UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`HOPEWELL PHARMA VENTURES, INC.,
`Petitioner,
`
`v.
`
`MERCK SERONO S.A.
`Patent Owner.
`
`_____________________
`
`Case IPR2023-00481
`U.S. Patent No. 8,377,903
`_____________________
`
`DECLARATION OF AARON E. MILLER, M.D.
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Hopewell EX1002
`
`

`

`Inter Partes Review of U.S. Patent No. 8,377,903
`Declaration of Aaron E. Miller, M.D.
`(EX1002)
`
`
`TABLE OF CONTENTS
`
`C.
`
`Introduction ...................................................................................................... 1
`I.
`II. My Background and Qualifications ................................................................. 2
`III.
`Summary of Opinions ...................................................................................... 5
`IV. List of documents I considered in formulating my opinions.........................10
`V.
`The Person of Ordinary Skill in the Art (“POSA”) .......................................13
`VI. State of the Art Prior to December 22, 2004 .................................................14
`A. Multiple sclerosis is a chronic disease with no known cure ............... 14
`B.
`Immunosuppression was a common therapeutic strategy to treat
`multiple sclerosis before December 2004 ........................................... 22
`Cladribine, a known immunosuppressant, was used to treat
`multiple sclerosis before December 2004 ........................................... 26
`1.
`Clinical studies assessing parenteral cladribine in MS
`patients began in the early 1990s .............................................. 27
`By December 2004, oral cladribine was favored to treat
`MS patients ............................................................................... 37
`D. MS often requires cyclical drug therapy to prevent relapses and
`limit progression of the disease ........................................................... 39
`VII. The ʼ903 Patent Specification and Claims ....................................................43
`VIII. Claim Construction ........................................................................................45
`B.
`“Total Dose of Cladribine” ................................................................. 45
`C.
`“Induction Period” ............................................................................... 46
`D.
`“Maintenance Period” ......................................................................... 47
`IX. Basis of my analysis with respect to obviousness .........................................48
`X. My analysis with respect to claim 17 ............................................................50
`
`2.
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`Inter Partes Review of U.S. Patent No. 8,377,903
`Declaration of Aaron E. Miller, M.D.
`(EX1002)
`
`
`A.
`
`B.
`
`C.
`
`E.
`
`F.
`
`D.
`
`Bodor and Stelmasiak teach orally administering cladribine to
`treat multiple sclerosis, including RRMS ........................................... 51
`Bodor’s and Stelmasiak’s cladribine dosing regimens include
`an “induction period;” Bodor’s induction period is 2 months
`long ...................................................................................................... 53
`Bodor teaches the claimed total dose of cladribine administered
`in an induction period .......................................................................... 55
`Bodor and Stelmasiak teach retreating with cladribine after a
`cladribine-free period .......................................................................... 56
`Stelmasiak teaches administering a lower dose of cladribine in
`the retreatment period compared to the induction period; a
`POSA would have known how to optimize the maintenance
`period dose and length ......................................................................... 58
`Stelmasiak teaches a second cladribine-free period after the
`maintenance period; a POSA would have known how to
`optimize the length of the second cladribine-free period .................... 65
`G. A POSA would have been motivated to combine Bodor and
`Stelmasiak with a reasonable expectation of success ......................... 67
`1.
`A POSA would have been motivated to formulate an oral
`cladribine composition per Bodor ............................................. 67
`A POSA would have been motivated to treat relapsing-
`remitting MS by administering Bodor’s oral cladribine
`composition according to Stelmasiak’s induction
`period/cladribine-free period/maintenance
`period/cladribine-free period framework .................................. 68
`A POSA would have been motivated to administer
`“about 1.7 mg/kg to about 3.5 mg/kg” in an induction
`period......................................................................................... 74
`A POSA would have administered a lower total dose of
`cladribine in the maintenance period compared to the
`total dose in the induction period .............................................. 75
`
`2.
`
`3.
`
`4.
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`Inter Partes Review of U.S. Patent No. 8,377,903
`Declaration of Aaron E. Miller, M.D.
`(EX1002)
`
`
`5.
