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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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`
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`
`
`TWI PHARMACEUTICALS, INC.,
`Petitioner,
`
`v.
`
`MERCK SERONO SA,
`Patent Owner.
`
`
`
`Case IPR2023-00049
`Patent 7,713,947
`
`Case IPR2023-00050
`Patent 8,377,903
`
`
`
`
`DECLARATION OF FRED D. LUBLIN, M.D.
`UNDER 37 C.F.R. § 1.68
`
`
`
`Merck 2019
`TWi v. Merck
`IPR2023-00049
`IPR2023-00050
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`TABLE OF CONTENTS
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`IPR2023-00049
`IPR2023-00050
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`I.
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`INTRODUCTION ........................................................................................... 1
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`II.
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`BACKGROUND AND QUALIFICATIONS ................................................. 2
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`III.
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`SUMMARY OF OPINIONS ........................................................................... 6
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`IV. LEVEL OF SKILL IN THE ART ................................................................. 12
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`V.
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`LEGAL STANDARDS ................................................................................. 13
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`A. NOVELTY .......................................................................................... 13
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`B.
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`OBVIOUSNESS ................................................................................. 14
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`C.
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`CLAIM CONSTRUCTION ................................................................ 15
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`VI. TECHNICAL FIELD OF THE ART ............................................................ 16
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`A. Multiple Sclerosis ................................................................................ 16
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`1. MS Clinical Course and Diagnosis ........................................... 17
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`2. MS Treatment as of 2004 .......................................................... 19
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`3.
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`4.
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`Outcome Measures in MS Clinical Trials................................. 28
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`Cladribine Investigations For MS ............................................. 31
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`B.
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`Alleged Prior Art ................................................................................. 36
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`1.
`
`2.
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`Bodor (Ex. 1029)....................................................................... 36
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`Rice (Ex. 1008) ......................................................................... 36
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`VII. THE ’947 AND ’903 PATENTS INVENTIONS ......................................... 39
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`A.
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`The ’947 Patent Invention ................................................................... 39
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`
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`i
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`The ’903 Patent Invention ................................................................... 43
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`B.
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`VIII. THE CHALLENGED CLAIMS OF THE ’947 AND ’903 PATENTS
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`ARE PATENTABLE..................................................................................... 46
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`A. Ground I: Claims 36, 38-39, and 41-48 of the ’947 Patent and
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`Claims 17, 19-20, and 22-29 of the ’903 Patent Are Not
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`Anticipated by Bodor .......................................................................... 47
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`1.
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`The Challenged Claims of the ’947 Patent and the ’903
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`Patent ......................................................................................... 47
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`a.
`
`Bodor Does Not Disclose All Claim Limitations ........... 47
`
`i.
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`Bodor Does Not Disclose the Claimed
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`Induction Period Dose of About 1.7 or 1.7-
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`3.5 Mg/Kg or Maintenance Period Dose of
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`About 1.7 Mg/Kg ................................................. 47
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`b.
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`Bodor Does Not Disclose a Maintenance Period as
`
`Claimed ........................................................................... 53
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`i.
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`Bodor Does Not Disclose Re-Treatment.............. 53
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`a) Cladribine Treatment Raises Safety
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`Concerns ..................................................... 54
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`
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`ii
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`b) There Was No “Standard Course of
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`Treatment” For Dosing
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`Immunosuppressants .................................. 57
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`c) The Art Did Not Disclose a Maintenance
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`Period as Claimed ...................................... 66
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`2.
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`The Challenged Claims of the ’903 Patent ............................... 75
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`B.
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`Ground II: Claims 36, 38-39, 41-48 of the ’947 Patent and
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`Claims 17, 19-20, and 22-29 of the ’903 Patent Would Not
`
`Have Been Obvious Over Bodor in View of the Knowledge of a
`
`POSA ................................................................................................... 77
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`1.
`
`The Challenged Claims of the ’947 Patent and the ’903
`
`Patent ......................................................................................... 77
`
`a.
`
`Bodor Does Not Disclose or Suggest All Claim
`
`Limitations ...................................................................... 77
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`b.
`
`A POSA Would Not Have Been Motivated to
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`Modify Bodor’s Method to Arrive at the Claims or
`
`Have Had Any Reasonable Expectation of Success
`
`in Doing So ..................................................................... 77
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`i.
