UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________________________
`
`TWI PHARMACEUTICALS, INC.
`Petitioner,
`
`v.
`
`MERCK SERONO SA
`Patent Owner.
`_______________________________
`
`Patent No. 8,377,903
`Patent No. 7,713,947
`_______________________________
`Inter Partes Review IPR2023-00049
`_______________________________
`
`DECLARATION OF BENJAMIN M. GREENBERG, M.D.
`
`Petitioner TWi Pharms., Inc.
`EX1005, Page 1 of 126
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`

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`TABLE OF CONTENTS
`
`
`
`I.
`
`QUALIFICATIONS AND BACKGROUND .............................................. 8
`A. Education and Experience ............................................................................. 8
`B. Bases for Opinions and Materials Considered ............................................11
`C.
`Scope of Work .............................................................................................11
`II.
`SUMMARY OF OPINIONS ......................................................................12
`III.
`PERSON OF ORDINARY SKILL IN THE ART ......................................13
`IV.
`THE ’947 PATENT (Ex. 1001) ..................................................................14
`A. Overview .....................................................................................................14
`B. The Challenged Claims of the ’947 Patent .................................................15
`V.
`THE ’903 PATENT (Ex. 1002) ..................................................................17
`A. Overview .....................................................................................................17
`B. The Challenged Claims of the ’903 Patent .................................................18
`VI.
`CLAIM CONSTRUCTION ........................................................................20
`VII. BACKGROUND AND STATE OF THE ART .........................................21
`A. Multiple Sclerosis ........................................................................................21
`B. Underlying Causes of MS ...........................................................................24
`C. Multiple Sclerosis Therapies .......................................................................25
`D. The Prior Art References .............................................................................37
`1. Bodor WO ’101 and Bodor ’328 .........................................................37
`2. Rice 2000 .............................................................................................40
`VIII. OPINIONS ON GROUNDS OF UNPATENTABILITY ..........................44
`A. Legal Standards ...........................................................................................44
`B. Ground 1: Claims 36, 38–39, 41–48 of the ’947 Patent, and claims 17, 19–
`20, and 22–29 of the ’903 Patent are unpatentable Under 35 U.S.C. § 102
`as Anticipated by Bodor ..............................................................................49
`1.
`Independent Claim 36 of the ’947 Patent ............................................50
`a.
`Limitation 1: Preamble: “A method of treating multiple sclerosis
`comprising the oral administration of a formulation comprising
`cladribine following the sequential steps below:” .......................50
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`c.
`
`d.
`
`b.
`
`Limitation 2: “an induction period lasting from about 2 months to
`about 4 months wherein said formulation is orally administered
`and wherein the total dose of cladribine reached at the end of the
`induction period is from about 1.7 mg/kg to about 3.5 mg/kg” ..51
`Limitation 3: “a cladribine-free period lasting from about 8
`months to about 10 months, wherein no cladribine is
`administered” ...............................................................................57
`Limitation 4: “a maintenance period lasting from about 2 months
`to about 4 months, wherein said formulation is orally
`administered and wherein the total dose of cladribine reached at
`the end of the maintenance period is about 1.7 mg/kg;” .............57
`Limitation 5: “a cladribine-free period wherein no cladribine is
`administered” ...............................................................................64
`2. Dependent Claim 38 of the ’947 Patent: “method according to claim
`36, wherein the induction period lasts about 2 months” .....................65
`3. Dependent Claim 39 of the ’947 Patent: “method according to claim
`36, wherein the total dose of cladribine reached at the end of the
`induction period is about 1.7 mg/kg” ..................................................65
`4. Dependent Claim 41 of the ’947 Patent: “method according to claim
`36, wherein the cladribine-free period (ii) lasts about 10 months” .....66
`5. Dependent Claim 42 of the ’947 Patent: “method according to claim
`36, wherein the cladribine-free (iv) period lasts 10 months ...............67
`6. Dependent Claim 43 of the ’947 Patent: “method according to claim
`36, wherein the maintenance period lasts about 2 months” ................67
`7. Dependent Claim 44 of the ’947 Patent: “method according to claim
`36, wherein the formulation is orally administered at a daily dose of 3
`to 30 mg cladribine” ............................................................................68
`8. Dependent Claim 45 of the ’947 Patent: “method according to claim
`36, wherein the formulation is orally administered at a daily dose of
`10 mg cladribine” ................................................................................69
`9. Dependent Claim 46 of the ’947 Patent: “method according to claim
`36, wherein the formulation is orally administered 1 to 7 days per
`month” .................................................................................................69
`10. Dependent Claim 47 of the ’947 Patent: “method according to claim
`36, wherein the steps (iii) to (iv) are repeated at least one or two
`times” ...................................................................................................70
`
`e.
