................................................... 24
`D.
`Schimrigk 2005 Abstract [Ex. 1014] ................................................. 25
`E.
`Kappos 2005 [Ex. 1015] ..................................................................... 26
`F.
`January 2006 Biogen Press Release [Ex. 1005] ................................. 27
`G. May 2006 Biogen Press Release [Ex. 1016] ...................................... 28
`H. Kappos 2006 [Ex. 1007] ..................................................................... 30
`I.
`Kappos 2006 Presentation [Ex. 1046] ................................................ 31
`J. WO ’342 [Ex. 1008] ........................................................................... 34
`K. Nieboer 1990 [Ex. 1017] .................................................................... 36
`L.
`Schimrigk 2006 [Ex. 1018] ................................................................ 37
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`TABLE OF CONTENTS
`(continued)
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`Page
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`
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`M. Mrowietz 2005 [Ex. 1019] ................................................................. 40
`N.
`Fumaderm® Label [Ex. 1020] ........................................................... 41
`O. Ockenfels 1998 [Ex. 1021] ................................................................. 41
`P.
`de Jong 1996 [Ex. 1023] .................................................................... 44
`Q. Nibbering 1993 [Ex. 1024] ................................................................. 46
`R.
`Clinical Trials [Ex. 1010] ................................................................... 46
`S.
`ICH Guidelines [Ex. 1011] ................................................................. 47
`T.
`Joshi Patents [Exs. 1009, 1025] ......................................................... 48
`U.
`Biogen 2005 Press Release [Ex. 1026] .............................................. 49
`V. Ormerod 2004 [Ex. 1027] .................................................................. 50
`W. Mrowietz 1998 [Ex. 1028] ................................................................. 51
`X. Drugs 2005 [Ex. 1118] ....................................................................... 52
`Y.
`Langner 2005 [Ex. 1116] ................................................................... 54
`Z.
`Kolbach 1992 [Ex. 1117] ................................................................... 55
`AA. Additional Prior Art References and Knowledge .............................. 55
`IX. SECONDARY CONSIDERATIONS OF NONOBVIOUSNESS DO
`NOT RENDER THE ’514 PATENT CLAIMS NONOBVIOUS ................ 56
`A.
`The Results of the DEFINE and CONFIRM Trials Are Not
`Unexpected. ........................................................................................ 56
`1.
`Background of DMF-related clinical studies. .......................... 58
`2.
`The results of the DEFINE and CONFIRM studies are
`not unexpected in view of the Kappos Phase II study. ............ 63
`a.
`Skilled artisans would have immediately
`recognized and corrected for the imbalance of
`baseline Gd+ lesions in the Kappos Phase II study. ...... 64
`(i)
`Skilled artisans confirm that the imbalance
`of baseline lesions would have been
`corrected. ............................................................. 72
`(ii) Mylan’s calculations are valid............................. 81
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`TABLE OF CONTENTS
`(continued)
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`Page
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`b.
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`c.
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`d.
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`b.
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`b.
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`c.
`d.
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`Even without adjusting for the baseline imbalance
`in the 360 mg/day group, a skilled artisan would
`have still concluded that 480 mg DMF achieving
`statistical significance was expected. ............................ 91
`Skilled artisans would not credit Biogen’s
`arguments related to the Kappos Phase II study. ........... 94
`Biogen’s unexpected results arguments are based
`on post hoc analyses. ..................................................... 99
`The results of the DEFINE and CONFIRM studies are
`not unexpected in view of the Schimrigk Study. ................... 101
`a.
`Skilled artisans would understand DMF to be the
`most active component of Fumaderm. ........................ 103
`The Schimrigk study suggested 360 mg/day and
`720 mg/day dose were effective in treating
`multiple sclerosis. ........................................................ 107
`DMF treatment of psoriasis would provide relevant
`information about DMF treatment of multiple sclerosis. ...... 114
`Skilled artisans had a motivation to pursue, with a
`reasonable expectation of success, a dose of 480 mg/day
`of DMF for the treatment of multiple sclerosis. .................... 119
`a.