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`A POSA Would Not Have Been Motivated
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`to Repeat Bodor’s Method to Treat MS or
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`iii
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`Have Had Any Reasonable Expectation of
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`Success in Doing So ............................................. 77
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`ii.
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`A POSA Would Not Have Been Motivated
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`to “Fine Tune Dosages” to Arrive at the
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`Claimed Method with a Reasonable
`
`Expectation of Success ......................................... 91
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`2.
`
`The Challenged Claims of the ’903 Patent ............................... 98
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`C.
`
`Ground III: Claims 36, 38-39, 41-48 of the ’947 Patent and
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`Claims 17, 19-20, and 22-29 of the ’903 Patent Would Not
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`Have Been Obvious Over Bodor and Rice ....................................... 100
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`1.
`
`The Challenged Claims of the ’947 Patent and the ’903
`
`Patent ....................................................................................... 100
`
`a.
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`Bodor and Rice Do Not Teach or Suggest All
`
`Claim Limitations ......................................................... 100
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`b.
`
`A POSA Would Not Have Been Motivated to
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`Combine or Modify Bodor and Rice to Arrive at
`
`the Claimed Method or Have Had a Reasonable
`
`Expectation of Success in Doing So ............................. 103
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`2.
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`The Challenged Claims of the ’903 Patent ............................. 109
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`
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`iv
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`IX. OBJECTIVE INDICIA SUPPORT THE NON-OBVIOUSNESS OF
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`THE CHALLENGED CLAIMS OF THE ’947 AND ’903 PATENTS ..... 110
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`A.
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`Skepticism Of Others ........................................................................ 111
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`B.
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`Unexpected Results ........................................................................... 115
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`C.
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`Long-Felt Need .................................................................................. 121
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`D. Nexus ................................................................................................. 124
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`X.
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`CONCLUSION ............................................................................................ 156
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`
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`v
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`IPR2023-00049
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`I, Fred D. Lublin, M.D., declare as follows:
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`I.
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`INTRODUCTION
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`1.
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`I am over eighteen years of age, and I am competent to testify as to
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`the matters set forth herein if I am called upon to do so.
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`2.
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`I have prepared this Declaration for consideration by the Patent Trial
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`and Appeal Board in the following Inter Partes Review proceedings: IPR2023-
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`00049 and IPR2023-00050. I understand that IPR2023-00049 corresponds to Inter
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`Partes Review of U.S. Patent No. 7,713,947 (the “’947 patent”) (Ex. 1001). I
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`understand that IPR2023-00050 corresponds to Inter Partes Review of U.S. Patent
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`No. 8,377,903 (the “’903 patent”) (Ex. 1002).1
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`3.
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`I have written this Declaration on behalf of Merck Serono SA in
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`connection with the above-captioned Inter Partes Review proceedings. I am being
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`compensated for my time at my normal consulting rate of $900 per hour for non-
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`deposition time and a $9,000 flat fee per day for deposition time. My
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`compensation is not dependent on the substance of my testimony or the outcome of
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`the proceedings.
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`1 The exhibit numbers in IPR2023-00049 and IPR2023-00050 are identical, i.e.,
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`the same exhibit number refers to the same document in both proceedings.
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`1
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`In forming my opinions, in addition to my knowledge and experience,
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`4.
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`I have considered the materials cited herein and listed in Appendix A.
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`5.
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`All statements in my Declaration, unless indicated otherwise, are
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`based on my knowledge and experience in the field.
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`II. BACKGROUND AND QUALIFICATIONS
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`6.
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`I am a Professor of Neurology and the Director of the Corinne
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`Goldsmith Dickinson Center for Multiple Sclerosis at the Icahn School of
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`Medicine at Mount Sinai in New York City. I am also an Attending Neurologist at
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`Mount Sinai Hospital. My full qualifications are below and in my CV, a copy of
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`which is attached as Appendix B to this Declaration.
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`7. My professional interests relate primarily to neurology and
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`neuroimmunology, and specifically to (1) the scientific and clinical aspects of
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`multiple sclerosis (“MS”) and (2) the research and development of therapies for
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`treating MS. I have authored or co-authored over 250 peer-reviewed academic
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`publications in the field of neurology, with an emphasis on MS. I have also written
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`or co-written over 240 textbook chapters, editorials, abstracts, and letters in my
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`areas of interest, including the textbook Multiple Sclerosis in Clinical Practice,
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`Martin Dunitz, Ltd. (2003).
