Paper 1, October 14, 2022
`
`In the United States Patent and Trademark Office
`
`Before the Patent Trial and Appeal Board
`
`TWI PHARMACEUTICALS INC.,
`Petitioner,
`v.
`MERCK SERONO SA,
`Patent Owner.
`
`U.S. Patent No. 8,377,903
`Ser. No. 12/766,173
`Issue Date: Feb. 19, 2013
`Title: Cladribine Regimen for Treating Multiple Sclerosis
`
`Case No. IPR2023-00050
`
`
`
`
`
`
`
`
`
`
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,377,903
`UNDER 35 U.S.C. §§ 311–319 AND 37 C.F.R. §§ 42.100 et. seq.
`
`
`
`

`

`
`
`TABLE OF CONTENTS
`
`TABLE OF CONTENTS ......................................................................................... i
`
`TABLE OF AUTHORITIES ................................................................................... v
`
`EXHIBIT LIST..................................................................................................... viii
`
`LISTING OF CLAIMS.......................................................................................... xi
`
`MANDATORY NOTICES .................................................................................. xiii
`
`1. Real Parties-In-Interest, § 42.8(b)(1) ..................................................... xiii
`
`2. Related Matters, § 42.8(b)(2) ................................................................. xiii
`
`3. Lead and Back-Up Counsel, § 42.8(b)(3) .............................................. xiv
`
`4. Service Information, § 42.8(b)(4) ........................................................... xiv
`
`(i) Electronic Mailing Address ............................................................. xiv
`
`(ii) Postal Mailing Address .................................................................... xiv
`
`(iii) Hand-Delivery Address ..................................................................... xv
`
`(iv) Telephone number ............................................................................. xv
`
`(v) Facsimile Number ............................................................................. xv
`
`5. Payment of Fees, § 42.15(a) ..................................................................... xv
`
`INTRODUCTION .................................................................................................... 1
`
`GROUNDS FOR STANDING ................................................................................ 2
`
`BACKGROUND ...................................................................................................... 3
`
`I.
`
`Scope And Content Of The Prior Art ......................................................... 3
`
`A. History of Cladribine Treating Multiple Sclerosis ............................. 3
`
`– i –
`
`

`

`
`
`B. Prior Art Patents And Printed Publications. ...................................... 7
`
`1. Bodor ........................................................................................... 7
`
`2. Rice .............................................................................................. 7
`
`II. Level of Ordinary Skill in the Art .............................................................. 8
`
`III. The ’903 Patent Prosecution History. ......................................................... 8
`
`V. Discretion Under 35 U.S.C. § 314(a) ....................................................... 19
`
`A. Whether the court granted a stay or evidence exists that
`one may be granted if a proceeding is instituted. ............................. 20
`
`B. Proximity of the court’s trial date to the Board’s projected
`statutory deadline. ............................................................................ 20
`
`C.
`
`Investment in the parallel proceeding by the court and parties. ...... 21
`
`D. Overlap between issues raised in the petition and in the
`parallel proceeding. .......................................................................... 21
`
`E. Whether the petitioner and the defendant in the parallel
`proceeding are the same party. ......................................................... 22
`
`F. Other circumstances and considerations that impact the
`Board’s exercise of discretion, including the merits. ........................ 22
`
`G. Conclusion ........................................................................................ 22
`
`IDENTIFICATION OF THE CHALLENGE ..................................................... 23
`
`I. The Claims Challenged ............................................................................ 23
`
`II. Specific Grounds And Art ........................................................................ 24
`
`III. Claim Construction ................................................................................... 25
`
`IV. Grounds of Unpatentability. ..................................................................... 25
`
`A. Explanation of Ground 1 For Unpatentability:
`
`– ii –
`
`