`Ground 1: January 2006 Press Release in view of
`the Schimrigk 2004 Abstract ....................................... 120
`Ground 2: Kappos 2006 in view of the Schimrigk
`2004 Abstract ............................................................... 123
`Ground 3: Kappos 2006 in view of WO ’342 ............. 127
`Ground 4: Kappos 2006, Clinical Trials, Joshi 999,
`and ICH Guidelines ..................................................... 128
`There Was No Failure of Others That the Claims of the ᾽514
`Patent Satisfied ................................................................................. 131
`The ᾽514 Patent Satisfied No Long-Felt But Unmet Need .............. 132
`C.
`CONCLUSION ........................................................................................... 134
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`X.
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`3.
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`4.
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`5.
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`B.
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`1. My name is Benjamin M. Greenberg, M.D. I have been retained by
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`counsel for Mylan Pharmaceuticals Inc. (“Mylan”). I understand that Mylan
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`submitted a petition for inter partes review (“IPR”) of U.S. Patent No. 8,399,514
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`(“the ’514 patent”), Ex. 1001, in which Mylan requested that the United States
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`Patent and Trademark Office cancel all claims of the ’514 patent as unpatentable. I
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`understand that the Patent Trial and Appeal Board (“PTAB”) instituted IPR of the
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`’514 patent. Paper No. 12. I submit this expert declaration to respond to opinions
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`expressed in the expert declarations submitted with Patent Owner’s Response to
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`the Petition dated May 31, 2019. Exs. 2057, 2058, 2060, 2061. I am also Mylan’s
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`expert witness in a parallel district court proceeding relating to the ’514 patent,
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`Biogen Int’l GmbH v. Mylan Pharms Inc., C.A. No. 1:17-cv-116-IMK (N.D.
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`W.Va.), in which I have submitted expert reports setting forth similar views of
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`obviousness and secondary considerations as set forth here.
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`I.
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`QUALIFICATIONS AND BACKGROUND
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`A. Education and Experience; Prior Testimony
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`2.
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`I received an M.D. from Baylor College of Medicine in 2001. In 2005
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`I completed a residency in Neurology at Johns Hopkins Hospital. From 2005 to
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`2007 I was a postdoctoral fellow in Microbiology and Immunology at Johns
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`Hopkins School of Public Health. From 2005 to 2008 I had an academic
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`appointment at Johns Hopkins, first as a Clinical Instructor, and then as an
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`Assistant Professor. During that same time, I was also a treating Neurologist.
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`Since 2009, I have been employed by the University of Texas Southwestern, first
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`as an Assistant Professor and more recently, since 2019 as a Professor. I have also
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`been a practicing Neurologist since 2009 at hospitals associated with the
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`University of Texas Southwestern. I was originally named the Deputy Director of
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`the Multiple Sclerosis Program and Director of the new Transverse Myelitis and
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`Neuromyelitis Optica Program and have since become the Director of all three
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`programs.
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`3.
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`Since 2009, I have treated over 1,250 patients with multiple sclerosis
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`(“MS”).
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`4. My duties at the University of Texas Southwestern include clinical,
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`research, education and administrative activities. I see both adults and children
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`with autoimmune disorders of the central nervous system. My outpatient clinics
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`involve evaluating patients who are being diagnosed with multiple sclerosis and
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`related conditions as well as formulating treatment plans for those patients. In this
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`role I act as a consultant to outside treating neurologists and as the primary
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`physician to patients with multiple sclerosis. My research activities involve both
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`clinical and translational research projects. I have served as the principal
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`investigator on numerous interventional and observational multiple sclerosis
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`clinical trials. I coordinate the activities of phase 1, phase 2, phase 3 and phase 4
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`-6-
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`clinical trials and I oversee a translational research program that identifies novel
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`biomarkers of disease in patients with multiple sclerosis. My educational roles
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`have included serving as course co-director of the medical school neurosciences
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`course, a teacher of residents on the inpatient services and as fellowship director
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`for the multiple sclerosis and autoimmune neurology fellowships. I have routinely
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`been a course director or lecturer at the American Academy of Neurology annual
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`meeting, including several years lecturing about multiple sclerosis therapeutics.
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`Finally, my administrative roles currently include serving as head of the
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`neuroimmunology program and the vice chair of research within the Department of
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`Neurology and Neurotherapeutics as well as the Director of the Neurosciences
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`Translational Research Center at the University of Texas Southwestern.
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`5.