`
`A POSA would have routinely optimized the prior art to
`arrive at the claimed total cladribine dose and length of
`the maintenance period ............................................................. 77
`H. A POSA would have had a reasonable expectation of success .......... 78
`XI. My analysis with respect to claim 19 ............................................................84
`XII. My analysis with respect to claim 20 ............................................................85
`XIII. My analysis with respect to claims 22 and 23 ...............................................86
`XIV. My analysis with respect to claim 24 ............................................................87
`XV. My analysis with respect to claim 25 and 26 ................................................88
`XVI. My analysis with respect to claim 27 ............................................................89
`XVII. No objective indicia of non-obviousness exist. .............................................90
`XVIII.
`Conclusion ...........................................................................................90
`
`
`
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`iii
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`Inter Partes Review of U.S. Patent No. 8,377,903
`Declaration of Aaron E. Miller, M.D.
`(EX1002)
`
`
`
`
`I, Aaron E. Miller, M.D., hereby declare as follows.
`
`I.
`
`Introduction
`I am over the age of eighteen (18) and otherwise competent to make
`1.
`
`this declaration.
`
`2.
`
`I have been retained as an expert witness on behalf of Petitioner
`
`Hopewell Pharma Ventures, Inc. (“Hopewell”) for the above-captioned inter partes
`
`review (“IPR”). I am being compensated for my time in connection with this IPR
`
`at my standard consulting rate, which is $790/hr.
`
`3.
`
`I understand that the petition for IPR involves U.S. Patent No.
`
`8,377,903 (“the ’903 patent”), EX1001, which resulted from U.S. Application No.
`
`12/766,173 (“the ʼ173 application”), filed on April 23, 2010, which is a
`
`continuation of U.S. Application No. 11,722,018, which is the National Phase
`
`Entry of International Patent Application No. PCT/EP2005/056954, filed on
`
`December 20, 2005, which claims the benefit of the U.S. Provisional Application
`
`No. 60/638,669, filed on December 22, 2004, and the Foreign Patent Application
`
`No. EP04106909, filed on December 22, 2004. EX1001, De Luca. The ’903 patent
`
`issued on February 19, 2013, from the ’173 application. Id. The ’903 patent names
`
`Giampiero De Luca, Arnaud Ythier, Alain Munafo, and Maria Lopez-Bresnahan as
`
`1
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`Inter Partes Review of U.S. Patent No. 8,377,903
`Declaration of Aaron E. Miller, M.D.
`(EX1002)
`
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`inventors. Id. The face of the ’903 patent states that it is assigned to Merck Serono
`
`S.A. (“Merck”). Id.
`
`II. My Background and Qualifications
`4. My Curriculum Vitae is submitted herewith as EX1003.
`
`5.
`
`I received my M.D. in 1968 from the New York University School of
`
`Medicine. I previously received my B.A. in 1964 in psychology from Brandeis
`
`University. From 1968-1970, I was an intern and resident at the Bronx Municipal
`
`Hospital Center. I completed two neurology residencies between 1970-1971 and
`
`1973-1975 at the Albert Einstein College of Medicine. In 1977, I completed a
`
`postdoctoral fellowship in neurovirology in the Department of Epidemiology,
`
`Division of Infectious Disease, at Johns Hopkins University School of Hygiene
`
`and Public Health. In 1978, I completed a postdoctoral fellowship in immunology
`
`at the Albert Einstein College of Medicine. I was also a recipient of a National
`
`Multiple Sclerosis Society Fellowship from 1976-1978. From July 1971-June
`
`1973, I served as a lieutenant commander in the U.S. Naval Reserve.
`
`6.
`
`I have received Certifications from the National Board of Medical
`
`Examiners (1969), the American Board of Internal Medicine (1972), and the
`
`American Board of Psychiatry and Neurology (1977). I have been licensed to
`
`practice medicine in the state of New York since 1969.
`
`2
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`Inter Partes Review of U.S. Patent No. 8,377,903
`Declaration of Aaron E. Miller, M.D.
`(EX1002)
`
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`I am currently the medical director of the Corinne Goldsmith
`
`7.