`
`-3-
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`EX1005, Page 3 of 126
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`11. Dependent Claim 48 of the ’947 Patent: “method according to claim
`36, wherein the formulation is administered in combination with
`interferon-beta” ...................................................................................71
`12. Independent Claim 17 of the ’903 Patent ............................................71
`13. Dependent Claim 19 of the ’903 Patent: “method according to claim
`17, wherein the induction period lasts about 2 months” .....................77
`14. Dependent Claim 20 of the ’903 Patent: “method according to claim
`17, wherein the total dose of cladribine reached at the end of the
`induction period is about 1.7 mg/kg” ..................................................77
`15. Dependent Claim 22 of the ’903 Patent: “method according to claim
`17, wherein the cladribine-free period (ii) lasts about 10 months” .....79
`16. Dependent Claim 23 of the ’903 Patent: “method according to claim
`17, wherein the cladribine-free (iv) period lasts 10 months” ..............79
`17. Dependent Claim 24 of the ’903 Patent: “method according to claim
`17, wherein the maintenance period lasts about 2 months” ................80
`18. Dependent Claim 25 of the ’903 Patent: “method according to claim
`17, wherein the formulation is orally administered at a daily dose of 3
`to 30mg” ..............................................................................................81
`19. Dependent Claim 26 of the ’903 Patent: “method according to claim
`17, wherein the formulation is orally administered at a daily dose of
`10mg cladribine” .................................................................................81
`20. Dependent Claim 27 of the ’903 Patent: “method according to claim
`17, wherein the formulation is orally administered 1 to 7 days per
`month during the induction period” ....................................................82
`21. Dependent Claim 28 of the ’903 Patent: “method according to claim
`17, wherein the steps (iii) to (iv) are repeated at least one or two
`times” ...................................................................................................83
`22. Dependent Claim 29 of the ’903 Patent: “method according to claim
`17, wherein the formulation is administered in combination with
`interferon-beta” ...................................................................................84
`C. Ground 2: Claims 36, 38–39, 41–48 of the ’947 Patent and claims 17, 19–
`20, and 22–29 of the ’903 Patent are Unpatentable Under 35 U.S.C. § 103
`Over Bodor. .................................................................................................84
`1.
`It would have been obvious to administer a total dosage amount of
`about 1.7 mg/kg per administration round ..........................................85
`
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`3.
`
`b.
`
`2.
`
`It would have been obvious to repeat the same administration regimen
`after the cladribine-free period ............................................................87
`It would have been obvious to use Bodor’s oral cladribine dosage
`form and treatment regimen to treat relapsing-remitting and early
`secondary progressive multiple sclerosis ............................................90
`D. Ground 3: Claims 36, 38–39, 41–48 of the ’947 Patent and claims 17, 19–
`20, and 22–29 of the ’903 Patent are Unpatentable Under 35 U.S.C. §
`103(a) Over Bodor in view of Rice 2000....................................................93
`1.
`Independent Claim 36 of the ’947 Patent ............................................95
`a.