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`8.
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`I received my A.B. in Biology from Temple University in 1968
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`(magna cum laude), and my M.D. from Jefferson Medical College in 1972 (summa
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`2
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`IPR2023-00049
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`cum laude). From 1972-1973, I interned at the Bronx Municipal Hospital-Albert
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`Einstein Medical Center in New York City, specializing in internal medicine. I
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`also completed an externship at the National Hospital for Nervous Disease in
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`London in 1972. From 1973-1976, I was a resident in Neurology at New York
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`Hospital-Cornell Medical Center in New York City, NY.
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`9.
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`For the last 48 years, I have maintained an active neurology practice.
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`I started as a resident at New York Hospital (1973-1976) and then as an attending
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`physician at Thomas Jefferson University Hospital (1976-1996), Medical College
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`of Pennsylvania Hospital and Hahnemann University Hospital (1996-2000), and
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`Mount Sinai Hospital (2000-present). Throughout this time, I have been regularly
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`treating Multiple Sclerosis patients and have treated thousands of MS patients
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`since 1976. I currently treat hundreds of MS patients a year.
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`10.
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`In addition to my clinical practice, I have been actively engaged in the
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`training of medical students, residents, fellows, and practicing clinicians in
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`neurology and neuroimmunology throughout my career. I was an Instructor in
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`Neurology at Cornell Medical College (1975-1976) and then an Instructor in
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`Neurology and a Research Associate in Biochemistry (Immunology) at Jefferson
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`Medical College of Thomas Jefferson University (1976-1978). In 1978, I was
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`promoted to Assistant Professor of Neurology and Assistant Professor of
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`Biochemistry and in 1982, to Associate Professor of Neurology. In 1983, I was
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`3
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`promoted to Associate Professor of Biochemistry & Molecular Biology, and in
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`1986, to Professor of Neurology. In 1987, I was appointed Director of the Division
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`of Neuroimmunology, and was named Vice-Chairman of the Department of
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`Neurology. In 1995, I was promoted to Acting Chairman of the Department of
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`Neurology.
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`11.
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`I then joined MCP Hahnemann University (formerly Allegheny
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`University of the Health Sciences) in 1996 as a Professor of Neurology, Vice-
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`Chairman for Clinical Affairs in Neurology, Director of the University’s newly-
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`created Multiple Sclerosis Center, and Director of the Neurological Clinical Trials
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`Center.
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`12. Since 2000, I have been Professor of Neurology and Director of the
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`Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai School
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`of Medicine. Four years after joining Mount Sinai School of Medicine (2004), I
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`was named the Saunders Family Professor of Neurology, an endowed chair that is
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`an honor I hold to this day.
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`13.
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`In addition to research and teaching, I have also served as a reviewer
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`for numerous scientific journals, including Annals of Neurology, Neurology,
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`Science, Brain, Lancet, Laboratory Investigation, Journal of Neuroimmunology,
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`Annals of Internal Medicine, Pediatrics, Journal of the Neurological Sciences,
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`Clinical Therapeutics, Multiple Sclerosis Journal, Journal of NeuroVirology,
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`4
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`Archives of Neurology, BioDrugs, Acta Neurologica Scandinavica, Lancet
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`Neurology, Multiple Sclerosis and Related Disorders, New England Journal of
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`Medicine, and JAMA Neurology. I have also served on the editorial boards of
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`several influential journals in my field. For example, I have served as Co-Chief
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`Editor for the journal Multiple Sclerosis and Related Disorders since its inception
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`in 2011 until December 2017.
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`14.
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`I am a member of several professional medical organizations,
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`including the American Academy of Neurology, where I was named a Fellow in
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`2004, and the American Neurological Association, where I was named a Fellow in
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`2013. I am also a member of the National Multiple Sclerosis Society, where I have
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`chaired several committees.
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`15.
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`I have been the recipient of numerous major grants from respected
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`institutions, including one of the largest grants ever given for MS research by the
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`National Institutes of Health.
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`16.
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`I have served as either Principal or Co-Investigator for numerous
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`clinical trials relating to a wide range of MS treatments, including interferons, of
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`which beta interferon (Betaseron®) was the first FDA-approved drug for MS, as
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`well as biologic medical products (e.g., Avonex®, Rebif®, Tysabri®) and chemical
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`drugs (e.g., cladribine, linomide, tizanidine, Copaxone®, Novantrone®, Ampyra®).