`
`Dickinson Center for Multiple Sclerosis at the Icahn School of Medicine at Mount
`
`Sinai, a position I have held since March 2004. I am also a professor of neurology
`
`at the Icahn School of Medicine at Mount Sinai, a position I have also held since
`
`March 2004. I was previously a clinical professor of neurology at the Mt. Sinai
`
`School of Medicine (2001-2004). Before that, I was an associate professor (1985-
`
`1992) and professor (1992-2003) of clinical neurology at the State University of
`
`New York Health Sciences Center at Brooklyn. I began my academic career at the
`
`Albert Einstein College of Medicine where I was an instructor in neurology from
`
`1977-1978, an assistant professor of neurology (1978-1981), and a visiting
`
`professor of clinical neurology (1981-1999).
`
`8.
`
`Prior to becoming the medical director at the Corinne Goldsmith
`
`Dickinson Center for Multiple Sclerosis, I was an attending neurologist at the Mt.
`
`Sinai Hospital, a position I have held since 1999. I am also an attending
`
`neurologist at the Metropolitan Jewish Geriatric Center, a position I have held
`
`since 1981. I am also the director of the division of neurology and an attending
`
`neurologist at the Maimonides Medical Center in Brooklyn, positions I have held
`
`since 1981. Previously, I was an attending neurologist at the Kings County
`
`Hospital Center (1981-2001), an attending neurologist at the Albert Einstein
`
`3
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`Inter Partes Review of U.S. Patent No. 8,377,903
`Declaration of Aaron E. Miller, M.D.
`(EX1002)
`
`College Hospital (1978-1981), and an attending neurologist at the Bronx Municipal
`
`Hospital Center (1978-1999).
`
`9.
`
`I have held many professional appointments during my career. I am
`
`currently a member of the Scientific Advisory Committee at the National Multiple
`
`Sclerosis Society, an organization I have been actively involved with since 1988. I
`
`have had several other appointments at the National MS Society, including acting
`
`as Chairman of the National Medical Advisory Committee (2002-2010), the
`
`Professional Education Committee (1993-2002), and the National Medical
`
`Advisory Committee (2018-2020). I served on the Board of Directors for the
`
`National MS Society from 2003-2017, and I have served on several other
`
`committees.
`
`10.
`
`I have also been involved with other MS organizations. For example, I
`
`was the co-chairman of the Professional Advisory Committee (1988-1991) and the
`
`chairman of the clinical advisory committee (1991-2004) for the New York
`
`Multiple Sclerosis Society. I have held various positions at the American Academy
`
`of Neurology, including as the chairman of the Annual Meeting Subcommittee
`
`(1997-2003), Co-Chairman of the Education Committee, (1997-2003), on the
`
`Board of Directors (2009-2013), and as the Chairman of the Editors-in-Chief
`
`Committee (2009-2011).
`
`4
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`Inter Partes Review of U.S. Patent No. 8,377,903
`Declaration of Aaron E. Miller, M.D.
`(EX1002)
`
`
`I have served on several committees to oversee data and safety
`
`11.
`
`monitoring, as well as end-point analysis, of various clinical trials. I have served as
`
`an Editor of several industry publications, including Continuum published by the
`
`American Academy of Neurology and Multiple Sclerosis and Related Disorders. I
`
`have also authored or co-authored over 125 papers published in peer-reviewed
`
`journals, over half of which were related to multiple sclerosis. I have also authored
`
`or co-authored over 25 books or book chapters.
`
`12.
`
`In my practice, I treat roughly 800-1000 unique patients a year with
`
`MS. As a neurologist, I have treated thousands of MS patients since the beginning
`
`of my career in 1977.
`
`13.
`
`In view of my education, experience, and expertise described above, I
`
`am an expert in the field of neurology. Accordingly, I am an expert in the field of
`
`the subject matter described and claimed in the ’903 patent.
`
`III. Summary of Opinions
`In this declaration, I consider the treatment methods of the ’903 patent
`14.
`
`in relation to the general knowledge in the art as of December 22, 2004. The prior
`
`art references that I considered included (but were not limited to) Bodor, Nicholas
`
`S. and Dandiker, Yogesh, “Oral Formulations of Cladribine,” International Patent
`
`Application Publication No. WO2004/087101 A2 (filed December 20, 2005;
`
`published October 14, 2004) (“Bodor,” EX1022), and Stelmasiak, Zbigniew, et al.,
`
`5
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`Inter Partes Review of U.S. Patent No. 8,377,903
`Declaration of Aaron E. Miller, M.D.