`Limitation 1: Preamble: “A method of treating multiple sclerosis
`comprising the oral administration of a formulation comprising
`cladribine following the sequential steps below:” .......................95
`Limitation 2: “an induction period lasting from about 2 months to
`about 4 months wherein said formulation is orally administered
`and wherein the total dose of cladribine reached at the end of the
`induction period is from about 1.7 mg/kg to about 3.5 mg/kg” ..95
`Limitation 3: “a cladribine-free period lasting from about 8
`months to about 10 months, wherein no cladribine is
`administered” .............................................................................102
`Limitation 4: “a maintenance period lasting from about 2 months
`to about 4 months, wherein said formulation is orally
`administered and wherein the total dose of cladribine reached at
`the end of the maintenance period is about 1.7 mg/kg;” ...........102
`Limitation 5: “a cladribine-free period wherein no cladribine is
`administered” .............................................................................105
`2. Dependent Claim 38 of the ’947 Patent: “method according to claim
`36, wherein the induction period lasts about 2 months” ...................106
`3. Dependent Claim 39 of the ’947 Patent: “method according to claim
`36, wherein the total dose of cladribine reached at the end of the
`induction period is about 1.7 mg/kg” ................................................106
`4. Dependent Claim 41 of the ’947 Patent: “method according to claim
`36, wherein the cladribine-free period (ii) lasts about 10 months” ...107
`5. Dependent Claim 42 of the ’947 Patent: “method according to claim
`36, wherein the cladribine-free (iv) period lasts 10 months” ............107
`6. Dependent Claim 43 of the ’947 Patent: “method according to claim
`36, wherein the maintenance period lasts about 2 months” ..............108
`
`c.
`
`d.
`
`e.
`
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`7. Dependent Claim 44 of the ’947 Patent: “method according to claim
`36, wherein the formulation is orally administered at a daily dose of 3
`to 30 mg cladribine” ..........................................................................109
`8. Dependent Claim 45 of the ’947 Patent: “method according to claim
`36, wherein the formulation is orally administered at a daily dose of
`10 mg cladribine” ..............................................................................109
`9. Dependent Claim 46 of the ’947 Patent: “method according to claim
`36, wherein the formulation is orally administered 1 to 7 days per
`month” ...............................................................................................110
`10. Dependent Claim 47 of the ’947 Patent: “method according to claim
`36, wherein the steps (iii) to (iv) are repeated at least one or two
`times” .................................................................................................110
`11. Dependent Claim 48 of the ’947 Patent: “method according to claim
`36, wherein the formulation is administered in combination with
`interferon-beta” .................................................................................112
`12. Independent Claim 17 of the ’903 Patent ..........................................112
`13. Dependent Claim 19 of the ’903 Patent: “method according to claim
`17, wherein the induction period lasts about 2 months” ...................118
`14. Dependent Claim 20 of the ’903 Patent: “method according to claim
`17, wherein the total dose of cladribine reached at the end of the
`induction period is about 1.7 mg/kg” ................................................119
`15. Dependent Claim 22 of the ’903 Patent: “method according to claim
`17, wherein the cladribine-free period (ii) lasts about 10 months.” ..119
`16. Dependent Claim 23 of the ’903 Patent: “method according to claim
`17, wherein the cladribine-free (iv) period lasts 10 months” ............120
`17. Dependent Claim 24 of the ’903 Patent: “method according to claim
`17, wherein the maintenance period lasts about 2 months” ..............120
`18. Dependent Claim 25 of the ’903 Patent: “method according to claim
`17, wherein the formulation is orally administered at a daily dose of 3
`to 30mg” ............................................................................................121
`19. Dependent Claim 26 of the ’903 Patent: “method according to claim
`17, wherein the formulation is orally administered at a daily dose of
`10 mg cladribine” ..............................................................................122
`20. Dependent Claim 27 of the ’903 Patent: “method according to claim
`17, wherein the formulation is orally administered 1 to 7 days per
`month during the induction period” ..................................................122
`
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`21. Dependent Claim 28 of the ’947 Patent: “method according to claim
`17, wherein the steps (iii) to (iv) are repeated at least one or two
`times” .................................................................................................123
`22. Dependent Claim 29 of the ’903 Patent: “method according to claim
`17, wherein the formulation is administered in combination with
`interferon-beta” .................................................................................124
`CONCLUSION .........................................................................................124
`
`
`
`IX.
`
`
`
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`Petitioner TWi Pharms., Inc.
`EX1005, Page 7 of 126
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`1. My name is Benjamin M. Greenberg, M.D. I have been retained by
`
`counsel for TWi Pharmaceuticals, Inc. (“TWi”) as an independent expert to analyze
`
`certain claims of the ’947 patent1 (Ex. 1001) and the ’903 patent2 (Ex. 1002) in view
`
`of the prior art and the knowledge of a person of ordinary skill in art as of the earliest
`
`claimed priority date of the ’947 and ’903 patents. I understand that TWi will be
`
`submitting a petition for inter partes review (“IPR”) of the ’947 and ’903 patents,
`
`which will include this Declaration.
