UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________________________________
`
`HOPEWELL PHARMA VENTURES, INC.,
`Petitioner,
`
`v.
`MERCK SERONO SA,
`Patent Owner.
`_________________________________________________
`Case IPR2023-00480
`Patent 7,713,947
`____________________________________________________
`
`DECLARATION OF FRED D. LUBLIN, M.D.
`UNDER 37 C.F.R. § 1.68
`
`(cid:48)(cid:72)(cid:85)(cid:70)(cid:78)(cid:3)(cid:21)(cid:19)(cid:24)(cid:20)(cid:3)
`(cid:43)(cid:82)(cid:83)(cid:72)(cid:90)(cid:72)(cid:79)(cid:79)(cid:3)(cid:89)(cid:3)(cid:48)(cid:72)(cid:85)(cid:70)(cid:78)(cid:3)
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:21)(cid:22)(cid:16)(cid:19)(cid:19)(cid:23)(cid:27)(cid:19)
`
`

`

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`TABLE OF CONTENTS
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`IPR2023-00480
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`INTRODUCTION ........................................................................................... 1(cid:3)
`I.
`BACKGROUND AND QUALIFICATIONS ................................................. 1(cid:3)
`II.
`III. SUMMARY OF OPINIONS ........................................................................... 6(cid:3)
`IV. LEVEL OF SKILL IN THE ART ................................................................. 11(cid:3)
`V.
`LEGAL STANDARDS ................................................................................. 12(cid:3)
`A. OBVIOUSNESS ................................................................................. 12(cid:3)
`B.
`CLAIM CONSTRUCTION ................................................................ 14(cid:3)
`VI. TECHNICAL FIELD OF THE ART ............................................................ 14(cid:3)
`A. Multiple Sclerosis ................................................................................ 14(cid:3)
`1. MS Clinical Course and Diagnosis ........................................... 15(cid:3)
`2. MS Treatment as of 2004 .......................................................... 18(cid:3)
`3.
`Outcome Measures In MS Clinical Trials ................................ 24(cid:3)
`4.
`Cladribine Investigations For MS ............................................. 26(cid:3)
`B. Alleged Prior Art ................................................................................. 31(cid:3)
`1.
`Bodor (Ex. 1022)....................................................................... 31(cid:3)
`2.
`Stelmasiak (Ex. 1013) ............................................................... 32(cid:3)
`VII. THE ’947 PATENT INVENTION ................................................................ 34(cid:3)
`VIII. THE CHALLENGED CLAIMS WOULD NOT HAVE BEEN
`OBVIOUS OVER BODOR AND STELMASIAK ...................................... 37(cid:3)
`A. Neither Bodor Nor Stelmasiak Discloses Or Suggests All
`Limitations Of The Challenged Claims .............................................. 38(cid:3)
`1.
`Neither Bodor Nor Stelmasiak Discloses Or Suggests
`The Claimed Weight-Based Induction Or Maintenance
`Dosing ....................................................................................... 38(cid:3)
`
`
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`i
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`2.
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`Neither Bodor Nor Stelmasiak Discloses Or Suggests A
`Maintenance Period As Claimed .............................................. 44(cid:3)
`a.
`Bodor Does Not Teach or Suggest Re-Treatment .......... 44(cid:3)
`
`i.
`
`ii.
`
`Cladribine Treatment Raises Safety
`Concerns ............................................................... 45(cid:3)
`
`Dosing of Approved Disease-Modifying
`Treatments For MS Was Based on
`Pharmacological Effects, Efficacy, And
`Safety .................................................................... 47(cid:3)
`
`iii.
`
`The Art Did Not Suggest A Maintenance
`Period As Claimed ............................................... 53(cid:3)
`
`Stelmasiak Does Not Teach Or Suggest A
`Maintenance Period As Claimed .................................... 57(cid:3)
`
`A POSA Would Not Have Arrived At The
`Claimed Maintenance Period Based on Routine
`Optimization ................................................................... 59(cid:3)
`
`b.
`
`c.
`
`B. A POSA Would Not Have Been Motivated To Combine Bodor
`With Stelmasiak To Arrive At The Challenged Claims With A
`Reasonable Expectation Of Success ................................................... 64(cid:3)
`1.
`A POSA Would Not Have Been Motivated To Arrive At
`The Claimed Dosing Methods Via Routine Optimization
`Or Have Had A Reasonable Expectation Of Success In
`Doing So ................................................................................... 65(cid:3)
`
`
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`ii
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`IPR2023-00480
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`2.