`(EX1002)
`
`
`“A pilot trial of cladribine (2-chlorodeoxyadenosine) in remitting-relapsing
`
`multiple sclerosis,” Med. Sci. Monit., 1998, 4(1):4-8 (“Stelmasiak,” EX1013). I
`
`also considered the file history of the ’903 patent (EX1004) and other exhibits
`
`cited herein. A summary of my opinions follows. The references I cite in this
`
`Declaration reflect the general knowledge in the art.
`
`15. Multiple sclerosis (“MS”) is a “lifelong and often disabling”
`
`“progressive, degenerative disease of the central nervous system whose
`
`distinguishing feature is the development of scattered, focal lesions of the myelin
`
`sheath of the axons.” EX1043, 565; EX1009, 263. As I explain in detail below,
`
`most patients experience a relapsing-remitting form of MS, in which “neurological
`
`symptoms and signs develop over several days, plateau, and then usually improve
`
`over days to weeks.” EX1009, 263; EX1007, 131. Many of these patients will go
`
`on to develop secondary progressive disease, characterized by emerging
`
`“progressive neurological dysfunction” “as relapse frequency lessens over time.”
`
`EX1009, 263. A smaller number of patients experience a primary progressive form
`
`of MS from onset, in which their disease gradually worsens over time without
`
`periods of remission. Id. Of the patients with progressive disease from onset, some
`
`may also experience relapses or exacerbations; this form was called progressive-
`
`relapsing MS (“PRMS”). EX1037, 909. A POSA would have also recognized
`
`6
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`Inter Partes Review of U.S. Patent No. 8,377,903
`Declaration of Aaron E. Miller, M.D.
`(EX1002)
`
`
`“early” secondary progressive MS (“ESPMS”) as a distinct disease form. EX1038,
`
`60. Some SPMS and ESPMS patients will continue to experience relapses.
`
`EX1037, 908; EX1009, 263. Therefore, a person of ordinary skill in the art
`
`(“POSA”) would have known before December 2004 that, as a rule, an MS patient
`
`typically needs ongoing care to treat episodic relapses and disease progression.
`
`EX1013, 6; EX1009, 263.
`
`16. Because of the role the immune system plays in the underlying
`
`pathophysiology of MS, immunosuppressive drugs was “[t]he most common
`
`therapeutic approach” for treating MS before December 2004. EX1013, 4;
`
`EX1007, 131. Cladribine was developed in the early 1990s to treat various
`
`leukemias and lymphomas. EX1015, Tortorella, Abstract. Because cladribine
`
`caused “prolonged, profound suppression of lymphocyte counts,” researchers
`
`began studying it in MS. EX1016, Langtry, 420. In early studies, cladribine was
`
`shown to “modulat[e] autoimmune processes involving lymphocyte abnormalities
`
`such as MS” and “impressively decrease[]” relapse rates in patients with RRMS.
`
`EX1018, Rice, 1146; EX1013, 5, 7. During treatment, neurologists commonly
`
`assessed the therapeutic effect of cladribine by monitoring a patient’s lymphocyte
`
`count, with a sustained reduction of lymphocytes, e.g. below 1000/µL, being
`
`characteristic of a treatment response. EX1018, 1146; EX1013, 5; EX1014, 1717.
`
`7
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`

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`Inter Partes Review of U.S. Patent No. 8,377,903
`Declaration of Aaron E. Miller, M.D.