`

`
`
`Claims 17, 19–20, and 22–29 of the ’903 Patent
`Anticipated by Bodor. ....................................................................... 27
`
`1.
`
`Independent Claim 17. .............................................................. 27
`
`a. Limitation 1(a): ................................................................... 27
`b. Limitation 1(b); ................................................................... 28
`c. Limitation 1(c) .................................................................... 33
`d. Limitation 1(d) .................................................................... 34
`e. Limitation 1(e). ................................................................... 40
`
`2. Dependent Claim 19. ................................................................ 40
`
`3. Dependent Claim 20. ................................................................ 40
`
`4. Dependent Claim 22. ................................................................ 40
`
`5. Dependent Claim 23. ................................................................ 40
`
`6. Dependent Claim 24. ................................................................ 41
`
`7. Dependent Claim 25. ................................................................ 41
`
`8. Dependent Claim 26. ................................................................ 41
`
`9. Dependent Claim 27. ................................................................ 41
`
`10. Dependent Claim 28. ................................................................ 41
`
`11. Dependent Claim 29. ................................................................ 42
`
`B. Explanation of Ground 2 for Unpatentability:
`Claims 17, 19–20, and 22–29 of the ’903 Patent
`Obvious over Bodor. ......................................................................... 42
`
`1. Repeating Bodor’s Method (Limitations (iii) and (iv) of
`claim 17) ................................................................................... 42
`
`2. Total Dosage Amount (Limitations (i) and (iii) of
`
`– iii –
`
`

`

`
`
`claim 17) ................................................................................... 45
`
`3. Obvious to Administer the Same Dosage as
`Induction Phase (1.7 mg/kg) during Maintenance Phase ......... 48
`
`4. Obvious to Use Bodor’s Method to Treat RRMS
`and SPMS ................................................................................. 49
`
`5. All Other Limitations ................................................................ 50
`
`C. Explanation Of Ground 3 For Unpatentability:
`Claims 17, 19–20, and 22–29 of the ’903 Patent obvious
`over Bodor in view of Rice. .............................................................. 50
`
`1. Repeating Bodor’s Method (Limitations (iii) and (iv) of
`claim 17) ................................................................................... 50
`
`2. Total Dosage Amount (Limitations (i) and (iii) of
`claim 17) ................................................................................... 52
`
`3. Obvious to Administer the Same Dosage as Induction
`Phase (1.7 mg/kg) during Maintenance Phase.......................... 55
`
`4. Obvious to Use Bodor’s Method in view of Rice to Treat
`RRMS and SPMS ..................................................................... 56
`
`5. All Other Limitations ................................................................ 57
`
`D. No Secondary Considerations Overcome This Strong
`Showing of Obviousness. .................................................................. 57
`
`CONCLUSION ....................................................................................................... 58
`
`CERTIFICATION OF WORD COUNT .............................................................. 60
`
`CERTIFICATE OF SERVICE ............................................................................. 61
`
`
`
`
`– iv –
`
`

`

`
`
`TABLE OF AUTHORITIES
`
`CASES
`Acoustic Tech., Inc. v. Itron Networked Sols., Inc.,
`949 F.3d 1366 (Fed. Cir. 2020) ............................................................................ 30
`
`Brown v. 3M,
`265 F.3d 1349 (Fed. Cir. 2001) ..................................................................... 14, 26
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) .......................................................................................... 26, 57
`Hoffmann-La Roche Inc. v. Apotex Inc.,
`748 F.3d 1326 (Fed. Cir. 2014) ............................................................................ 26
`
`In re Baxter Travenol Labs.,
`952 F.2d 388 (Fed. Cir. 1991) .............................................................................. 58
`In re Gershon,
`372 F.2d 535 (CCPA 1967) .................................................................................. 58
`In re Petering,
`301 F.2d 676 (CCPA 1962) .................................................................................. 13
`In re Piasecki,
`745 F.2d 1468 (Fed. Cir. 1984) ............................................................................ 57
`In re Preda,
`401 F.2d 825 (C.C.P.A. 1985) ....................................................................... 30, 36
`Kao Corp. v. Unilever United States, Inc.,
`441 F.3d 963 (Fed. Cir. 2006) .............................................................................. 58
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ................................................................................ 26, 47, 50
`
`Newell Cos., Inc. v. Kenney Mfg. Co.,
`864 F.2d 757 (Fed. Cir. 1988) .............................................................................. 58
`
`– v –
`
`