`
`3.
`
`4.
`
`5.
`
`
`A POSA Would Not Have Been Motivated To Adopt
`Weight-Based Dosing Or Have Reasonably Expected To
`Arrive At The Claimed Weight-Based Dosing Regimen ......... 86(cid:3)
`A POSA Would Not Have Been Motivated To Combine
`Bodor With Stelmasiak To Arrive At The Claimed
`Induction Doses Or Have Had A Reasonable Expectation
`Of Success In Doing So ............................................................ 87(cid:3)
`A POSA Would Not Have Been Motivated To
`Immediately Re-Treat Patients After Bodor’s 10-Month
`Cladribine-Free Period Or Have Had A Reasonable
`Expectation Of Success In Doing So ........................................ 94(cid:3)
`A POSA Would Not Have Been Motivated To Combine
`Bodor With Stelmasiak To Arrive At The Claimed 1.7
`Mg/Kg Maintenance Dose Or Have Had A Reasonable
`Expectation Of Success In Doing So ........................................ 98(cid:3)
`The Dependent Claims Would Not Have Been Obvious Over
`Bodor And Stelmasiak ...................................................................... 101(cid:3)
`IX. OBJECTIVE INDICIA SUPPORT THE NON-OBVIOUSNESS OF
`THE CHALLENGED CLAIMS OF THE ’947 PATENT .......................... 103(cid:3)
`A.
`Skepticism Of Others ........................................................................ 103(cid:3)
`B. Unexpected Results ........................................................................... 107(cid:3)
`C.
`Long-Felt Need .................................................................................. 113(cid:3)
`D. Nexus ................................................................................................. 116(cid:3)
`CONCLUSION ............................................................................................ 135(cid:3)
`
`C.
`
`X.
`
`
`
`
`iii
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`
`I, Fred D. Lublin, M.D., declare as follows:
`I.
`INTRODUCTION
`1.
`I am over eighteen years of age, and I am competent to testify as to
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`IPR2023-00480
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`the matters set forth herein if I am called upon to do so.
`
`2.
`
`I have prepared this Declaration for consideration by the Patent Trial
`
`and Appeal Board in the following Inter Partes Review proceeding: IPR2023-
`
`00480. I understand that IPR2023-00480 corresponds to Inter Partes Review of
`
`U.S. Patent No. 7,713,947 (the “’947 patent”) (Ex. 1001).
`
`3.
`
`I have written this Declaration on behalf of Merck Serono SA in
`
`connection with the above-captioned Inter Partes Review proceeding. I am being
`
`compensated for my time at my normal consulting rate of $900 per hour for non-
`
`deposition time and a $9,000 flat fee per day for deposition time. My
`
`compensation is not dependent on the substance of my testimony or the outcome of
`
`the proceedings.
`
`4.
`
`In forming my opinions, in addition to my knowledge and experience,
`
`I have considered the materials cited herein and listed in Appendix A.
`
`5.
`
`All statements in my Declaration, unless indicated otherwise, are
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`based on my knowledge and experience in the field.
`
`II. BACKGROUND AND QUALIFICATIONS
`6.
`I am a Professor of Neurology and the Director of the Corinne
`
`Goldsmith Dickinson Center for Multiple Sclerosis at the Icahn School of
`
`
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`

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`Medicine at Mount Sinai in New York City. I am also an Attending Neurologist at
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`IPR2023-00480
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`Mount Sinai Hospital. My full qualifications are below and in my CV, a copy of
`
`which is attached as Appendix B to this Declaration.
`
`7. My professional interests relate primarily to neurology and
`
`neuroimmunology, and specifically to (1) the scientific and clinical aspects of
`
`multiple sclerosis (“MS”) and (2) the research and development of therapies for
`
`treating MS. I have authored or co-authored over 250 peer-reviewed academic
`
`publications in the field of neurology, with an emphasis on MS. I have also written
`
`or co-written over 240 textbook chapters, editorials, abstracts, and letters in my
`
`areas of interest, including the textbook Multiple Sclerosis in Clinical Practice,
`
`Martin Dunitz, Ltd. (2003).
`
`8.