`
`Additionally, I was a section editor for JAMA Neurology and have
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`been a reviewer for European Neurology, Neurology, Annals of Neurology,
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`Journal of Neurology, Journal of Immunology, and Multiple Sclerosis Journal.
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`6.
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`As of September 2019, my research has resulted in more than 110
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`publications. I have also been invited to present my work on more than 50
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`occasions.
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`7.
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`I have over 15 years of practical and research experience in the
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`treatment of patients with MS, and in the field of neurology.
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`8. My curriculum vitae is attached hereto as Exhibit A.
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`9.
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`In the past four years, I have testified as an expert at trial or by
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`deposition in the following case: Biogen Int’l GmbH v. Mylan Pharms Inc., C.A.
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`No. 1:17-cv-116-IMK (N.D. W.Va.).
`
`B.
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`Bases for Opinions and Materials Considered
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`10. Exhibit B includes a list of the materials I considered, in addition to
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`my experience, education, and training, in providing the opinions contained herein.
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`C.
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`11.
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`Scope of Work
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`I have been retained by Mylan as a technical expert in this matter to
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`provide various opinions regarding the ’514 patent. I receive $600 per hour for
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`services related to drafting the declaration and will receive $1000 per hour for
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`services related to depositions. No part of my compensation is dependent upon my
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`opinions given or the outcome of this case. I do not have any affiliations with
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`Biogen MA Inc., or any affiliates presently known to me, or the named inventors
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`on the ’514 patent.
`
`II.
`
`SUMMARY OF OPINIONS
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`12. There is nothing surprising about the magnitude of efficacy of the 480
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`mg/day dose of DMF to treat multiple sclerosis in Biogen’s Phase III clinical trials,
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`the Determination of the Efficacy and Safety of Oral fumarate in Relapsing-
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`Remitting MS (“DEFINE”) study and the Comparator and an Oral Fumarate in
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`Relapsing–Remitting Multiple Sclerosis (“CONFIRM”) study. The magnitude of
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`efficacy demonstrated by the 480 mg/day dose of DMF would be expected based
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`on the prior art.
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`13.
`
`In addition, I have reviewed the Expert Declarations of Dr. John
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`Corboy and Dr. Leslie Benet, which were submitted in support of Mylan’s Petition
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`for Inter Partes Review of the ’514 patent. Exs. 1002, 1003. I agree with Drs.
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`Corboy and Benet’s opinions that the ’514 patent is obvious based on the following
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`combinations in Grounds 1-4:
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`(1) the Schimrigk 2004 Abstract (Ex. 1006) and the January 2006 Biogen
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`Press Release (Ex. 1005);
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`(2) the Schimrigk 2004 Abstract (Ex. 1006) and Kappos 2006 (Ex. 1007);
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`(3) Kappos 2006 (Ex. 1007) and WO ’342 (Ex. 1008); and
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`(4) Kappos 2006 (Ex. 1007), Joshi ’999 (Ex. 1009), Clinical Trials (Ex.
`
`1010, 1057), and the ICH Guidelines (Ex. 1011).
`
`14. As described below and in Drs. Corboy and Benet’s declarations, each
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`of the combinations provide disclosures that would have motivated skilled artisans,
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`with a reasonable expectation of success, to administer 480 mg of DMF per day to
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`treat MS.
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`III. LEGAL STANDARDS
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`15.
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`In preparing and forming my opinions set forth in this declaration, I
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`have been informed regarding the relevant legal principles. I have used my
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`understanding of those principles in forming my opinions. My understanding of
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`those principles is summarized below.
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`16.
`
`I have been told that Mylan bears the burden of proving
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`unpatentability by a preponderance of the evidence. I am informed that this
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`“preponderance-of-the-evidence” standard means that Mylan must show that
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`unpatentability is more probable than not. I have taken these principles into
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`account when forming my opinions in this case.
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`17.
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`I am told that the concept of patent obviousness involves four factual
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`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
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`(4) secondary considerations of non-obviousness.
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`IV. PERSON OF ORDINARY SKILL IN THE ART
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`18.
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`I have been informed by counsel that the obviousness analysis is to be
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`conducted from the perspective of a person of ordinary skill in the art (a “person of
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`ordinary skill” or “skilled artisan”) at the time of the invention.
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`19.