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`I have also served as a member for the Data Safety and Monitoring Boards for
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`5
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`many MS treatments, including Antegren (now called Tysabri®; Biogen-Idec), and
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`Gilenya® (Novartis). In my work in clinical trials, I have witnessed first-hand how
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`drug doses are determined.
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`17.
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`I have also consulted with various pharmaceutical companies,
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`including Serono. I have received one research grant from Serono to support a
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`clinical study on “Rebif Injection with and without the use of Rebiject Mini in
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`Relapsing-Remitting Multiple Sclerosis.”
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`III. SUMMARY OF OPINIONS
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`18.
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`I understand that the Petition for IPR2023-00049 (“Pet.”) challenges
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`claims 36, 38-39, and 41-48 of the ’947 patent (“challenged claims”) as allegedly
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`invalid on three grounds: (1) as allegedly anticipated by Bodor, (2) as allegedly
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`obvious over Bodor in view of the common knowledge of a person having ordinary
`
`skill in the art (“POSA”), and (3) as allegedly obvious over Bodor and Rice. Pet.
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`24-25. I also understand that the Petition for IPR2023-00050 (“’050 Pet.”)
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`challenges claims 17, 19-20, and 22-29 (“’903 challenged claims”) of the ’903
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`Patent on the same grounds. ’050 Pet. 23-24. It is my opinion that the challenged
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`claims of the ’947 and ’903 patents are not invalid on any of these grounds.
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`19. First, Bodor does not teach (or suggest), either expressly or
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`inherently, the claimed weight-based induction or maintenance dosing. Contrary
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`to Dr. Greenberg’s assertion that a POSA would have inferred weight-based dosing
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`6
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`from Bodor by accounting for the supposed weight of an average patient, Bodor is
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`silent as to any patient weight and does not disclose any relationship between the
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`number of days of dosing/cumulative dose and patient weight. A POSA would
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`have understood that Bodor expressly teaches flat, fixed dosing, which is
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`fundamentally different from weight-based dosing.
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`20. Second, Bodor also does not teach (or suggest) the claimed
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`maintenance period or the cladribine-free period thereafter. Bodor does not state
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`(or suggest), either expressly or inherently, either (1) that re-treatment with
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`cladribine would occur immediately after completion of the 10-month cladribine-
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`free period (or otherwise), or (2) how any such re-treatment would be
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`administered, including what dosing would be administered. It was well-known
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`that cladribine may cause significant safety concerns, e.g., lymphocytotoxicity, and
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`thus a POSA would have understood that any subsequent re-treatment would have
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`been based on a combination of factors, such as evidence of disease progression,
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`time course of therapeutic effects, and safety considerations, rather than
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`automatically re-treating after a set period of time, as the Petition suggests. See,
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`e.g., Ex. 1016, 36; Ex. 1008, 1146.
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`21. Contrary to Dr. Greenberg’s assertion, there was (and still is) no
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`standard course of treatment for immunosuppressants that uses intermittent equal
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`dosing. A POSA would have known that approved DMAs in 2004 were dosed
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`7
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`continuously to maintain the drugs’ pharmacological effects, whereas trials that
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`included re-treatment had specified criteria for potential re-treatment and did not
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`automatically or immediately re-treat patients after a period of non-treatment. See
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`Ex. 1008, 1146; Ex. 1016, 43.
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`22. Third, a POSA would not have been motivated to modify Bodor’s
`
`method to arrive at the claimed method with any reasonable expectation of success.
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`A POSA would have had myriad options to choose from in terms of whether or
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`when to begin re-treatment, for how long, and at what dosage(s). There was no
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`consensus in the art for selecting these parameters, and Petitioner and Dr.
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`Greenberg provided none. Given the dissociation between MRI results and lack of
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`clinical efficacy in each of the Rice and Romine studies (e.g., Ex. 1008, 1153; Ex.
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`2014, 34), and the absence of any efficacy data for Bodor’s cladribine formulation,
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`a POSA would not have been motivated to modify Bodor to obtain the claimed
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`regimen based on these or other studies. None of Bodor, Rice, or Romine taught
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`or suggested repeating Bodor’s method to treat MS, nor did they provide a POSA
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`with any motivation or a reasonable expectation of success in doing so.
