throbber
MarsHaA.ROSE
`DIRECTOR
`(202) 772-8692
`MROSE@SKGF.COM
`
`February 14, 2012
`
`Commissioner for Patents
`PO Box 1450
`Alexandria, VA 22313-1450
`
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`
`
`Confirmation No. 5998
`Art Unit To be assigned
`
`Re:—U.S. Utility Patent Application
`Appl. No. 13/372,426; Filing Date: February 13, 2012
`For:
`Treatment for Multiple Sclerosis (As Amended)
`Inventors: LUKASHEVefal.
`Our Ref: 2159.3210002/JMC/MRG/U-S
`
`Sir:
`
`Transmitted herewith for appropriate action are the following documents:
`
`1. Preliminary Amendment Under 37 C.F.R. § 1.115;
`
`2. Exhibit 1 - Declaration of Katherine T. Dawson, M.D. Under 37 C.F.R. § 1.132;
`
`3. Exhibit A to Exhibit 1;
`
`4, Exhibit B to Exhibit 1;
`
`5. Exhibit C to Exhibit 1;
`
`6. Exhibit D to Exhibit 1;
`
`7. Exhibit E to Exhibit 1; and
`
`8. Exhibit 2.
`
`The above-listed documents arefiled electronically through EFS-Web.
`
`to the Preliminary
`identical
`submitted herewith is
`The Preliminary Amendment
`Amendment Under 37 C.F.R. § 1.115 submitted on February 13, 2012, and is being resubmitted
`with the Exhibits which were inadvertently omitted from the filing on February 13, 2012.
`
`
`
`
`
`
`
`
`Sawai (IPR2019-00789), Ex. 1053, p. 001
`
`Sawai (IPR2019-00789), Ex. 1053, p. 001
`
`

`

`Commissioner for Patents
`February 14, 2012
`Page 2
`
`The U.S. Patent and Trademark Office is hereby authorized to charge any fee deficiency,
`or credit any overpayment, to our Deposit Account No. 19-0036.
`
`Respectfully submitted,
`
`STERNE, KESSLER, GOLDSTEIN &FOX P.LLL.C.
`
`
`
`Marsh.
`Attorney for Applicants
`Registration No. 58,403
`
`MRG/U-S:enm
`Enclosures
`
`1484850_1.DOCX
`
`
`
`
`Sawai (IPR2019-00789), Ex. 1053, p. 002
`
`SRP. Sfap 4&
`
`Sawai (IPR2019-00789), Ex. 1053, p. 002
`
`

`

`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re application of:
`
`LUKASHEVetal.
`
`| Confirmation No.: To be assigned
`
`Art Unit: To be assigned
`
`Appl. No.: To be assigned
`
`(Continuation ofAppl. No. 12/526,296,
`
`$ 371(c) Date: January 13, 201T)
`
`Examiner: To be assigned
`
`Filing Date: Herewith
`
`Atty. Docket: 2159.3210002/TIMC/MRG/U-S
`
`For: Treatment for Multiple Sclerosis
`(As Amended)
`
`Preliminary Amendment Under 37 C.RR. § 1.115
`
`Commissioner for Patents
`PO Box 1450
`Alexandria, VA 22313-1450
`
`Sir:
`
`In advance of prosecution, Applicants submit the following amendments and
`
`remarks.
`
`Amendments to the Specification begin on page 2 of this paper.
`
`Amendments to the Claimsare reflected in the listing of claims which begins on
`
`page 3 of this paper.
`
`Remarks and Arguments begin on page 6 ofthis paper.
`
`It is not believed that extensions of time or fees for net addition of claims are
`
`required beyond those that may otherwise be provided for in documents accompanying
`
`this paper. However,
`
`if additional extensions of time are necessary to prevent
`
`abandonment of this application, then such extensions of time are hereby petitioned
`
`under 37 C.F.R. § 1.136(a), and any fees required therefor (including fees for net
`
`addition of claims) are hereby authorized to be charged to our Deposit Account No.
`
`19-0036.
`
`Sawai (IPR2019-00789), Ex. 1053, p. 003
`
`Sawai (IPR2019-00789), Ex. 1053, p. 003
`
`