`

`
`
`PAR Pharm., Inc. v. TWi Pharms., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) ............................................................................ 26
`Pitney Bowes, Inc. v. Hewlett-Packard Co.,
`182 F.3d 1298 (Fed. Cir. 1999) ............................................................................ 27
`
`Ryko Mfg. Co. v. Nu–Star, Inc.,
`950 F.2d 714 (Fed. Cir. 1991) .............................................................................. 58
`Titanium Metals Corp. v. Banner,
`778 F.2d 775 (Fed. Cir. 1985) .............................................................................. 13
`Verdegaal Bros. v. Union Oil Co. of California,
`814 F.2d 628 (Fed. Cir. 1987) .............................................................................. 25
`Wyers v. Master Lock Co.,
`616 F.3d 1231 (Fed. Cir. 2010) ............................................................................ 58
`STATUTES
`35 U.S.C. § 102 ........................................................................................... 23, 24, 37
`35 U.S.C. § 103 ..................................................................................... 23, 24, 26, 37
`35 U.S.C. § 311-319 ................................................................................................... 1
`35 U.S.C. § 314(a) ................................................................................................... 20
`35 U.S.C. § 315(b) ................................................................................................. xiii
`35 U.S.C. § 316(e) ................................................................................................... 23
`35 U.S.C. § 325(d) ............................................................................................. 11, 18
`REGULATIONS
`37 C.F.R. § 42.1(d) ................................................................................................... 23
`37 C.F.R. § 42.8 .............................................................................................. xiii, xiv
`37 C.F.R. § 42.10 ................................................................................................... xiv
`37 C.F.R. § 42.15(a) ................................................................................................. xv
`37 C.F.R. § 42.24 ..................................................................................................... 60
`
`– vi –
`
`

`

`
`
`37 C.F.R. § 42.63(e) ............................................................................................... viii
`37 C.F.R. § 42.101 ..................................................................................................... 2
`37 C.F.R. § 42.102 ..................................................................................................... 2
`37 C.F.R. § 42.104 .................................................................................. 2, 23, 24, 25
`37 C.F.R. § 42.105 ................................................................................................... 61
`OTHER AUTHORITIES
`MPEP § 2131 ........................................................................................................... 14
`MPEP § 2111.02 ....................................................................................................... 27
`MPEP § 2131.03 ............................................................................. 13, 15, 17, 19, 33
`
`
`
`
`
`– vii –
`
`

`

`
`
`EXHIBIT LIST
`
`Pursuant to 37 C.F.R. § 42.63(e), Petitioner provides the following exhibit list
`
`with the exhibit number, a brief description of each exhibit, and where applicable
`
`the short form used herein.
`
`EXHIBIT
`Ex. 1001
`
`DESCRIPTION
`US 7,713,947 B2.
`
`SHORT FORM
`’947 Patent
`
`’903 Patent
`’018 File
`Wrapper
`’173 File
`Wrapper
`Greenberg Decl.
`
`Greenberg CV
`
`Bodor ‘WO 101
`
`Rice 2000 or
`Rice
`
`Liliemark 1997
`
`Merck
`Complaint
`Mavenclad
`Package Insert
`
`Lublin 1996
`
`
`
`Ex. 1002
`
`Ex. 1003
`
`Ex. 1004
`
`Ex. 1005
`
`Ex. 1006
`
`US 8,377,903 B2.
`File History for Ser. No. 11/722,018, which
`issued as the ’947 patent.
`File History Ser. No. 12/766,173, which issued
`as the ’903 patent.
`Declaration of Dr. Benjamin M. Greenberg,
`M.D.
`Curriculum Vitae of Dr. Benjamin M.
`Greenberg, M.D.
`Ex. 1007 WO 2004/087101 A2.
`Ex. 1008
`Rice, George P.A., Massimo Filippi, and
`Giancarlo Comi. ““Cladribine and progressive
`MS: clinical and MRI outcomes of a multicenter
`controlled trial.” Neurology Vol. 54, no. 5
`(2000) pp. 1145–1155.
`Liliemark, Jan. “The clinical pharmacokinetics
`of cladribine.” Clinical pharmacokinetics Vol.
`32, no. 2 (1997) pp. 120–131.
`Ex. 1010 Merck KGaA et al v. Accord Healthcare, Inc. et
`al 1-22-cv-00974 (DDE) Complaint.
`EMD Serano Inc., Mavenclad® (Cladribine)
`Package Insert, Mar. 2019
`Lublin FD, Reingold SC. Defining the clinical
`course of multiple sclerosis: results of an
`international survey. Neurology 1996;46:907–
`911.
`National Multiple Sclerosis Society, What is
`
`Ex. 1009
`
`Ex. 1011
`
`Ex. 1012
`
`Ex. 1013
`
`– viii –
`
`