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`I have also been informed by counsel that in defining a person of
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`ordinary skill the following factors may be considered: (1) the educational level of
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`the inventor; (2) the type of problems encountered in the art; (3) prior art solutions
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`to those problems; (4) rapidity with which innovations are made; and (5)
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`sophistication of the technology and educational level of active workers in the
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`field.
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`20. Here, a person having ordinary skill in the art would have had (1)
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`several years’ experience in designing clinical studies to meet regulatory
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`expectations or analyzing data from such studies; (2) an advanced degree (PhD,
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`MD, PharmD) and training in clinical pharmacology or experience treating MS;
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`and (3) experience with the administration or formulation of therapeutic agents,
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`their dosing, and the literature concerning drug developmental study and design.
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`21.
`
`I understand that Patent Owner’s definition of a person of ordinary
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`still in the art is “a person with a medical degree with at least three years of
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`training in neurology and at least three years of clinical experience treating MS.”
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`Paper 38 at 14.
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`22. Regardless of which definition of a skilled artisan is ultimately
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`chosen, my opinions set forth below are identical under either definition.
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`V. THE ’514 PATENT [EX. 1001]
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`A. Claims of the ’514 Patent
`
`23.
`
`I have read the ’514 patent and the issued claims entitled “Treatment
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`for Multiple Sclerosis.” The ’514 patent was filed on February 13, 2012 and
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`claims priority to a provisional application filed on February 8, 2007. The ’514
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`patent issued on March 19, 2013 and lists Matvey Lukashev and Gilmore O’Neill
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`as inventors.
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`24. The ’514 patent has four independent claims—claims 1, 11, 15, and
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`20.
`
`25.
`
`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.
`
`26. Dependent claims 2-10 and 17 depend from claim 1. Dependent
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`claim 2 recites the form of a pharmaceutical preparation. Dependent claims 3-5,
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`and 8-10 recite various dosing schedules. Dependent claims 6-7 recite dimethyl
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`fumarate or monomethyl fumarate, respectively. Dependent claim 17 recites a
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`limitation related to the expression levels of NQO1.
`
`27.
`
`Independent claims 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
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`combination thereof.”
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`-12-
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`28. Dependent claims 12-14 and 18 depend from claim 11. Dependent
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`claim 12 recites the administration of 480 mg of dimethyl fumarate to a subject.
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`Dependent claims 13-14 recite specific dosing schedules. Dependent claim 18
`
`recites a limitation related to the expression levels of NQO1.
`
`29.
`
`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.
`
`30. Dependent claims 16 and 19 depend from claim 15. Dependent claim
`
`16 and recites a dosing schedule and dependent claim 19 recites a limitation related
`
`to the expression levels of NQO1.
`
`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.”
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`VI. CLAIM CONSTRUCTION
`
`32.
`
`I understand that the claim terms used in the ’514 patent are given
`
`their ordinary and customary meaning when read in light of the specification and
`
`prosecution history from the perspective of a person of ordinary skill in the art.
`
`VII. BACKGROUND
`
`A. Multiple Sclerosis
`
`33. MS is an autoimmune disease of the central nervous system (CNS).
`
`MS largely effects young adults, with onset often occurring around 30 years of age.
`
`Early in the disease, an MS patient experiences intermittent potentially debilitating
`
`events in which the patient’s immune system attacks the patient’s own nervous
`
`system cells. In MS, a patient’s immune system attacks the myelin that usually
`
`forms a protective sheath around nerve fibers, resulting in damage known as
`
`“demyelination.” Without the protective myelin layer, signal transduction is
`
`impaired, and the nerve cells become damaged. The areas of demyelination in the
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`brain, spinal cord and optic nerves are known as plaques or lesions. The damage
`
`that occurs with MS presents with a wide array of potential physical symptoms
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`such as vision changes, numbness, muscle weakness and spasticity, loss of control
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`of bladder and/or bowel control, fatigue, and depression.
`
`34. There are several clinical patterns of MS in terms of the progression
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`of the disease. They include clinically-isolated syndrome (CIS), relapsing-
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`remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis
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`(SPMS) and primary progressive multiple sclerosis (PPMS). RRMS is the most
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`common type of MS today. Patients with RRMS experience defined relapses, or
`
`exacerbations, followed by partial to full recovery of neurological deficits over
`
`weeks to months, although recovery is often not complete. Over time, patients
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`may experience fewer relapses, but have increasing underlying disease progression
`
`and related neurological dysfunction. When patients no longer experience specific
`
`relapses, but continue to acquire disability, the disease has transitioned into SPMS.