`
`I received my A.B. in Biology from Temple University in 1968
`
`(magna cum laude), and my M.D. from Jefferson Medical College in 1972 (summa
`
`cum laude). From 1972-1973, I interned at the Bronx Municipal Hospital-Albert
`
`Einstein Medical Center in New York City, specializing in internal medicine. I
`
`also completed an externship at the National Hospital for Nervous Disease in
`
`London in 1972. From 1973-1976, I was a resident in Neurology at New York
`
`Hospital-Cornell Medical Center in New York City, NY.
`
`9.
`
`For the last 47 years, I have maintained an active neurology practice.
`
`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
`
`treating Multiple Sclerosis patients and have treated thousands of Multiple
`
`Sclerosis patients since 1976. I currently treat hundreds of Multiple Sclerosis
`
`patients a year.
`
`10.
`
`In addition to my clinical practice, I have been actively engaged in the
`
`training of medical students, residents, fellows, and practicing clinicians in
`
`neurology and neuroimmunology throughout my career. I was an Instructor in
`
`Neurology at Cornell Medical College (1975-1976) and then an Instructor in
`
`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
`
`promoted to Assistant Professor of Neurology and Assistant Professor of
`
`Biochemistry and in 1982, to Associate Professor of Neurology. In 1983, I was
`
`promoted to Associate Professor of Biochemistry & Molecular Biology, and in
`
`1986, to Professor of Neurology. In 1987, I was appointed Director of the Division
`
`of Neuroimmunology, and was named Vice-Chairman of the Department of
`
`Neurology. In 1995, I was promoted to Acting Chairman of the Department of
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`Neurology.
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`I then joined MCP Hahnemann University (formerly Allegheny
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`11.
`
`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-
`
`created Multiple Sclerosis Center, and Director of the Neurological Clinical Trials
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`Center.
`
`12. Since 2000, I have been Professor of Neurology and Director of the
`
`Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai School
`
`of Medicine. Four years after joining Mount Sinai School of Medicine (2004), I
`
`was named the Saunders Family Professor of Neurology, an endowed chair that is
`
`an honor I hold to this day.
`
`13.
`
`In addition to research and teaching, I have also served as a reviewer
`
`for numerous scientific journals, including Annals of Neurology, Neurology,
`
`Science, Brain, Lancet, Laboratory Investigation, Journal of Neuroimmunology,
`
`Annals of Internal Medicine, Pediatrics, Journal of the Neurological Sciences,
`
`Clinical Therapeutics, Multiple Sclerosis Journal, Journal of NeuroVirology,
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`Archives of Neurology, BioDrugs, Acta Neurologica Scandinavica, Lancet
`
`Neurology, Multiple Sclerosis and Related Disorders, New England Journal of
`
`Medicine, and JAMA Neurology. I have also served on the editorial boards of
`
`several influential journals in my field. For example, I have served as Co-Chief
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`
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`4
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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.
`
`14.
`
`I am a member of several professional medical organizations,
`
`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.
`
`15.
`
`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
`
`National Institutes of Health.
`
`16.
`
`I have served as either Principal or Co-Investigator for numerous
`
`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®).
`
`I have also served as a member for the Data Safety and Monitoring Boards for
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`many MS treatments, including Antegren (Biogen-Idec), and Gilenya (Novartis).
`
`In my work in clinical trials, I have witnessed first-hand how drug doses are
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`determined.
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`

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`I have also consulted with various pharmaceutical companies,
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`17.
`
`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.”
`
`III. SUMMARY OF OPINIONS
`18.
`I understand that the Petition for IPR2023-00480 (“Pet.”) challenges
`
`claims 36, 38, 39, and 41-46 of the ’947 patent (“challenged claims”) as allegedly
`
`obvious over Bodor and Stelmasiak. Pet. 8-9. It is my opinion that the challenged
`
`claims would not have been obvious over Bodor and Stelmasiak.
`
`19. First, neither Bodor nor Stelmasiak discloses or suggests all
`
`limitations of the challenged claims, including (1) the claimed weight-based
`
`induction or maintenance dosing and (2) the claimed maintenance period. A
`
`POSA would have understood that both Bodor and Stelmasiak teach flat, fixed
`
`dosing, which is fundamentally different from weight-based dosing. Indeed, even
`
`Dr. Miller distinguished between weight-based dosing and fixed dosing for MS
`
`drugs, characterizing MAVENCLAD®’s weight-based dosing as “unique.”