`

`
`
`EXHIBIT
`
`Ex. 1014
`
`Ex. 1015
`
`Ex. 1016
`
`Ex. 1017
`
`Ex. 1018
`
`Ex. 1019
`
`Ex. 1020
`
`Ex. 1021
`
`Ex. 1022
`
`Ex. 1023
`
`Ex. 1024
`
`DESCRIPTION
`MS, Types of MS,
`https://www.nationalmssociety.org/What-is-
`MS/Types-of-MS, retrieved Sept. 20, 2022.
`National Multiple Sclerosis Society, What is
`MS, Types of MS, Secondary Progressive MS,
`https://www.nationalmssociety.org/What-is-
`MS/Types-of-MS/Secondary-progressive-MS.
`Casanova, B., et al. “High clinical inflammatory
`activity prior to the development of secondary
`progression: a prospective 5-year follow-up
`study,” Multiple Sclerosis Journal, Feb. 2002,
`pp. 59-63, vol. 8.
`Romine, J. et al. “A Double-Blind, Placebo-
`Controlled, Randomized Trial of Cladribine in
`Relapsing-Remitting Multiple Sclerosis,”
`Proceedings of the Association of American
`Physicians, Jan./Feb. 1999, pp. 35-44, vol. 111,
`No. 1.
`Immunex Corporation, Novantrone®
`(Mixantrone) Package Insert, Oct. 13, 2000
`(“Novantrone® Package Insert”).
`Langtry, H. et al. “Cladribine: A Review of its
`Use in Multiple Sclerosis,” Biodrugs, May
`1998, pp. 419-433, vol. 9, No. 3.
`Biogen Idec Inc., Tysarbi® (natazlizumab)
`Package Insert, Nov. 2004.
`Chiron Corporation, Betaseron® (Interferon
`beta- lb) Package Insert, 1993.
`Biogen, Inc., Avonex™ (Interferon Beta-1a)
`Package Insert, Nov. 1996.
`Teva Pharms USA, Copaxone® (glatiramer
`acetate for injection) Package Insert, 2001.
`Serano, Inc., Rebif® (Interferon Beta-1a)
`Package Insert, May 2003.
`Cursiefen, Simone, et al. “Escalating
`immunotherapy with mitoxantrone in patients
`with very active relapsing-remitting or
`progressive multiple sclerosis,” European
`neurology, Apr. 2000, pp. 186–187, vol. 43, No.
`3.
`
`SHORT FORM
`
`
`
`Casanova 2002
`
`Romine 1999
`
`Novantrone
`Package Insert
`
`Langtry 1998
`
`Tysabri Package
`Insert
`Betaseron
`Package Insert
`Avonex Package
`Insert
`Copaxone
`Package Insert
`Rebif Package
`Insert
`
`Cursiefen 2000
`
`– ix –
`
`