`(EX1002)
`
`
`17. As I explain in detail below, claims 17, 19, 20, and 22-27 of the ’903
`
`patent would have been obvious in view of Bodor and Stelmasiak. Bodor discloses
`
`administering an oral cladribine tablet to treat RRMS “once per day for a period of
`
`five to seven days in the first month, repeated for another period of five to seven
`
`days in the second month, followed by ten months of no treatment.” EX1022,
`
`23:15-20. Thus, Bodor discloses a cladribine induction period in which 100 mg to
`
`140 mg of cladribine was administered over 2 months followed by 10 months of no
`
`treatment. Stelmasiak discloses an oral cladribine dosing regimen for RRMS in
`
`which “[s]ix cladribine courses were given at monthly intervals, and two additional
`
`courses were given at 9 and 12 or 15 months,” with “[e]ach course consist[ing] of
`
`five doses of the drug taken once daily on consecutive days.” EX1013, 5. Thus, a
`
`POSA would have recognized that Stelmasiak administered cladribine in a cyclical
`
`manner. A POSA would have had a reason to add a “maintenance period” followed
`
`by a “cladribine-free period” to Bodor’s cladribine dosing regimen, as taught by
`
`Stelmasiak, to treat RRMS because RRMS is a chronic, progressive disease that
`
`typically requires periodic treatment. A POSA would have understood that
`
`cladribine is a “disease-modifying” therapy—i.e., cladribine does not cure MS, but
`
`can reduce the number of relapses by causing “prolonged, profound suppression of
`
`lymphocyte counts.” EX1016, 420; EX1013, 6. In fact, the general knowledge in
`
`8
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`

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`Inter Partes Review of U.S. Patent No. 8,377,903
`Declaration of Aaron E. Miller, M.D.
`(EX1002)
`
`
`the art recognized that “the beneficial effect of a single course of cladribine” is
`
`“not permanent” and investigating “retreatment with cladribine will be especially
`
`important.” EX1046, 392. Thus, a POSA would have expected some patients to
`
`relapse after cladribine therapy, as evidenced in some cladribine clinical trials. For
`
`example, Stelmasiak reports that “a total of 6 relapses during the two-year study
`
`period (average relapse rate 0.43 per patient per year)” was reported in the
`
`“responders” group. EX1013, 6. Thus, a POSA would have understood from prior
`
`clinical studies that patients may relapse during or after cladribine therapy. As
`
`such, a POSA would have been motivated to retreat the relapsing patients with
`
`cladribine after “ten months of no treatment.” And because cladribine has been
`
`previously shown to have clinical efficacy in patients with RRMS, a POSA would
`
`have had a reasonable expectation of retreating a patient with cladribine.
`
`18. Further, as I explain in more detail below, a POSA would have had a
`
`reason to lower the total dose of cladribine administered during the maintenance
`
`period, compared to the total dose administered during the induction period, and
`
`would have optimized the maintenance period dose. A POSA would have known
`
`that monitoring a patient’s lymphocyte counts was necessary because “cladribine
`
`causes prolonged, profound suppression of lymphocyte counts.” See ¶¶ 31-32,
`
`infra. Based on the lymphocyte data in Figure 1 of Stelmasiak, a POSA would
`
`9
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`

`

`Inter Partes Review of U.S. Patent No. 8,377,903
`Declaration of Aaron E. Miller, M.D.
`(EX1002)
`
`
`have understood that a lower dose of cladribine was sufficient to maintain the
`
`lymphocyte suppression effected during an induction period. Bodor instructs a
`
`POSA to optimize the cladribine dose: “one of skill will appreciate that the
`
`therapeutically effective amount of cladribine administered herein may be lowered
`
`or increased by fine tuning.” EX1022, 24:1-4. A POSA would have known how to
`
`adjust a patient’s cladribine dose depending on the patient’s lymphocyte counts
`
`because, as explained in more detail below, the dose of cladribine was a result-
`
`effective variable. Also, it would have been well within the skill of a POSA to
`
`optimize the maintenance period dose because it is a common practice in the field
`
`to treat patients on an individual basis. In other words, different patients may
`
`require different dosages and/or lengths of treatment, and it would have been
`
`within the skill and expertise of a POSA to optimize the dose/length of the
`
`maintenance period for different patients.
`
`IV. List of documents I considered in formulating my opinions
`In formulating my opinions, I considered the following documents:
`19.
`
`Exhibit
`No. Description
`De Luca, G., et al., “Cladribine Regimen for Treating Multiple
`Sclerosis,” U.S. Patent No. 8,377,903 B2 (filed April 23, 2010; issued
`1001
`February 19, 2013)
`1004 File History for U.S. Patent No. 8,377,903
`1006 Noseworthy, J.H., et al., “Multiple Sclerosis,” The New England
`Journal of Medicine, 343(13):938-952 (2000)
`
`10
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`Inter Partes Review of U.S. Patent No. 8,377,903
`Declaration of Aaron E. Miller, M.D.