`

`- 2-
`
`LUKASHEVetal.
`Appl. No. To be assigned
`
`Amendments to the Specification
`
`Please amendthetitle as follows:
`
`TreatmentforMultiple Sclerosis KRF2-asrening-assays—and-—related-matheds—and
`we
`
`Please amend paragraph [0128], beginning on page 33, line 21, as follows:
`
`[0128]
`
`Immunohistochemistry was performed using the Dakoautostainer as
`
`follows. Endogenous peroxidase was quenched by a 10 minute incubation in 3% H202 /|
`
`Methanol. The rabbit anti Nrf2 antibody C-20 (sc-722, Santa Cruz Biotechnology) was
`
`added at a 1:250 dilution in Dako Diluent with Background Reducing Components
`
`(Dako # $3022) C-20 antibody was detected using the Envision anti rabbit labeled
`
`polymer-HRP (Dako #K4003) and DAB (Vector Labs #SK-4100) was used as the
`
`chromogenic substrate. Morphometric analysis of Nrf2 immunostaining was performed
`
`using ImageJ software from NIH Gx#tssbiniosth:ews.
`
`
`On page 1, below thetitle of the invention, please add the following new paragraph:
`
`CROSS REFERENCE TO RELATED APPLICATIONS
`
`This application is a continuation of U.S. Patent Application No. 12/526,296,
`
`§ 371(c) Date January 13, 2011, now pending, which is the U.S. National Phase of
`
`International Application No. PCT/US2008/001602, filed February 7, 2008, which
`
`claims the benefit of U.S. Provisional Application 60/888,921, filed February 8, 2007.
`
`Atty. Dkt. No. 2159.3210002/JMC/MRG/U-S
`
`Sawai (IPR2019-00789), Ex. 1053, p. 004
`
`Sawai (IPR2019-00789), Ex. 1053, p. 004
`
`

`

`- 3-
`
`LUKASHEVetal.
`Appl. No. To be assigned
`
`Amendments to the Claims
`
`This listing of claims will replace all prior versions, and listings, of claims in the
`
`application.
`
`1-17.
`
`(Cancelled)
`
`18.
`
`(New) A method of treating a subject in need of treatment for multiple sclerosis
`
`comprising orally administering to the subject in need thereof a pharmaceutical
`
`composition consisting essentially of (a) a therapeutically effective amount of
`
`dimethyl fumarate, monomethyl fumarate, or a combination thereof, and (b) one
`
`or more pharmaceutically acceptable excipients, wherein the therapeutically
`
`effective amount of dimethyl fumarate, monomethyl fumarate, or a combination
`
`thereof is about 480 mg per day.
`
`19,
`
`(New) The method of claim 18, wherein the pharmaceutical composition is
`
`administered in the form of a tablet, a suspension, or a capsule.
`
`20.
`
`(New) The method of claim 18, wherein the therapeutically effective amountis
`
`administered in separate administrations of 2, 3, 4, or 6 equal doses.
`
`21.
`
`(New) The method of claim 20, wherein the therapeutically effective amount is
`
`administered in separate administrations of 2 equal doses.
`
`22,
`
`(New) The method of claim 20, wherein the therapeutically effective amountis
`
`administered in separate administrations of 3 equal doses.
`
`23.
`
`(New) The methodofclaim 18, wherein the pharmaceutical composition consists
`
`essentially of dimethyl fumarate and one or more pharmaceutically acceptable
`
`excipients.
`
`Atty. Dkt. No. 2159.3210002/JMC/MRG/U-S
`
`Sawai (IPR2019-00789), Ex. 1053, p. 005
`
`Sawai (IPR2019-00789), Ex. 1053, p. 005
`
`