`

`DESCRIPTION
`Burt, Richard K., et al. “Treatment of
`autoimmune disease by intense
`immunosuppressive conditioning and
`autologous hematopoietic stem cell
`transplantation,” Blood, The Journal of the
`American Society of Hematology, Nov. 1998,
`pp. 3505–3514, vol. 92, No. 10.
`Tortorella, Carla, et al. “Cladribine. Ortho
`Biotech Inc.” Current Opinion in
`Investigational Drugs, Dec. 2001, pp. 1751–
`1756, vol. 2, no. 12.
`Beutler, E. et al. “The treatment of chronic
`progressive multiple sclerosis with cladribine,”
`Proc. Natl. Acad. Sci. USA, Feb. 1996, pp.
`1716–1720, vol. 93.
`Coles, Alasdair, et al. “Campath-1H treatment
`of multiple sclerosis: lessons from the bedside
`for the bench,” Clinical neurology and
`neurosurgery, June 2004, pp. 270–274, vol. 106,
`no. 3.
`U.S. Patent No. 7,888,328
`Center for Disease Control, Office of Enterprise
`Communication, Press Release, Oct. 27, 2004,
`https://www.cdc.gov/media/pressrel/r041027.ht
`m.
`Selby, R. et al. “Safety and Tolerability of
`Subcutaneous Cladribine Therapy in
`Progressive Multiple Sclerosis,” Can. J. Neurol.
`Sci., 1998, pp. 295-299, vol. 25.
`Docket Navigator Printout of Case Activity for
`Merck KGaA et al v. Accord Healthcare, Inc. et
`al
`Food and Drug Administration, Orange Book:
`Approved Drug Products with Therapeutic
`Equivalence Evaluations, Patent and
`Exclusivity for: N022561,
`https://www.accessdata.fda.gov/scripts/cder/ob/
`patent_info.cfm?Product_No=001&Appl_No=0
`22561&Appl_type=N, retrieved Oct. 5, 2022.
`Ex. 1034 Merck KGaA et al v. Accord Healthcare, Inc. et
`al 1-22-cv-00974 (DDE) Answer.
`
`Ex. 1026
`
`Ex. 1027
`
`Ex. 1028
`
`Ex. 1029
`Ex. 1030
`
`Ex. 1031
`
`Ex. 1032
`
`Ex. 1033
`
`
`
`EXHIBIT
`Ex. 1025
`
`SHORT FORM
`
`Burt 1998
`
`Tortorella 2001
`
`Beutler 1996
`
`Coles 2004
`
`Bodor’328
`
`CDC Press
`Release
`
`Selby 1998
`
`
`
`
`
`Accord
`Complaint
`
`– x –
`
`

`

`
`
`
`
`LISTING OF CLAIMS
`
`U.S. Patent No. 8,377,903 (Claims 17, 19-20, 22-29)
`
`Claim
`Designation
`Independent
`Claim 17 –
`Limitation (a)
`
`
`Independent
`Claim 17 –
`Limitation (b)
`
`
`Independent
`Claim 17 –
`Limitation (c)
`
`Independent
`Claim 17 –
`Limitation (d)
`
`
`Independent
`Claim 17 –
`Limitation (e)
`
`Dependent Claim
`19
`
`Dependent Claim
`20
`
`Claim Language
`
`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
`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 adminis
`tered 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 method according to claim 17, wherein the induction
`period lasts about 2 months.
`
`The 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.
`
`– xi –
`
`

`

`
`
`
`
`
`
`Claim
`Designation
`
`Dependent Claim
`22
`
`Dependent Claim
`23
`
`Dependent Claim
`24
`
`Dependent Claim
`25
`
`
`Dependent Claim
`26
`
`Dependent Claim
`27
`
`
`Dependent Claim
`28
`
`Dependent Claim
`29
`
`
`Claim Language
`
`
`The method according to claim 17, wherein the cladribine-
`free period (ii) lasts about 10 months.
`
`The method according to claim 17, wherein the cladribine-
`free (iv) period lasts 10 months.
`
`The method according to claim 17, wherein the maintenance
`period lasts about 2 months.
`
`The method according to claim 17, wherein the formulation
`is orally administered at a daily dose of 3 to 30 mg
`cladribine.
`
`The method according to claim 17, wherein the formulation
`is orally administered at a daily dose of 10 mg cladribine.
`
`The method according to claim 17, wherein the formulation
`is orally administered 1 to 7 days per month during the
`induction period.
`
`The method according to claim 17, wherein the steps (iii) to
`(iv) are repeated at least one or two times.
`
`The method according to claim 17, wherein the formulation
`is administered in combination with interferon-beta.
`
`
`
`
`– xii –
`
`