`
`I.
`
`QUALIFICATIONS AND BACKGROUND
`
`A. Education and Experience
`
`2.
`
`I received an M.D. from Baylor College of Medicine in 2001. In 2005
`
`I completed a residency in Neurology at Johns Hopkins Hospital. From 2004 to
`
`2005, I was Chief Resident in Neurology at John’s Hopkins, during which time I
`
`treated numerous multiple sclerosis patients and conducted research relating to
`
`multiple sclerosis and its related disorders.
`
`3.
`
`As part of my neurology training from 2002 to 2004 I cared for multiple
`
`sclerosis patients at Johns Hopkins in both the outpatient and inpatient settings. I
`
`prescribed disease modifying therapies and immunosuppressants under the
`
`supervision of attending physicians and routinely attended the neuroimmunology
`
`
`1 U.S. Patent No. 7,713,947 (“the ’947 patent”) (Ex. 1001).
`2 U.S. Patent No. 8,377,903 (“the ’903 patent”) (Ex. 1002).
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`section conferences. These conferences included case presentations, research
`
`presentations, journal clubs and discussions of patient management. I became
`
`involved in neuroimmunology research projects, assisting in data gathering and
`
`patient management for individuals undergoing advanced immunotherapy, such as
`
`mitoxantrone and cyclophosphamide therapy.
`
`4.
`
`From 2005 to 2007 I was a postdoctoral fellow in Microbiology and
`
`Immunology at Johns Hopkins School of Public Health. From 2005 to 2008 I had an
`
`academic appointment at Johns Hopkins, first as a Clinical Instructor, and then as an
`
`Assistant Professor. During that same time, I was also a treating Neurologist. Since
`
`2009, I have been employed by the University of Texas Southwestern, first as an
`
`Assistant Professor and more recently since 2019 as a Professor. I have also been a
`
`practicing Neurologist since 2009 at hospitals associated with the University of
`
`Texas Southwestern. I was originally named the Deputy Director of the Multiple
`
`Sclerosis Program and Director of the new Transverse Myelitis and Neuromyelitis
`
`Optica Program. I served as section head for Neuroimmunology from 2019 to 2022.
`
`5.
`
`Since 2002, I have treated over 1,500 patients with multiple sclerosis
`
`(“MS”).
`
`6. My duties at the University of Texas Southwestern include clinical,
`
`research, education and administrative activities. I see both adults and children with
`
`autoimmune disorders of the central nervous system. My outpatient clinics involve
`
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`evaluating patients who are being diagnosed with multiple sclerosis and related
`
`conditions as well as formulating treatment plans for those patients. In this role I act
`
`as a consultant to outside treating neurologists and as the primary physician to
`
`patients with multiple sclerosis. My research activities involve both clinical and
`
`translational research projects. I have served as the principal investigator on
`
`numerous interventional and observational multiple sclerosis clinical trials. I
`
`coordinate the activities of phase 1, phase 2, phase 3 and phase 4 clinical trials and
`
`I oversee a translational research program that identifies novel biomarkers of disease
`
`in patients with multiple sclerosis. My educational roles have included serving as
`
`course co-director of the medical school neurosciences course, a teacher of residents
`
`on the inpatient services and as fellowship director for the multiple sclerosis and
`
`autoimmune neurology fellowships. I have routinely been a course director or
`
`lecturer at the American Academy of Neurology annual meeting, including several
`
`years lecturing about multiple sclerosis therapeutics. Finally, my administrative
`
`roles currently include serving as head of the neuroimmunology fellowship program
`
`and the vice chair of research within the Department of Neurology as well as the
`
`Director of the Neurosciences Translational Research Center at the University of
`
`Texas Southwestern.
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`7.
`
`Additionally, I was a section editor for JAMA Neurology and have been
`
`a reviewer for European Neurology, Neurology, Annals of Neurology, Journal of
`
`Neurology, Journal of Immunology, and Multiple Sclerosis Journal.
`
`8.
`
`As of September 2019, my research has resulted in more than 120
`
`publications. I have also been invited to present my work on more than 50 occasions.