`

`- 4-
`
`LUKASHEVetal.
`Appl. No. To be assigned
`
`24.
`
`(New) The method of claim 18, wherein the pharmaceutical composition consists
`
`essentially of monomethy! fumarate and one or more pharmaceutically acceptable
`
`excipients.
`
`25.
`
`(New) The method of claim 18, wherein the pharmaceutical composition is
`
`administered to the subject for at least 12 weeks.
`
`26.
`
`(New) The method of claim 23, wherein the therapeutically effective amount is
`
`administered to the subject in 2 equal doses.
`
`27,
`
`(New) The method of claim 26, wherein the therapeutically effective amountis
`
`administered to the subject for at least 12 weeks.
`
`28.
`
`(New) A method of treating a subject in need of treatment for multiple sclerosis
`
`consisting essentially of orally administering to the subject about 480 mg per day
`
`of dimethyl fumarate, monomethyl fumarate, or a combination thereof.
`
`29.
`
`(New) The method of claim 28, wherein about 480 mg of dimethyl fumarate per
`
`day is administered to the subject.
`
`30.
`
`(New) The method of claim 29, wherein the dimethy] fumarate is administered in
`
`separate administrations of 2 equal doses.
`
`31.
`
`(New) The method of claim 29, wherein the dimethyl fiimarate is administered in
`
`separate administrations of 3 equal doses.
`
`32.
`
`(New) A method of treating a subject in need of treatment. for multiple sclerosis
`
`comprising orally administering to the subject a pharmaceutical composition
`
`consisting essentially of (a) a therapeutically effective amount of dimethyl
`
`fumarate and (b) one or more pharmaceutically acceptable excipients, wherein
`
`Atty. Dkt. No. 2159.3210002/JMC/MRG/U-S
`
`Sawai (IPR2019-00789), Ex. 1053, p. 006
`
`Sawai (IPR2019-00789), Ex. 1053, p. 006
`
`

`

`- 5-
`
`LUKASHEVetal.
`Appl. No. To be assigned
`
`the therapeutically effective amount of dimethyl fumarate is about 480 mg per
`
`day.
`
`33.
`
`(New) The method of claim 32, wherein the dimethyl fumarate is administered in
`
`separate administrations of 2 equal doses.
`
`34.
`
`(New) The method of claim 18, wherein the expression level of NQO1 in the
`
`subject is elevated after administering to the subject the therapeutically effective
`
`amount of dimethyl fumarate,monomethy! fumarate, or a combination thereof.
`
`35.
`
`(New) The method of claim 28, wherein the expression level of NQO1 in the
`
`subject is elevated after administering to the subject about 480 mg per day of
`
`dimethyl fumarate, monomethyl fumarate, or a combinationthereof.
`
`36.
`
`(New) The method of claim 32, wherein the expression level of NQO1 in the
`
`subject is elevated after administering to the subject the therapeutically effective
`
`amount of dimethyl fumarate.
`
`Atty. Dkt. No. 2159.3210002/JMC/MRG/U-S
`
`Sawai (IPR2019-00789), Ex. 1053, p. 007
`
`Sawai (IPR2019-00789), Ex. 1053, p. 007
`
`

`

`- 6-
`
`Remarks
`
`LUKASHEVetal.
`Appl. No. To be assigned
`
`Upon entry of the foregoing amendment, claims 18-36 are pending in the
`
`application, with claims 18, 28, and 32 being the independent claims.
`
`Claims 1-17 are sought to be cancelled without prejudice or disclaimer thereof.
`
`New claims 18-36 are sought to be added. Support for claims 18-36 is set forth in
`
`Section I below.
`
`L.
`
`Summary of the Claimed Subject Matter
`
`The claimed invention is generally directed to methods of orally treating multiple
`
`sclerosis (MS). MSis a chronic disease for which only a limited number of disease-
`
`modifying treatment options are currently available, most of which are administered by
`
`injection. Only one disease-modifying oral drug has been approved in the United States
`
`and that has only recently been approved.
`
`In addition, not all MS drugs are indicated for
`
`every MS patient. Furthermore, patients must carefully weigh the risks associated with
`
`each drug at a given disease state.
`
`It is very clear that additional medications are needed
`
`to provide better life quality and reduced risk of disability for MS patients. Oral MS
`
`medications with favorable safety profiles are particularly desired. Applicants' invention
`
`satisfies this desire.
`
`Applicants disclose a method for treating a neurological disease with at least one
`
`fumaric acid derivative, including dimethyl fumarate (DMF) or monomethyl fumarate
`
`(MMF), as "method 4" in paragraph [0009], lines 9-11 and paragraphs [0062-0063] of
`
`the specification.
`
`The application discloses
`
`that
`
`"/iJn some embodiments
`
`the
`
`neurological disease
`
`is MS or another demyelinating neurological disease."
`
`Atty. Dkt. No. 2159.3210002/JMC/MRG/U-S
`
`Sawai (IPR2019-00789), Ex. 1053, p. 008
`
`Sawai (IPR2019-00789), Ex. 1053, p. 008
`
`