`
`20. Further, as I will discuss in detail below, a POSA would not have
`
`understood Bodor to teach re-treatment immediately after its 10-month cladribine-
`
`free period at least because (1) a POSA would have been concerned about the
`
`safety of cladribine treatment; (2) dosing of approved disease-modifying
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`
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`6
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`

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`treatments for MS was based on pharmacological effects, efficacy, and safety
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`IPR2023-00480
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`rather than based on the purported “cyclical” nature of MS; and (3) the art did not
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`suggest a maintenance period as claimed. A POSA would have understood that
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`any subsequent re-treatment would have been based on a combination of factors,
`
`such as evidence of disease progression, time course of therapeutic effects, and
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`safety considerations, rather than automatically re-treating after a set period of
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`time, as the Petition suggests. Stelmasiak does not remedy the deficiencies of
`
`Bodor, at least because Stelmasiak does not teach or suggest the claimed
`
`maintenance period, occurring about 8-10 months after the induction period;
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`instead, Stelmasiak teaches treatment after only two months of no treatment.
`
`21. Second, a POSA would not have been motivated to arrive at the
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`claimed dosing methods via routine optimization or have had a reasonable
`
`expectation of success in doing so. Petitioner’s routine optimization argument is
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`premised on measuring a patient’s lymphocyte counts and evaluating the efficacy
`
`of a given dose based on the change in the count. However, as I explain in detail
`
`below, lymphocyte count is a metric of safety, not a metric of efficacy. Indeed, Dr.
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`Miller admitted during his deposition that “[l]ymphocyte suppression is not a
`
`measure of efficacy.” As such, a POSA would not have used lymphocyte count to
`
`evaluate the efficacy of any “optimization” to a dosing regimen.
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`7
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`22. Further, Petitioner’s “routine optimization” suggestion disregards the
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`variable and complex nature of MS, including that MS is a chronic disease in
`
`which changes occur relatively slowly in most people. A POSA would have
`
`understood that due to the complex nature of MS disease course, including that
`
`disability in MS evolves slowly over years, the therapeutic effects of any dosing
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`schedule can likewise only be assessed over time.
`
`23. Petitioner’s “routine optimization” suggestion also ignores the
`
`numerous possible combinations of dose, dosing period length/number, and drug-
`
`free period length/number that a POSA could have “optimized.” As of 2004,
`
`nothing in the prior art taught a POSA what specific combination (if any) of the
`
`different variables—dose, length and number of dosing periods or drug-free
`
`periods—would result in a safe and effective MS treatment method.
`
`24. Third, a POSA would not have been motivated to adopt weight-based
`
`dosing or have reasonably expected to arrive at the claimed weight-based dosing
`
`regimen. Neither Bodor nor Stelmasiak would have motivated a POSA to shift
`
`from their respective flat, fixed dosing method to a weight-based dosing method.
`
`Further, Stelmasiak teaches the effects of cladribine were not related to its dose per
`
`body weight and thus teaches away from weight-based dosing.
`
`25. Fourth, a POSA would not have been motivated to combine Bodor
`
`with Stelmasiak to arrive at the claimed induction doses or have had a reasonable
`
`
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`8
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`

`

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`expectation of success in doing so. A POSA would not have started with Bodor’s
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`treatment regimen at least because (1) Bodor’s maximum cladribine dose of 140
`
`mg is lower than Stelmasiak’s 150 mg dose (after three months) and (2) Bodor’s
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`oral cladribine formulation has lower bioavailability than Stelmasiak’s, and thus
`
`Bodor’s treatment regimen would have been less likely to reduce lymphocytes to a
`
`level below 1000 cells/(cid:541)L, under Dr. Miller’s theory that lymphocyte suppression
`
`to such a level is required for an MS “therapeutic effect.” Further, a POSA would
`
`not have been motivated to modify the teachings of Bodor and Stelmasiak to arrive
`
`at the claimed induction dose at least because Stelmasiak’s higher dosing regimen
`
`did not ultimately result in any change in EDSS score at the end of the study. Even
`
`if one were to convert Stelmasiak’s 300 mg initial dose into mg/kg based on the
`
`reported patient weight range, that would correspond to 4.0-5.77 mg/kg—this is
`
`significantly higher than the claimed induction period doses of about 1.7-3.5 or 1.7
`
`mg/kg. A POSA would not have been motivated to lower Stelmasiak’s dose to
`
`arrive at the claimed induction period dose of about 1.7-3.5 or 1.7 mg/kg, nor have
`
`had a reasonable expectation of success in doing so.
`
`26.