`
`9.
`
`I have over 20 years of practical and research experience in the
`
`treatment of patients with MS, and in the field of neurology.
`
`10. My curriculum vitae is attached hereto as Ex. 1006.
`
`11.
`
`In the past four years, I have testified as an expert at trial or by
`
`deposition in the following case: Biogen Int’l GmbH v. Mylan Pharms Inc., C.A.
`
`No. 1:17-cv-116-IMK (N.D. W.Va.).
`
`B.
`
`12.
`
`Bases for Opinions and Materials Considered
`
`I have considered the facts and data contained in the references cited
`
`herein, as well as my experience, education, and training, in providing the opinions
`
`contained herein.
`
`C.
`
`13.
`
`Scope of Work
`
`I have been retained by TWi as a technical expert in this matter to
`
`provide my opinions regarding certain claims of the ’903 and ’947 patents in view
`
`of the prior art and the knowledge of a person of ordinary skill in the art as of the
`
`earliest claimed priority date of the ’903 and ’947 patents. I receive $600 per hour
`
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`for services related to drafting the declaration and will receive $1000 per hour for
`
`time spent testifying in deposition. No part of my compensation is dependent upon
`
`my opinions or the outcome of this matter.
`
`14. Other than serving as a paid journal club leader, I do not have any
`
`affiliations with Merck Serono SA or any affiliates presently known to me
`
`(“Merck”). I have not participated as a paid investigator in any research or clinical
`
`trials for or on behalf of Merck, and have no affiliation with the named inventors on
`
`the ’903 and ’947 patents.
`
`II.
`
`SUMMARY OF OPINIONS
`
`15.
`
`It is my opinion that at least claims 36, 38–39, and 41–48 of the ’947
`
`patent are invalid because they are either anticipated by or obvious over Bodor
`
`WO ’1013 (Ex. 1007) and/or its US counterpart, Bodor ’3284 (Ex. 1029) (collectively
`
`“Bodor”). It is further my opinion that each of these claims are invalid as obvious
`
`over Bodor in view of Rice 20005 (Ex. 1008).
`
`16.
`
`It is my opinion that at least claims 17, 19–20, and 22–29 of the ’903
`
`patent are invalid because they are either anticipated by or obvious over Bodor. It is
`
`
`3International Patent Publication WO 2004/087101 (“Bodor WO ’101”) (EX1007).
`4U.S. Patent No. 7,888,328(“ Bodor ’328”) (EX1029).
`5Rice, G. et al. “Cladribine and progressive MS: Clinical and MRI outcomes of a
`multicenter controlled trial”. Neurology, Mar. 2000, pp. 1145-1155, vol. 54 (“Rice
`2000”) (Ex. 1008).
`
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`further my opinion that these claims are invalid as obvious over Bodor in view of
`
`Rice 2000.
`
`III. PERSON OF ORDINARY SKILL IN THE ART
`
`17.
`
`I have been informed by counsel that the anticipation and obviousness
`
`analyses are to be conducted from the perspective of a person of ordinary skill in the
`
`art at the time of the invention.
`
`18.
`
`I have been informed that the following five factors inform the analysis
`
`for determining the level of ordinary skill in the art: (1) type of problems encountered
`
`in the art; (2) prior art solutions to those problems; (3) rapidity with which
`
`innovations are made; (4) sophistication of the technology; and (5) educational level
`
`of active workers in the field. I have also been informed that the level of ordinary
`
`skill in the art usually is evidenced by the prior art references themselves. I apply
`
`these factors in providing my opinion as to the level of one having ordinary skill in
`
`the art.
`
`19.
`
`I have knowledge relevant to what a person of ordinary skill in the art
`
`at the time of the claimed invention would understand and do. In my opinion, and
`
`applying the factors set forth above, person of ordinary skill in the art at the time of
`
`the alleged invention would have a doctorate of medicine and two-years’ experience
`
`treating neurological conditions and prescribing
`
`immunotherapies
`
`to
`
`treat
`
`neurological conditions. At their core, the challenged claims of the ’903 patent and
`
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`’947 patent relate to oral dosing regimens for use with the treatment of multiple
`
`sclerosis with a known drug compound, cladribine, consisting of a range of dosage
`
`strengths and treatment schedules. A person with a doctorate of medicine and two-
`
`years’ experience treating neurological conditions and prescribing immunotherapies
`
`to treat neurological conditions would have been familiar with a sufficiently broad
`
`array of treatment options, regimens, and published literature discussing the same as
`
`of the alleged date of the invention, and would have personally managed patients
`
`considering or being treated with medications of a similar class as cladribine that
`
`they would understand treating criteria, decision making, and standard courses of
`
`treatment for such drug products.