`
`Many patients with RRMS ultimately develop SPMS.
`
`35. Diagnosis of MS relies on several lines of evidence, including the
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`clinical exam, magnetic resonance imaging (MRI), evaluation of cerebrospinal
`
`fluid and exclusion of potential alternative diagnoses. Monitoring of MS patients
`
`involves measures of clinical disability such as the Expanded Disability Status
`
`Scale (EDSS), Ambulation Index (AI), relapse frequency and MRI. Prior to 2007,
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`MRI was used, and continues to be used today to assess brain lesions indicative of
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`disease activity. See, e.g., Ex. 1006 (Schimrigk 2004 Abstract).
`
`B. Underlying Causes of MS
`
`36. The underlying mechanism by which MS causes neurological damage
`
`is not completely understood today. However, prior to 2007 and continuing today,
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`the underlying cause of damage in MS has been understood to involve cells that
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`are active in immunological responses known as T cells. It is thought today, and it
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`was thought prior to 2007, that a significant number of patients have Th1 cells (a
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`specific type of T-helper cell) reacting to a patient’s own nervous system.
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`37.
`
`It is (and was prior to 2007) thought that Th1 cells are “activated”
`
`outside the central nervous system. Activation of T cells occur when an antigen
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`presenting cell presents a specific protein sequence to a T cell that is able to
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`“recognize” the protein. Normally, if that protein belongs to an infectious
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`organism (e.g. a virus or bacteria), the T cell is activated to hunt for the organism
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`and kill it, thereby protecting humans from infections. If the protein presented is
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`of human origin, the T cell is supposed to become “tolerized” to the protein and as
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`such able to distinguish between “self” and “non-self,” thereby preventing immune
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`mediated attacks on the human body. When Th1 cells fail to become tolerized and
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`are mistakenly activated in the periphery against a brain-based protein,
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`autoimmune conditions of the central nervous system such as MS are the result.
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`The activation of these T cells allows for those cells to cross the “blood-brain
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`barrier” and “attack” the brain, leading to inflammatory lesions and damage to the
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`nervous system.
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`C. Multiple Sclerosis Therapies
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`38. While multiple sclerosis remains incurable today, there are several
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`therapies available to treat MS. Skilled artisans generally take three approaches to
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`treat MS and its symptoms: (1) prescribe corticosteroids to speed recovery from
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`symptoms associated with relapses, (2) prescribe disease modifying therapies
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`(“DMTs”) which are agents that are thought to alter the course of the disease and
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`are known to reduce the number of relapses, and (3) prescribe agents and/or
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`therapy to treat the variety of neurological symptoms a patient may develop during
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`the course of the condition.
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`39. As noted above, DMTs are agents that work to modify the course of
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`the disease, and in particular, work to address the underlying immune system
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`disease. DMTs are used to reduce brain inflammatory injury and to reduce the
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`number of relapses, by modifying the peripheral immune system. The alteration of
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`the immune system reduces relapses and thus slows disease progression. To
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`determine efficacy of potential DMTs, skilled artisans look to disease markers such
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`as brain lesions on MRI and effect on reducing frequency of relapses.
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`40. Prior to February 2007, the following DMTs were available to treat
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`MS:
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`1) Interferon beta-1b (Betaseron®), which was approved by the FDA in
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`1993, is administered via subcutaneous injection, every-other-day, and
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`indicated for the treatment of patients with RRMS.
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`2) Interferon beta-1a (Avonex®), which was approved by the FDA in
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`1996, is administered weekly intramuscularly, and was originally
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`indicated for the treatment of patients with RRMS. It is also now
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`indicated for patients with CIS who have had a first clinical episode
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`along with MRI results consistent with MS.
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`3) Glatiramer acetate (Copaxone®), which was approved by the FDA in
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`1996, was administered via subcutaneous injection daily, and was
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`indicated for the treatment of patients with RRMS. It is also now
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`indicated for patients with CIS who have had a first clinical episode
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`along with MRI results consistent with MS.
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`4) Mitoxantrone hydrochloride (Novantrone®), which was approved by
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`the FDA in 2000, is administered intravenously and indicated for the
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`treatment of patients with secondary progressive MS (SPMS), in
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`progressive-relapsing MS, and for patients with worsening RRMS.