`
` Fifth, a POSA would not have been motivated to immediately re-
`
`treat patients after Bodor’s 10-month cladribine-free period or have had a
`
`reasonable expectation of success in doing so. Contrary to the Petition’s
`
`suggestion, a POSA would not have understood there to be a “general
`
`
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`9
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`immunosuppression framework common with MS therapies” based on the
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`purported “cyclical” nature of MS. Pet. 36. Instead, by 2004, the art showed that
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`approved disease-modifying treatments for MS were dosed continuously to
`
`maintain the drug’s pharmacological effects, efficacy, and safety. Further, as I
`
`explain in detail below, that some “patients may relapse during or after cladribine
`
`therapy” does not suggest that a POSA “would have been motivated to retreat the
`
`relapsing patients with cladribine after [Bodor’s] ‘ten months of no treatment.’”
`
`See Ex. 1002, ¶100. A POSA could have treated a relapsing patient by switching
`
`the patient to an alternative MS therapy. Further, in view of the reported inability
`
`of Stelmasiak’s dosing regimen to maintain efficacy during a 9-month cladribine-
`
`free period, a POSA would not have had a reasonable expectation of success in re-
`
`treating patients after Bodor’s 10-month cladribine-free period.
`
`27. Sixth, a POSA would not have been motivated to combine Bodor with
`
`Stelmasiak to arrive at the claimed 1.7 mg/kg maintenance dose or have had a
`
`reasonable expectation of success in doing so. Dr. Miller opines that a POSA
`
`would have been motivated to administer a lower total dose of cladribine in the
`
`maintenance period compared to the total dose in the induction period. However,
`
`regardless of whether any alleged maintenance dose would have been the same as
`
`or lower than the initial dose, a POSA would not have had any teaching or
`
`guidance from Bodor or Stelmasiak as to what cladribine dose would have been
`
`
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`10
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`

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`required to maintain any effects of Bodor’s treatment method comprising using
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`100-140 mg cladribine.
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`28. Lastly, the non-obviousness of challenged claims of the ’947 patent is
`
`further demonstrated by at least: (1) the skepticism of others, (2) the unexpected
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`durable efficacy and safety of the claimed dosing regimen, and (3) the satisfaction
`
`of a long-felt unmet need for a short-course, oral therapy for MS.
`
`IV. LEVEL OF SKILL IN THE ART
`29.
`I understand that a person having ordinary skill in the art (“POSA”) is
`
`a hypothetical person from whose perspective the patentability analysis is
`
`performed, and who is presumed to have knowledge of the relevant art at the time
`
`of the invention. In my opinion, the definition of a POSA for the ’947 patent
`
`should be a person having an M.D. with at least two years of experience treating
`
`neurological conditions, with a focus on autoimmune disorders, including but not
`
`limited to multiple sclerosis, and prescribing immunotherapies to treat such
`
`neurological conditions, and that a POSA would also be part of a team including
`
`individuals with experience in investigation of the pharmacokinetics (PK) and
`
`pharmacodynamics (PD) of drugs, pharmaceutical drug development, and clinical
`
`trial design.
`
`30.
`
`I understand that Petitioner has also proposed a definition of a POSA
`
`for the ’947 patent, specifically: “A POSA for the ’947 patent would have the
`
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`11
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`knowledge of multiple disciplines, such as immunology, biochemistry, and human
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`physiology and anatomy, and also typically be a clinician with experience and/or
`
`training in neurology” and that “[t]he POSA typically would be a medical doctor
`
`with a specialty in neurology, specifically in treating autoimmune disorders of the
`
`nervous system, such as multiple sclerosis, and typically at least 2 years of
`
`experience with administering treatments to patients and evaluating results of such
`
`treatments, as well as experience or knowledge in related research and
`
`development.” Pet. 28-29.
`
`31. As of the priority date of the ’947 patent in 2004, I qualified as a
`
`POSA under either of these definitions.
`
`32.
`
`I provide my analysis from the perspective of a POSA. My analysis
`
`would be the same regardless of which party’s definition is applied.
`
`V. LEGAL STANDARDS
`33. This section sets forth certain legal standards that have been provided
`
`to me by attorneys for Patent Owner, Merck Serono SA. I understand that the
`
`issues presented in this Inter Partes Review proceeding must be considered in
`
`view of these legal standards.
`
`A. OBVIOUSNESS
`34.
`I understand that a claim is obvious in light of the prior art if the
`
`difference or differences between the claimed subject matter and the prior art are
`
`
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`12
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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 person having ordinary skill in the art.
`
`35.