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`23. Fourth, a POSA would not have “fine-tuned” the dosing regimen of
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`Bodor (or Rice) to arrive at the claimed method. Neither Petitioner nor Dr.
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`Greenberg explain how a POSA would have realistically “fine-tuned” cladribine’s
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`therapeutic efficacy for treating a complex and slowly progressing disease like MS.
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`A POSA would have understood that the benefits of an MS drug can only be
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`assessed over time, and that it would require years to evaluate how changes made
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`to an MS drug’s dose and/or dosing schedule would impact clinical outcomes, and
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`to draw any meaningful conclusions regarding efficacy and safety.
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`24. Additionally, Petitioner and Dr. Greenberg’s unrealistic “fine tuning”
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`arguments ignore the numerous possible combinations of dose, dosing period
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`length/number, and drug-free period length/number that a POSA could have “fine-
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`tuned.” A POSA would have had no motivation or reasonable expectation of
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`success to “fine tune” the various parameters to arrive at the claimed specific
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`dosing regimen, because the art provides no guidance regarding how to select a
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`specific dosing regimen from numerous possible combinations nor how to “fine
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`tune” a dosing regimen to arrive at a safe and effective regimen. Notably, as of
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`2004 (and even now), there was no MS medication that was “fine-tuned;” rather,
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`dosing was limited to a few doses tested over years.
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`25. Fifth, Rice does not remedy the deficiencies of Bodor. Rice merely
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`references “retreatment,” but does not disclose using the same dosing regimen for a
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`second treatment period. The art includes examples where the term “retreatment”
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`(or a variation thereof) is used to describe MS treatment methods where the
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`subsequent treatment period could employ a different dose than the initial
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`treatment period. Ex. 1016, 42-43; Ex. 1028, 271; Ex. 2004, 9-10. Additionally,
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`Rice required that “at least 12 months” elapse after the last dose of cladribine
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`before any re-treatment would even occur, and thus does not teach any
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`maintenance period after an 8-10-month cladribine-free period. Ex. 1008, 1146.
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`26. Sixth, a POSA would not have been motivated to combine Bodor with
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`Rice, or have had any reasonable expectation of success of achieving the claimed
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`invention, at least because (1) Bodor discloses no efficacy data for its dosing
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`regimen; (2) Rice reports “clinical efficacy was not shown,” (Ex. 1008, 1153); and
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`(3) Rice was considered unsuccessful by skilled artisans. Although Rice reported
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`positive MRI results (for T1 enhanced and T2 lesions), Dr. Rice later questioned
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`the “subsequent clinical impact of these results” (e.g., Ex. 2016, 44; Ex. 2065,
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`1714, 1716) and looked instead to other MRI results (T1-hypointense lesions);
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`however, Dr. Rice deemed them to be “clinically unimportant.” Id. Further,
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`skilled artisans, including Dr. Greenberg, noted skepticism of Rice’s results (e.g.,
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`Ex. 2005, 698). Even following Dr. Greenberg’s arguments that a POSA would
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`have focused on Rice’s MRI results, Rice does not report that its MRI results were
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`results of re-treatment. Further, following Dr. Greenberg’s theory, a POSA
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`focusing on Rice’s MRI results would have been motivated to focus on Rice’s 2.1
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`mg/kg subcutaneous cladribine dose, which Rice reported caused greater
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`reductions in both T1 enhanced and T2 lesions.
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`27. Seventh, neither Bodor nor Rice provides any teaching or guidance as
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`to how to modify the prior art to arrive at a safe and effective MS treatment
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`method. Even today, cladribine’s mechanism of action has not been fully
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`elucidated. By the priority date, nothing in the art would have taught a POSA how
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`the combination of the different dosing variables—dose, length and number of
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`dosing period, or length of drug-free periods—would impact the safety/efficacy of
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`the treatment of MS or what specific combination (if any) would result in a safe
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`and effective MS treatment method.
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`28. Eighth, (1) Bodor does not teach (or suggest) treatment of relapsing-
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`remitting multiple sclerosis (“RRMS”) or early secondary progressive multiple
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`sclerosis (“SPMS”) using its dosing method or the method claimed in the ’903
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`patent, nor would a POSA have inferred the same from Bodor’s disclosure; and (2)
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`a POSA would not have been motivated to modify Bodor’s method in view of a
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`POSA’s knowledge to arrive at the method of treating RRMS or early SPMS
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`claimed in the ’903 patent with any reasonable expectation of success. Indeed,
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`Bodor does not discuss treating RRMS or early SPMS with its dosing method or
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`the method claimed in the ’903 patent. Rice does not cure Bodor’s deficiencies
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`and would not have provided a POSA with any motivation to modify Bodor’s
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`method to arrive at the method of treating RRMS or early SPMS claimed in the
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`’903 patent with a reasonable expectation of success.