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`5) Interferon beta-1a (Rebif®), which was approved by the FDA in
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`2002, is administered via subcutaneous injection three times weekly
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`with at least 48 hours between doses and is indicated for the treatment
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`of patients with RRMS.
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`6) Natalizumab (Tysabri®), which was approved by the FDA in 2004, is
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`administered intravenously every four weeks, and is indicated for the
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`treatment of patients with RRMS and for patients with Crohn’s
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`disease.
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`VIII. SCOPE AND CONTENT OF THE PRIOR ART REFERENCES
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`A.
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`Schimrigk 2004 Abstract [Ex. 1006]
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`41. 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-
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`Remitting Multiple Sclerosis.” Ex. 1006. It is my understanding that Schimrigk
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`2004 Abstract is prior art to the ’514 patent because it was published prior to
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`February 2007.
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`42. The Schimrigk 2004 Abstract begins “[o]ral fumarate is an effective
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`and safe therapy for the treatment of psoriasis.” Id. at 4. It goes on to state that
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`“[s]imilar to psoriasis, the inflammatory process in [MS]” is thought to be
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`mediated by the same immune system mechanisms. Id. at 4-5.
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`43. The study states it was performed “[t]o evaluate the safety and
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`efficacy of oral fumarate therapy (Fumaderm) in patients with relapsing-remitting
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`MS (RRMS).” Id. at 5. “The study consisted of four phases, a 6-week baseline,
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`an 18-week treatment, a 4-week wash-out, and a second 70-week treatment phase.”
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`Id. The dosing of Fumaderm® used in the study is described as follows: “slowly
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`titrated up to a maximum of 6 tablets per day (720 mg daily) in the first treatment
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`period and up to 3 tablets per day (360 mg daily) in the second treatment period.”
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`Id. Skilled artisans understand that the 720 mg/day and 360 mg/day doses referred
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`to are the amount of DMF in the dose of Fumaderm®.
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`44. The primary outcome measures of the study were “the number and
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`volume of [Gd+] lesions on serial T1-weighted [MRI] scans.” Id. Additionally,
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`“[c]linical outcomes included [EDSS] score, [AI], and nine-hole peg test (9-HPT).”
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`Id.
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`45. The study discloses that “[m]ild to moderate gastrointestinal
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`discomfort was initially experienced by 6 of 7 patients but decreased gradually
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`during the first 6 weeks of treatment in all patients.” Id. Schimrigk 2004 Abstract
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`further discloses that patients experienced “[s]ignificant reductions from baseline
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`in the number of Gd+ lesions . . . starting after week 12 of treatment with fumarate
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`(p< 0.05),” as well as “[s]ignificant reductions from baseline in Gd+ lesion volume
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`starting after week 12 (p<0.01).” Id. The Schimrigk 2004 Abstract also states
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`“EDSS scores, AI, and 9-HPT remained stable or slightly improved from baseline
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`in all patients,” but those effects were not statistically significant. Id.
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`46. Therefore, the study finds that “[o]ral fumarate therapy significantly
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`reduced the number and volume of Gd+ lesions over 70 weeks of treatment” and
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`concludes that the findings “indicate that oral fumarates may be a promising new
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`treatment for RRMS.” Id.
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`B.
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`Schimrigk 2004 Poster [Ex. 1012]
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`47. The Schimrigk 2004 Poster is titled “A Prospective, Open-Label,
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`Phase II Study of Oral Fumarate Therapy for the Treatment of Relapsing-
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`Remitting Multiple Sclerosis.” Ex. 1012. The Schimrigk 2004 Poster was
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`presented at the 20th Congress of the European Committee for Treatment and
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`Research in Multiple Sclerosis (ECTRIMS) which took place October 6-9, 2004 in
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`Vienna, Austria. It is my understanding that the Schimrigk 2004 Poster is prior art
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`to the ’514 patent because it was published prior to February 2007.
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`48. The Schimrigk 2004 Poster provides results of the same study as
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`discussed in the Schimrigk 2004 Abstract. The presentation of the Schimrigk 2004
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`Poster was “supported by Biogen Idec, Inc.” Id.
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`49. The Schimrigk 2004 Poster discloses that the study was “to d