`
`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-
`
`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,
`
`praise by others, teaching away by others, recognition of a problem, laudatory
`
`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.
`
`36.
`
`In connection with obviousness, I have been informed that there must
`
`have been some reason or motivation that would have led a person of ordinary skill
`
`in the art to combine or modify the relevant teachings in the prior art to obtain the
`
`claimed invention, and one of ordinary skill in the art must have had a reasonable
`
`expectation of success in doing so. I understand further that it is incorrect to
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`evaluate obviousness from a hindsight perspective using the teachings of the patent
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`at issue as a guide.
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`B. CLAIM CONSTRUCTION
`37.
`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.
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`38.
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`I have reviewed the Decision on Institution and understand that in its
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`preliminary findings, the Board found the challenged claims do not require that the
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`total maintenance dose be lower than the total induction dose. Paper 10, 17.
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`Additionally, the Board found the challenged claims cover embodiments in which
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`the same total dose, e.g., about 1.7 mg/kg, is used for both the induction and the
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`maintenance periods. Id., 13-14, 17.
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`VI. TECHNICAL FIELD OF THE ART
`A. Multiple Sclerosis
`39. MS is an autoimmune disease of the central nervous system (CNS).
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`Ex. 2010, 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. 2010, 18; Ex. 1001, 1:24-26; Ex. 1007, 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. 2010, 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. 2010, 29.
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`40. 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. 1016, 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. 1007, 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. 2010, 68-70.
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`1. MS Clinical Course and Diagnosis
`41. 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. 1037, 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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`42. 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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`43. 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. 1037, 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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`44. 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 of
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`SPMS can be referred to as early SPMS. Ex. 1038, 60-63. As shown in the
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`following graph of a disease course for SPMS, progression worsens and includes
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`occasional relapses and minor remissions. Ex. 1037, 909.
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`In contrast to SPMS patients, PPMS patients experience disease
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`45.
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`progression from the onset, and is characterized by a “gradual[,] nearly
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`continuously worsening baseline with minor fluctuations but no distinct relapses.”
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`Id., 908. The disease course of PPMS, as understood in 2004, is shown in the
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`following graph, and shows “progression of disability from onset,” with occasional
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`plateaus and temporary minor improvements.” Id., 909.
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`46. PRMS patients also experience disease progression from the onset,
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`but with clear acute relapses and periods between relapses characterized by
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`continuing progression. Id., 909-10.
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`2. MS Treatment as of 2004
`It was not until the 1990s that MS was considered a “treatable”
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`47.
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`
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`neurologic disease. Id., 907; Ex. 2011, 3.
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`48.
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`Initially, in the 1960s, corticosteroids were used to reduce the severity
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`of relapses but were “not effective at reducing the number of relapses or the rate of
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`disease progression.” Ex. 2011, 4.1 Notably, corticosteroids have not been proven
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`to alter the natural course of MS, i.e., they are not established disease modifying
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`agents (“DMAs”), and were taken as needed to treat attacks when they occur. Ex.
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`2006, 273; Ex. 2011, 4; Ex. 1016, 431; Ex. 1006, 946 (“Corticosteroids are often
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`used to treat clinically significant relapses in an attempt to hasten recovery[.]”);
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`1 Hereinafter, all emphasis is added unless otherwise noted.
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`Ex. 1017, 1607 (“Corticosteroid therapy shortens the duration of the relapse and
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`accelerates recovery[.]”); Ex. 2013, 176.
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`49. By 2004, therapy for MS generally involved disease modifying
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`agents, which segregate into immunosuppressive and immunomodulatory
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`therapies. Ex. 2006, 273. Immunosuppressants cause general suppression of the
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`immune system and can inhibit crucial components of the immune system, leading
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`to generalized immune dysfunction. Id.; Ex. 1007, 131. In contrast,
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`immunomodulators do not cause general suppression of the immune system, but
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`have more targeted effects and are usually less toxic. Ex. 2006, 273. For example,
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`immunomodulators can shift immune responses from pro-inflammatory
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`autoimmune conditions towards more beneficial anti-inflammatory circumstances.
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`Ex. 1007, 131.
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`50. The therapeutic era in MS finally started in 1993, when FDA
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`approved interferon beta-1b (IFN(cid:533)-1b; Betaseron®), the first therapy proven
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`effective in altering the natural history of RRMS. Ex. 2011, 3; Ex. 1037, 907. By
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`2004, FDA had approved six MS drugs, all disease-modif