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`29. Lastly, the non-obviousness of challenged claims of the ’947 and ’903
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`patents is further demonstrated by at least: (1) the skepticism of others, (2) the
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`unexpected durable efficacy and safety of the claimed dosing regimen, and (3) the
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`satisfaction of a long-felt unmet need for a short-course, oral therapy for MS.
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`IV. LEVEL OF SKILL IN THE ART
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`30.
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`I understand that a person having ordinary skill in the art (“POSA”) is
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`a hypothetical person from whose perspective the patentability analysis is
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`performed, and who is presumed to have knowledge of the relevant art at the time
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`of the invention. In my opinion, the definition of a POSA for the ’947 patent and
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`’903 patent should be a person having an M.D. with at least two years of
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`experience treating neurological conditions, with a focus on autoimmune disorders,
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`including but not limited to MS, and prescribing immunotherapies to treat such
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`neurological conditions, and that a POSA would also be part of a team including
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`individuals with experience in investigation of the pharmacokinetics (“PK”) and
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`pharmacodynamics (“PD”) of drugs, pharmaceutical drug development, and
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`clinical trial design.
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`31.
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`I understand that Petitioner has also proposed a definition of a POSA
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`for the ’947 and ’903 patents, specifically: “A person of ordinary skill in the art at
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`the time of the alleged invention would have a Doctor of Medicine and at least
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`two-years’ experience treating neurological conditions and prescribing
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`immunotherapies to treat neurological conditions.” Pet. 8; ’050 Pet. 8.
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`32. As of the priority dates of the ’947 and ’903 patents in 2004, I
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`qualified as a POSA under either of these definitions.
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`33.
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`I provide my analysis from the perspective of a POSA. My analysis
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`would be the same regardless of which party’s definition is applied.
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`V. LEGAL STANDARDS
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`34. This section sets forth certain legal standards that have been provided
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`to me by attorneys for Patent Owner, Merck Serono SA. I understand that the
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`issues presented in these Inter Partes Review proceedings must be considered in
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`view of these legal standards.
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`A. NOVELTY
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`35.
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`I understand that a claim lacks novelty in light of a prior art reference
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`if the prior art reference discloses, either expressly or inherently, each and every
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`limitation of the claim, and additionally that the limitations must be present as
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`arranged in the claim. I understand that identical terminology between the prior art
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`reference and the claim is not required for the prior art reference to anticipate the
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`claim, although the prior art reference must include each and every limitation of
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`the claimed invention.
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`I understand that, when a claim recites a range, a prior art reference
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`36.
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`need only provide one example within that range, rather than recite the entire
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`range, in order to anticipate the claim.
`
`37.
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`I understand that, even if a prior art reference does not explicitly state
`
`a claim limitation, that limitation may be inherent. I understand that inherent
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`anticipation may not be established by probabilities or possibilities. The mere fact
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`that a certain thing may result from a given set of circumstances is not sufficient.
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`B. OBVIOUSNESS
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`38.
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`I understand that a claim is obvious in light of the prior art if the
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`difference or differences between the claimed subject matter and the prior art are
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`such that the subject matter as a whole would have been obvious, at the time the
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`invention was made, to a POSA.
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`39.
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`I understand that several factual inquiries underlie a determination of
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`obviousness. These inquiries include (1) scope and content of the prior art, (2) the
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`level of ordinary skill in the field of the invention, (3) the differences between the
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`claimed invention and the prior art, and (4) any objective evidence of non-
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`obviousness. Such objective evidence of non-obviousness may include the
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`invention’s commercial success, commercial acquiescence (i.e., licensing),
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`satisfaction of a long felt but unresolved need, the failure of others, skepticism,
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`praise by others, teaching away by others, recognition of a problem, laudatory
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`statements by an infringer, unexpected and superior results, and copying of the
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`invention by others. I understand that for objective indicia to be given weight,
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`there must be a nexus between the evidence and the claimed invention.
`
`40.