`

`
`
`MANDATORY NOTICES
`
`Petitioner provides the following mandatory disclosures pursuant to 37 C.F.R.
`
`§ 42.8.
`
`1.
`
`Real Parties-In-Interest, § 42.8(b)(1)
`
`The sole real party-in-interest is TWi Pharmaceuticals, Inc. (“TWi” or
`
`“Petitioner”), and further certifies that no other party exercised control or could have
`
`exercised control over TWi’s participation in this proceeding, the filing of this
`
`petition, or the conduct of any ensuing trial.
`
`2.
`
`Related Matters, § 42.8(b)(2)
`
`The ’903 Patent is presently asserted in Merck KGaA et al v. Accord
`
`Healthcare, Inc. et al 1-22-cv-00974 (DDE). A finding of invalidity may affect that
`
`judicial matter. Petitioner is not a party to this judicial matter, and Patent Owner has
`
`not asserted the ’903 Patent against Petitioner in district court, so 35 U.S.C. § 315(b)
`
`does not apply here.
`
`Petitioner has concurrently filed a companion petition requesting inter partes
`
`review of US 7,713,947 B2, IPR2023-00049. That proceeding could affect, or be
`
`affected by, a decision in this proceeding.
`
`EMD Serano Inc. lists the patent at issue US 8,377,903 as potentially covering
`
`certain uses of the product Mavenclad under NDA 022561. Ex. 1033 at 1.
`
`– xiii –
`
`

`

`
`
`3.
`
`Lead and Back-Up Counsel, § 42.8(b)(3)
`
`The following are designated as lead counsel and back-up counsel, pursuant
`
`to 37 C.F.R. § 42.10. A Power of Attorney is being filed concurrently herewith.
`
`Lead counsel is:
`
`Philip D. Segrest, Jr. (Reg. No. 39,021)
`
`Back-up counsel is:
`
`Nathan P. Sportel (Reg. No. 67,980)
`
`Steven R. Howe (Reg. No. 67,015)
`
`Service Information, § 42.8(b)(4)
`
`4.
`
`Papers concerning this matter should be served on the following:
`
`(i)
`
`Electronic Mailing Address
`
`Petitioner consents to service by email at:
`
`Philip.Segrest@HuschBlackwell.com
`
`Nathan.Sportel@huschblackwell.com
`
`Steve.Howe@HuschBlackwell.com
`
`(ii) Postal Mailing Address
`
`HUSCH BLACKWELL, LLP
`Attn: Philip D. Segrest, Jr.
`120 South Riverside Plaza
`Suite 2200
`Chicago, Illinois 60606
`
`
`– xiv –
`
`

`

`
`
`(iii) Hand-Delivery Address
`
`Same as postal mailing address.
`
`(iv) Telephone number
`
`(312) 655-1500
`
`(v) Facsimile Number
`
`(312) 655-1501
`
`5.
`
`Payment of Fees, § 42.15(a)
`
`The Office is authorized to charge petition fees and deficiencies to Deposit
`
`Acct. No. 23-0920, Cust. ID No. 24628.
`
`– xv –
`
`

`

`
`
`INTRODUCTION
`
`TWi requests inter partes review under 35 U.S.C. §§ 311–319 and
`
`cancellation of claims 17 and 19–20, 22–29 (“Challenged Claims”) of U.S. Patent
`
`No. 8,377,903 (“the ’903 patent,” Ex. 1002). The Challenged Claims of the ’903
`
`patent are invalid over prior art.
`
`During prosecution, Patent Owner presented legally and factually inaccurate
`
`arguments that all claims recite that a “total dose of cladribine” administered during
`
`a claimed “maintenance period” is “lower than the total dose of the cladribine
`
`reached at the end of the induction period.” Ex. 1002 at 10–11, claim 1; Ex. 1004 at
`
`156. However, this “lower than…” language only appears in claim 1, and the same
`
`or similar language does not appear in challenged claim 17. Unlike claim 1, claim
`
`17 recites that “about 1.7 mg/kg to about 3.5 mg/kg” of cladribine is administered
`
`during the induction period, and “about 1.7 mg/kg of cladribine” is administered
`
`during the maintenance period. Ex. 1002 at 11, claim 17. As written, claim 17 is
`
`broader than claim 1 because it also covers an embodiment where the total dose of
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`cladribine during the maintenance period is equal to the total dose of cladribine
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`during the induction period (1.7 mg/kg of cladribine in both the induction and
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`maintenance periods).
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`Despite claim 17’s breadth, the Examiner examined only the embodiment
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`where the total dose of cladribine administered during the maintenance period is
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`– 1 –
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`