`(EX1002)
`
`
`1013
`
`1018
`
`1009
`
`Exhibit
`No. Description
`Neuhaus, O., et al., “Immunomodulation in multiple sclerosis: from
`immunosuppression to neuroprotection,” TRENDS in Pharmaceutical
`1007
`Sciences, 24(3):131-138 (2003)
`1008 Weiner, H.L., et al., “Immunotherapy of Multiple Sclerosis,” Annals
`of Neurology, 23(3):211-222 (1988)
`Wingerchuk, D.M., et al., “Biology of Disease, Multiple Sclerosis:
`Current Pathophysiological Concepts,” Laboratory Investigation,
`81(3):263-281 (2001)
`Kurtzke, J.F., “Rating neurologic impairment in multiple sclerosis:
`An expanded disability status scale (EDSS),” Neurology, 33:1444-
`1010
`1452 (1983)
`1012 Whitaker, J.N., “Rationale for Immunotherapy in Multiple Sclerosis,”
`Annals of Neurology, 36:S103-S107 (1994)
`Stelmasiak, Z., et al., “A pilot trial of cladribine (2-
`chlorodeoxyadenosine) in remitting-relapsing multiple sclerosis,”
`Medical Science Monitor, 4(1):4-8 (1998)
`Beutler, E., et al., “The treatment of chronic progressive multiple
`sclerosis with cladribine,” Pro. Natl. Acad. Sci., USA 93:1716-1720
`1014
`(1996)
`1015 Tortorella, C., et al., “Cladribine Ortho Biotech Inc,” Current
`Opinion in Investigational Drugs, 2(12):1751-1756 (2001)
`1016 Langtry, H.D., et al., “Cladribine, A Review of its Use in Multiple
`Sclerosis,” BioDrugs, 9(5):419-433 (1998)
`1017 Rudick, R.A., et al., “Management of Multiple Sclerosis,” The New
`England Journal of Medicine, 337(22):1604-1611 (1997)
`Rice, G.P.A., et al., “Cladribine and progressive MS, Clinical and
`MRI outcomes of a multicenter controlled trial,” Neurology, 54:1145-
`1155 (2000)
`Barkhof, R., et al., “Limited duration of the effect of
`methylprednisolone on changes on MRI in multiple sclerosis,”
`Neuroradiology, 36:382-387 (1994)
`Pirko, I. and Rodriguez, M., “Pulsed Intravenous Methylprednisolone
`Therapy in Progressive Multiple Sclerosis: Need for a Controlled
`Trial,” Archives of Neurology, 61:1148-1149 (2004)
`
`1019
`
`1020
`
`11
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`Inter Partes Review of U.S. Patent No. 8,377,903
`Declaration of Aaron E. Miller, M.D.
`(EX1002)
`
`
`1022
`
`1023
`
`1024
`
`1021
`
`Exhibit
`No. Description
`Weiner, H.L., et al., “Intermittent cyclophosphamide pulse therapy in
`progressive multiple sclerosis: Final report of the Northeast
`Cooperative Multiple Sclerosis Treatment Group,” Neurology,
`43:910-918 (1993)
`Bodor, N. and Dandiker, Y., “Oral Formulation of Cladribine,”
`International Publication No. WO 2004/087101 A2 (filed March 26,
`2004; published October 14, 2004)
`Grieb, P., et al., “Effect of Repeated Treatments with Cladrabine (2-
`Chlorodeoxyadenosine) on Blood Counts in Multiple Sclerosis
`Patients,” Archivum Immunologiae Experimentalis, 43:323-327
`(1995)
`Schultz, T.W., et al., “Cyclodextrine Cladrabine Formulations,” U.S.