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`In connection with obviousness, I have been informed that there must
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`have been some reason or motivation that would have led a POSA to combine or
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`modify the relevant teachings in the prior art to obtain the claimed invention, and
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`one of ordinary skill in the art must have had a reasonable expectation of success in
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`doing so. I understand further that it is incorrect to evaluate obviousness from a
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`hindsight perspective using the teachings of the patent at issue as a guide.
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`C. CLAIM CONSTRUCTION
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`41.
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`I understand that each term of the claims of a patent should be
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`interpreted according to its plain and ordinary meaning to a POSA at the time of
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`the invention in the context of the patent and the file history.
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`42. With respect to challenged claims 36, 38, and 41-48 of the ’947 patent
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`and challenged claims 17, 19, and 22-29 of the ’903 patent, I understand the plain
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`and ordinary meaning to provide that the total dose of cladribine administered
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`during the maintenance period can be the same as or lower than the total dose of
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`cladribine administered during the induction period.
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`VI. TECHNICAL FIELD OF THE ART
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`A. Multiple Sclerosis
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`43. MS is an autoimmune disease of the central nervous system (“CNS”).
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`Ex. 2017, 18; Ex. 1001, 1:24-26. The body’s immune system attacks the CNS,
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`leading to destruction of myelin, the substance that surrounds and insulates nerve
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`fibers. Ex. 2017, 18; Ex. 1001, 1:24-26; Ex. 2018, 131. Without myelin, the nerve
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`fibers, or axons, become damaged, and the loss of axons correlates with permanent
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`functional deficit. Ex. 1001, 1:24-26; Ex. 2017, 56, 58. The dead nerve cells
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`accumulate in the brain and spinal cord during the course of the disease, leading to
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`lesions, or scars; hence, the name “multiple sclerosis,” which literally means
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`“many scars.” Ex. 2017, 29.
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`44. While the cause of MS is unknown, by 2004, MS was thought to be a
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`lymphocyte-dependent autoimmune disease, in which lymphocytes, a type of white
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`blood cell that is part of the immune system, become “auto-reactive,” i.e., they
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`recognize and react with endogenous antigens. Ex. 1018, 421. By 2004, these
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`“autoantigen-specific T lymphocytes” were thought to be activated peripherally,
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`i.e., outside of the CNS, before migrating to the CNS. Id. However, the specific
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`antigens and triggering agents involved were unknown. Id. Following migration
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`to the CNS, the T lymphocytes (either CD4+ or CD8+) were thought to be
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`reactivated, where they released pro-inflammatory Th1 (T helper 1) cell cytokines
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`and mediated the destruction of the myelin sheath by various types of immune
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`cells. Ex. 2018, 131. Thus, as of 2004, “T cells and the inflammatory molecules
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`they secrete [we]re not the only players. Many cells and molecules of the immune
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`system … participate in demyelination. The entire cascade of immune system
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`events eventually culminates in myelin destruction.” Ex. 2017, 68-70.
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`1. MS Clinical Course and Diagnosis
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`45. MS is a complex neurological disease. Id., 1. The clinical course of
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`MS is variable such that patients experience the disease and its effects in disparate
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`ways, making it difficult to predict for individual patients. Ex. 1012, 907.
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`Nevertheless, MS “usually can be characterized by either episodic acute periods of
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`worsening (relapses, exacerbations, bouts, attacks), gradual progressive
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`deterioration of neurologic function, or combinations of both.” Id.
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`46. The disease course has been used to define the clinical subtypes of
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`MS. As of 2004, the clinical subtypes included (1) “relapsing-remitting” MS
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`(“RRMS”), (2) “secondary progressive” MS (“SPMS”), (3) “primary progressive”
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`MS (“PPMS”), and (4) progressive-relapsing (“PRMS”). Ex. 1001, 1:48-50.
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`47. RRMS is the most common presenting form of MS. RRMS patients
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`experience relapses or attacks, i.e., “episodes of acute worsening of neurologic
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`function followed by a variable degree of recovery, with a stable course between
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`attacks” characterized by a lack of disease progression. Ex. 1012, 908. The
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`disease course of RRMS, as understood in 2004, is shown in the following graph,
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`in which periods between attacks, i.e., disease relapses, are characterized by lack of
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`disease progression. Id.
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`48. The RRMS disease course can be followed by disease progression
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`with or without relapses, leading to SPMS. Id. An initial, transitional stage
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