`

`
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`lower than the total dose of cladribine administered during the induction period, as
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`specifically recited in claim 1, but nothing in the prosecution history suggests that
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`the Examiner examined claims 17–29 under the proper claim interpretation that
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`claim 17 also covers the embodiment where the total dose of cladribine administered
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`during the maintenance period is equal to the total dose of cladribine administered
`
`during the induction period.
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`Due to this broader scope, claim 17 is invalid over the prior art. The Examiner
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`either overlooked or misapprehended the broader scope of claim 17. When the
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`proper scope of claim 17 is considered, the Challenged Claims are invalid for the
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`reasons the Examiner already articulated. In fact, the Examiner’s primary reference
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`alone invalidates independent claim 17.
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`GROUNDS FOR STANDING
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`Petitioner certifies pursuant to 37 C.F.R. § 42.104(a) that the ’903 patent is
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`available for inter partes review and that Petitioner is not estopped or barred from
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`requesting inter partes review challenging the identified ’903 patent claims on the
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`grounds identified herein. Petitioner is a person who may petition for inter partes
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`review under 37 C.F.R. § 42.101, and this petition is timely under 37 C.F.R. § 42.102.
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`– 2 –
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`

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`BACKGROUND
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`I.
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`Scope And Content Of The Prior Art
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`A. History of Cladribine Treating Multiple Sclerosis
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`Multiple sclerosis (MS) is an autoimmune disease of the central nervous
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`system in which a patient’s immune system attacks the patient’s own nervous system
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`cells. Ex. 1005, ¶ 36. There are several clinical patterns of MS in terms of the
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`progression of the disease, including relapsing-remitting MS (RRMS) and secondary
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`progressive MS (SPMS), with RRMS being the most common MS type and
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`commonly developing into SPMS. Ex. 1005, ¶¶ 37–40; Lublin 1996 at 908, Ex. 1012
`
`at 2; Ex. 1013; Ex. 1014; Casanova 2002 at 61, Ex. 1015 at 3. Monitoring MS
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`patients involves MRI examination for assessment of lesion formation and
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`progression, as well as measures of clinical disability with a neurologic physical
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`exam, defined clinical scales such as the Expanded Disability Status Scale (EDSS),
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`and relapse frequency. Ex. 1005, ¶ 40; Ex. 1008 at 1; Romine 1999 at 36–37, Ex.
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`1016 at 36–37; Novantrone Package Insert at 7, Ex. 1017 at 8; Langtry 1998 at 424,
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`Ex. 1018 at 6.
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`The underlying cause of MS is not fully understood, but MS has been
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`understood to involve cells that are active in immunological responses attacking
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`“self” proteins, which are typically ignored by healthy lymphocytes. Ex. 1005,
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`– 3 –
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`