`
`IV. THE ’947 PATENT (Ex. 1001)6
`
`A. Overview
`
`20. The ’947 patent, titled “Cladribine Regimen for Treating Multiple
`
`Sclerosis,” was filed on December 20, 2005 and claims priority to U.S. Provisional
`
`Application Number 60/638,669, filed on December 22, 2004. (the ’947 patent at
`
`[45], [54] and [60], Ex. 1001 at 1; Ex. 1003 at 2-3). For purposes of the analysis
`
`contained in this declaration, I have considered prior art dated prior to December 22,
`
`2004.
`
`6Supra, note 1.
`
`
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`21. The ’947 patent issued on May 11, 2010 and lists Giampiero De Luca,
`
`Arnaud Ythier, Alain Munafo, and Maria Lopez-Breshnahan as inventors. (the ’947
`
`patent at [45], [75], Ex. 1001 at 1).
`
`22. The abstract of the ’947 patent states that the invention relates to the
`
`use of Cladribine for the preparation of a pharmaceutical formulation for the
`
`treatment of multiple sclerosis, especially relapsing-remitting multiple sclerosis
`
`(RRMS) or early secondary progressive multiple sclerosis wherein the preparation
`
`is to be orally administered and wherein re-treatments are possible. (the ’947 patent
`
`at [57], Ex. 1001 at 1).
`
`23. The claims generally recite a method of treating multiple sclerosis with
`
`an oral cladribine dosage form, and with a dosing regimen comprising the
`
`administration of cladribine during a first administration period (i.e. an induction
`
`period), a cladribine-free period, administration of cladribine during second
`
`administration period (i.e. a maintenance period), and a subsequent cladribine-free
`
`period. (the ’947 patent col. 16, ℓ. 54–col. 20, ℓ. 29, Ex. 1001 at 10–13).
`
`B.
`
`24.
`
`The Challenged Claims of the ’947 Patent
`
`I have considered the patentability of claims 36, 38–39, and 41–48 of
`
`the ’947 patent, of which only claim 36 is an independent claim.
`
`25.
`
`Independent claim 36 recites:
`
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`A method of treating multiple sclerosis comprising the oral administration of
`a formulation comprising cladribine following the sequential steps below:
`(i) an induction period lasting from about 2 months to about 4 months
`wherein said formulation is orally administered and wherein the total
`dose of cladribine reached at the end of the induction period is from
`about 1.7 mg/kg to about 3.5 mg/kg;
`(ii) a cladribine-free period lasting from about 8 months to about 10
`months, wherein no cladribine is administered;
`(iii) a maintenance period lasting from about 2 months to about 4
`months, wherein said formulation is orally administered and wherein
`the total dose of cladribine reached at the end of the maintenance period
`is about 1.7 mg/kg;
`(iv) a cladribine-free period wherein no cladribine is administered.
`(the ’947 patent col. 19, ℓℓ. 14–29, Ex. 1001 at 13).
`26. Claims 38, 39, and 41–48 each depend from claim 36, and recite
`
`additional limitations on the claimed method of treating multiple sclerosis,
`
`including:
`
`- Limiting the length of the induction period to “about 2 months” (claim 38),
`
`the length of the cladribine free period to “about 10 months” (claims 41,
`
`42), and the length of the maintenance period to “about 2 months” (claim
`
`43).
`
`- Limiting the total dose of cladribine reached at the end of the induction
`
`period to “about 1.7 mg/kg.” (Claim 39).
`
`- Administering the formulation of claim 36 “at a daily dose of 3 to 30 mg
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`cladribine ” (claim 44), and separately “at a daily dose of 10 mg cladribine”
`
`(claim 45).
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`-16-
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`Petitioner TWi Pharms., Inc.