`Patent No. 6,194,395 B1 (filed February 25, 1999; issued February
`27, 2001)
`1025 File History for U.S. Patent No. 7,713,947
`Beutler, E., “Use of Substituted Adenine Derivatives for Treating
`Multiple Sclerosis,” U.S. Patent No. 5,506,214 B2 (filed February 18,
`1993; issued April 9, 1996)
`Romine, J. S., et al., “A Double-Blind, Placebo-Controlled,
`Randomized Trial of Cladribine in Relapsing-Remitting Multiple
`Sclerosis,” Proceedings of the Association of American Physicians,
`111(1):35-44 (1999)
`Bloom, P.M., “Treatment of Multiple Sclerosis With
`Lymphocytapheresis and Chemo-Immunosuppression,” U.S. Patent
`No. 4,964,848 (filed June 27, 1988; issued October 23, 1990)
`Lassmann, H., et al., “Heterogeneity of multiple sclerosis
`pathogenesis: implications for diagnosis and therapy,” TRENDS in
`1036
`Molecular Medicine, 7(3):115-121 (March 2001)
`1037 Lublin, F. D., et al., “Defining The Clinical Course of Multiple
`Sclerosis,” Neurology, 46:907-911 (1996)
`Casanova, B., et al., “High Clinical Inflammatory Activity Prior to
`the Develipment of Secondary Progression: A Perspective of 5-year
`Follow-up Study,” Multiple Sclerosis, 8:59-63 (2002)
`Shurkovich, S., et al., “Randomized Study of Antibodies to INF-γ and
`TND- α in Secondary Progressive Multiple Sclerosis,” Multiple
`Sclerosis, 7:277-84 (2001)
`
`1026
`
`1031
`
`1033
`
`1038
`
`1042
`
`12
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`

`

`Inter Partes Review of U.S. Patent No. 8,377,903
`Declaration of Aaron E. Miller, M.D.
`(EX1002)
`
`
`Exhibit
`No. Description
`Khoury, S. J., “Multiple Sclerosis: What Have We learned From
`Magnetic Resonance Imaging Studies,” Archives of Internal
`1043
`Medicine, 158:565-73 (1998)
`1044 Roitt, I. M., “Essential Immunology, Sixth Edition,” Blackwell
`Scientific Publications, 1-29 (1988) (Excerpt)
`Filippi, M., et al., “The Effect of Cladribine on T1 'Black Hole'
`Changes in Progressive MS,” Journal of Neurological Sciences,
`1045
`176:42-44 (2000)
`1046 Romine, J. S., et al., “Cladribine: Use in Therapy of Multiple
`Sclerosis,” Biodrugs, 7(5):386-93 (1997)
`Selby, R., et al., “Safety and Tolerability of Subcutaneous Cladribine
`Therapy in Progressive Multiple Sclerosis,” Canadian Journal of
`1047
`Neurological Sciences, 25:295-99 (1998)
`1048 Liliemark, J., “The Clinical Pharmacokinetics and Cladribine,”
`Clinical Pharmacokinetics, 32(2):120-31 (1997)
`Barkhof, F., et al., “Limited duration of the effect of
`methylprednisolone on changes on MRI in multiple sclerosis,”
`Neuroradiology, 36:382-387 (1994)
`Chumlea, W.C., “Total body water data for white adults 18 to 64
`years of age: The Fels Longitudinal Study,” Kidney International,
`56:244-252 (1999)
`
`1049
`
`1050
`
`
`
`
`V. The Person of Ordinary Skill in the Art (“POSA”)
`I understand that a POSA is a hypothetical person who is presumed to
`20.
`
`be aware of all pertinent art, thinks along conventional wisdom in the art, and is a
`
`person of ordinary creativity. Because the ’903 patent relates to methods of human
`
`therapeutic treatments, the level of skill of a POSA in this field is high. Given the
`
`high level of skill, a POSA would draw upon the knowledge and experience of
`
`related disciplines of a multi-disciplinary team that might lie outside the POSA’s
`
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`Inter Partes Review of U.S. Patent No. 8,377,903
`Declaration of Aaron E. Miller, M.D.
`(EX1002)
`
`
`primary training. For example, a physician might rely upon the knowledge and
`
`experience of a pharmacologist on a multi-disciplinary team to determine the
`
`appropriate dose for a particular patient. Thus, a POSA for the ’903 patent would
`
`have had the knowledge of multiple disciplines, such as immunology,
`
`biochemistry, and human physiology and anatomy, and also typically be a clinician
`
`with experience and/or training in neurology. The POSA would typically 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.