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`
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`¶¶ 41–42. These “self” proteins include brain cells, meaning that MS damages the
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`nervous system. Id.
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`The study of MS, which led to new MS treatments, was expanded by the
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`creation and widespread use of MRI technology because clinicians were able to
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`understand MS as a condition related to an abnormal immune system. Ex. 1005,
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`¶ 43. As such, clinicians began to use immunotherapies to treat MS. Ex. 1005, ¶¶
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`44–47.
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`As of December 2004, there were six FDA approved therapies for MS. Ex.
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`1005, ¶¶ 45–46, see also Ex. 1017; Ex. 1019; Ex. 1020; Ex. 1021; Ex. 1022; Ex.
`
`1023. Also, practitioners and persons having ordinary skill in the art (“PHOSITA”)
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`utilized a variety of immunomodulatory and immunosuppressive strategies. Id. All
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`these therapies and medications achieved their efficacy through multiple therapy
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`rounds or doses because, if dosing ceased, clinicians expected a return of disease
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`activity. Id. Clinicians studied multiple immunosuppression strategies prior to 2004,
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`including FDA approved therapies, such as mitoxantrone, and off-label therapies,
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`such as cyclophosphamide and bone marrow transplants. Ex. 1005, ¶¶ 47–49, 51–
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`52; Burt 1998 at 3512, Ex. 1025 at 8. Of particular note, Mitoxantrone was an
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`immunosuppressant medication that was dosed intermittently, with breaks in
`
`between doses to allow for immune reconstitution. Ex. 1005, ¶ 50; Ex. 1017;
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`Cursiefen 2000 at 186, Ex. 1024 at 1.
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`– 4 –
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`

`

`
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`Meanwhile, cladribine has been known since the 1960s. Ex. 1005, ¶¶ 53–54;
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`Tortorella 2001 at 1751, 1756, Ex. 1026 at 1, 6. It had been discussed as a treatment
`
`for MS numerous times throughout medical literature. Id. Cladribine was historically
`
`given to leukemia patients, but it was recognized as a treatment option for MS in the
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`early 1990s. Ex. 1005, ¶¶ 55–57; Beutler 1996 at 1716, Ex. 1027 at 1; Tortorella
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`2001 at 1752–1753, Ex. 1026 at 2–3.
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`Cladribine was conventionally administered to MS patients subcutaneously or
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`intravenously, but oral administration was suggested and studied. Romine 1999 at
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`35, Ex. 1016 at 1; Ex. 1005, ¶¶ 55, 58–59. Attempts to administer cladribine orally
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`typically failed to provide effective treatment due to low bioavailability. Ex. 1029 at
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`4, col. 2, ℓℓ. 10–16. Methods to improve the bioavailability of orally administered
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`cladribine were also studied prior to the priority date of the ’903 Patent to create a
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`known reference point for calculation of therapeutically effective doses. Ex. 1005,
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`¶ 58; Ex. 1009 at 120 (oral bioavailability of 37–51% overall); Ex. 1029 at 13, col.
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`19, ℓℓ. 45–67 (Table VI) (oral bioavailibility for cladribine is 41.9%). Thus, by 2004,
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`the use of cladribine to treat various forms of MS, including oral administration of
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`cladribine to treat MS, was well-known to clinicians and PHOSITAs. Ex. 1005, ¶ 60.
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`Additionally, by 2004, PHOSITAs had significant training and experience with
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`respect to immunosuppressants (e.g., mitoxantrone). Ex. 1005, ¶ 61.
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`– 5 –
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`

`

`
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`The method of treating a patient with an immunosuppressant, like cladribine
`
`or mitoxantrone, followed a basic method: administer medication to a patient for a
`
`period, stop administering medication for a period, resume administration of
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`medication to the patient for a period, and again stop administration for a period. Ex.
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`1005, ¶¶ 61–63; Ex. 1017 at 14, 30, 29; Romine 1999 at 1, 5, Ex. 1016 at 35, 43;
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`Coles 2004 at 270, Ex. 1028 at 1. It was typical, if not standard, that retreatment at
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`regular intervals would be necessary for a drug-based immunotherapy, such as
`
`mitoxantrone and cladribine. Ex. 1005, ¶ 65. These therapies were cyclical because
`
`an immunosuppressor attacks the immune system to rid the immune system of the
`
`disease state, but then administration ceases so that the immune system can reset and
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`heal after the effects of the drug wear off, in hopes that the immune system recovers
`
`in a healthy manner. Ex. 1005, ¶¶ 64–67, 50–52. This process can repeat as
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`necessary. Ex. 1005, ¶ 65; Ex. 1008 at 4–5. Indeed, mitoxantrone (also known as
`
`Novantrone) followed this very sequence (intrav