`EX1005, Page 16 of 126
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`- Orally administering the formulation of claim 36 “1 to 7 days per month
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`during the induction period.” (Claim 46).
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`- Repeating the maintenance period and cladribine-free period “at least one
`
`or two times.” (Claim 47).
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`- Administering the formulation in combination with interferon-beta. (Claim
`
`48).
`
`(the ’947 patent col. 19, ℓ. 14–col. 20, ℓ. 29, Ex. 1001 at 13).
`
`V. THE ’903 PATENT (Ex. 1002)7
`
`A. Overview
`
`27. The ’903 patent, titled “Cladribine Regimen for Treating Multiple
`
`Sclerosis,” was filed on April 23, 2010 and claims priority to U.S. Provisional Patent
`
`Application No. 60/638,669, filed on December 22, 2004. (the ’903 patent at [45],
`
`[54] and [60]. Ex. 1002 at 1; Ex. 1004 at 26). For purposes of the analysis contained
`
`in this declaration, I have considered prior art dated prior to December 22, 2004.
`
`28. The ’903 patent issued on February 19, 2013, listing Giampiero De
`
`Luca, Arnaud Ythier, Alain Munafo, and Maria Lopez-Breshnahan as inventors. (the
`
`’903 patent at [45], [75], Ex. 1002 at 1).
`
`7Supra, note 2.
`
`
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`-17-
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`EX1005, Page 17 of 126
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`29. The abstract of the ’903 patent states that the invention relates to the
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`use of Cladribine for the preparation of a pharmaceutical formulation for the
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`treatment of multiple sclerosis, especially relapsing-remitting multiple sclerosis
`
`(RRMS) or early secondary progressive multiple sclerosis wherein the preparation
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`is to be orally administered and wherein re-treatments are possible. (the ’903 patent
`
`at [57], Ex. 1002 at 1).
`
`30. The claims generally recite a method of treating certain forms of
`
`multiple sclerosis with an oral cladribine dosage form, and with a dosing regimen
`
`comprising the administration of cladribine during a first administration period (i.e.
`
`an induction period), a cladribine-free period, administration of cladribine during
`
`second administration period (i.e. a maintenance period), and a subsequent
`
`cladribine-free period. (the ’903 patent col. 16, ℓ. 52–col. 18, ℓ. 55, Ex. 1002 at 10–
`
`11).
`
`B.
`
`31.
`
`The Challenged Claims of the ’903 Patent
`
`I have considered the patentability of claims 17, 19–20, and 22–29 of
`
`the ’903 patent, of which only claim 17 is an independent claim. (the ’903 patent
`
`col. 16, ℓ. 52–col. 18, ℓ. 55, Ex. 1002 at 10–11).
`
`32.
`
`Independent claim 17 recites:
`
`A method of treating relapsing-remitting multiple sclerosis or early secondary
`progressive multiple sclerosis comprising the oral administration of a
`formulation comprising cladribine to an individual having relapsing-remitting
`
`-18-
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`Petitioner TWi Pharms., Inc.
`EX1005, Page 18 of 126
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`multiple sclerosis or early secondary progressive multiple sclerosis following
`the sequential steps below:
`(i) an induction period lasting from about 2 months to about 4 months
`wherein said formulation is orally administered and wherein the total
`dose of cladribine reached at the end of the induction period is from
`about 1.7 mg/kg to about 3.5 mg/kg;
`(ii) a cladribine-free period lasting from about 8 months to about 10
`months, wherein no cladribine is administered;
`(iii) a maintenance period lasting from about 2 months to about 4
`months, wherein said formulation is orally administered and wherein
`the total dose of cladribine reached at the end of the maintenance period
`is about 1.7 mg/kg, and
`(iv) a cladribine-free period wherein no cladribine is administered.
`(the ’903 patent col. 18, ℓℓ. 7–26, Ex. 1002 at 11).
`33. Claims 19–20, 22, and 24–27 depend from claim 17, and recite
`
`additional limitations on the claimed method of treating relapsing-remitting multiple
`
`sclerosis or early secondary progressive multiple sclerosis, including:
`
`- Limiting the length of the induction period to “about 2 months” (claim 19),
`
`the length of the cladribine free period to “about 10 months” (claims