`
`21. A POSA would have also known how to research the scientific
`
`literature in the field relating to the treatment of autoimmune diseases, which
`
`would have included the underlying pathogenic mechanisms of multiple sclerosis,
`
`as well as various approaches to treating multiple sclerosis, and have knowledge
`
`of, and skills relating to, useful techniques for accomplishing the same.
`
`VI. State of the Art Prior to December 22, 2004
`A. Multiple sclerosis is a chronic disease with no known cure
`22. Multiple sclerosis (“MS”) is “a chronic inflammatory disease of the
`
`nervous system in which a T-cell-mediated inflammatory process is associated
`
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`Inter Partes Review of U.S. Patent No. 8,377,903
`Declaration of Aaron E. Miller, M.D.
`(EX1002)
`
`
`with destruction of myelin sheaths.” EX1036, Abstract. To date, there is no known
`
`cure for MS. EX1024, 35. The clinical course of MS typically follows a “variable
`
`pattern over time but usually can be characterized by either episodic acute periods
`
`of worsening (relapses, exacerbations, bouts, attacks), gradual progressive
`
`deterioration of neurologic function, or combinations of both.” EX1037, 907. The
`
`heterogeneous nature of the disease prompted clinicians to adopt a standardized
`
`terminology “to describe the pattern and course of MS.” Id., Abstract.
`
`23. Thus, in 1996, the US National Multiple Sclerosis Society Advisory
`
`(NMSS) Committee on Clinical Trials in Multiple Sclerosis (“the Committee”)
`
`provided standardized definitions of the following MS clinical forms: relapsing-
`
`remitting MS (“RRMS”), secondary progressive MS (“SPMS”), primary
`
`progressive MS (“PPMS”), and progressive-relapsing MS (“PRMS”). Id., 908-909.
`
`I have provided the following table containing the 1996 Committee’s standardized
`
`definitions and illustrations for each form of MS as shown below:
`
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`Inter Partes Review of U.S. Patent No. 8,377,903
`Declaration of Aaron E. Miller, M.D.
`(EX1002)
`
`
`MS Type and Definition
`Relapsing-Remitting (RRMS)
`
`Illustration
`
`“[C]learly defined disease relapses
`with full recovery or with sequelae
`and residual deficit… characterized
`by a lack of disease progression.”
`
`
`
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`Inter Partes Review of U.S. Patent No. 8,377,903
`Declaration of Aaron E. Miller, M.D.
`(EX1002)
`
`
`MS Type and Definition
`Secondary Progressive (SPMS)
`
`Illustration
`
`“[I]nitial RR disease course followed
`by progression with or without
`occasional relapses, minor remissions,
`and plateaus.”
`
`
`
`17
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`Inter Partes Review of U.S. Patent No. 8,377,903
`Declaration of Aaron E. Miller, M.D.
`(EX1002)
`
`
`Illustration
`
`MS Type and Definition
`Primary Progressive (PPMS)
`
`“[D]isease progression from onset
`with occasional plateaus and
`temporary minor improvements
`allowed.”
`
`
`
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`Inter Partes Review of U.S. Patent No. 8,377,903
`Declaration of Aaron E. Miller, M.D.
`(EX1002)
`
`
`MS Type and Definition
`Progressive Relapsing (PRMS)
`
`Illustration
`
`“[P]rogressive disease from onset,
`with clear acute relapses…
`characterized by continuing
`progression.”
`
`
`
`
`
`Id., 908-909, FIGs. 1-4.
`
`24. As shown above, the Committee recognized that the progressive
`
`courses of MS – SPMS and PPMS – may exhibit relapses and exacerbations like
`
`the RRMS course, in addition to disease progression. It was also known that
`
`despite the disease form, “[a]ll actively demyelinating lesions were associated with
`
`an inflammatory process, with the inflammatory infiltrates composed mainly of T
`
`cells and macrophages. EX1036, 118. As also shown above, the PPMS and PRMS
`
`forms show disease progression “from onset” without first exhibiting a relapsing-
`
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`Inter Partes Review of U.S. Patent No. 8,377,903
`Declaration of Aaron E. Miller, M.D.
`(EX1002)
`
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`remitting course, in contrast to the SPMS form, which shows an “initial RR
`
`cours