`

`- 7-
`
`LUKASHEVetal.
`Appl. No. To be assigned
`
`(Specification, p. 4, paragraph [0010]) (emphasis added). Applicants also discussed a
`
`MSanimal model, Experimental Autoimmune Encephalomyelitis (EAE), in paragraphs
`
`[0108] and [0109], as well as Example 3. Therefore, MS is supported in the application.
`
`Additionally, Applicants disclose that DMF and/or MMFareeffective in treating
`
`MS. For example, DMF and MMFarelisted as specific examples of neuroprotective
`
`compounds.
`
`(Specification, p. 13, paragraph [0063}.) Specifically, the specification
`
`indicates that
`
`[ijn some embodiments of method 4, a methodoftreating a
`
`mammal whohasoris at risk for a neurological disease is
`
`provided. The methods comprises administering to the
`
`mammala therapeutically effective amount of at least one
`
`neuroprotective compound which has Formula I, Il, III, or
`
`IV, e.g., a fumaric acid derivative (e.g., DMF or MMF).
`
`Ud.) As such, DMF and MMFare specifically named in the application as compounds
`
`effective in treating neurological diseases such as MS.
`
`Furthermore,
`
`the dosages
`
`disclosed in paragraph [0116] of the application refer to the specific compounds "DMF"
`
`and "MMF". Accordingly, Applicants teach that DMF and MMFareeffective in treating
`
`MS.
`
`Applicants also disclose that orally administering 480 mg per day of DMF and/or
`
`MMFiseffective in treating MS. (Specification, p. 30, paragraph [0116].) Specifically,
`
`the specification discloses that
`
`[a]Jn effective dose of DMF or MMR [sic]
`
`to be
`
`administered to a subject orally can be from about 0.1 g to
`
`1 g per pay [sic], 200 mg to about 800 mg per day (e.g.,
`
`Atty. Dkt. No. 2159.3210002/IMC/MRG/U-S
`
`Sawai (IPR2019-00789), Ex. 1053, p. 009
`
`Sawai (IPR2019-00789), Ex. 1053, p. 009
`
`

`

`- 8-
`
`LUKASHEVeral.
`Appl. No. To be assigned
`
`from about 240 mg to about 720 mg per day; or from
`
`about 480 mg to about 720 mg per day; or about 720 mg
`
`per day).
`
`(/d.) (emphasis added). Because Applicants teach 480 to 720 mg/day, and further
`
`disclose this dosage range as the most narrow range, it is clear that Applicants describe
`
`orally administering 480 mg DMFdaily to treat MS. See, e.g., Inre Wertheim, 541 F.2d
`
`257, 191 U.S.P.Q. 90 (C.C.P.A. 1976).
`
`The specification further discloses that the daily dose of DMF and/or MMFcan
`
`be administered in 2, 3, 4, or 6 equal doses. See, e.g., Specification, pp. 29-30, paragraph
`
`[0116]
`
`("[FJor example,
`
`the 720 mg per day may be administered in separate
`
`administrations of 2, 3, 4, or 6 equal doses.") It is clear from the entire paragraph [0116]
`
`that, although the above citation from the specification refers to 720 mg/day as an
`
`example, the disclosure of multiple separate administrations equally applies to other
`
`dosages, e.g., the 480 mg/day dose.
`
`The specification further discloses that the expression level of NQO1 is elevated
`
`in vivo after administration of DMF or MMF. See, e.g., original claims 1, 5, and 11; p. 2,
`
`paragraph [0006]; pp. 4-5, paragraph [0012]; pp. 22-23, paragraph [0092]; p. 31,
`
`paragraph [0122], Example 1, Figure 1; p. 31-32, paragraph [0123], Example 2, Figure 2.
`
`Accordingly, Applicants disclose treating a subject with MS by orally
`
`administering 480 mg/day DMF and/or MMFto the subject.
`
`Applicants’ claimed method involves the oral administration of a specific daily
`
`dose of about 480 mg/day of dimethyl fumarate (DMF) and/or monomethy! fumarate
`
`(MMF)(the physiologically active metabolite of DMF). The claimed method has been
`
`Atty. Dkt. No. 2159.3210002/IMC/MRG/U-S
`
`Sawai (IPR2019-00789), Ex. 1053, p. 010
`
`Sawai (IPR2019-00789), Ex. 1053, p. 010
`
`

`

`- 9-
`
`LUKASHEVeral.
`Appl. No. To be assigned
`
`proven effective for the treatment of MS in humanpatients in two large-scale Phase 3
`
`clinical studies (further discussed herein below). Quite surprisingly, it was found in
`
`those clinical studies that the 480 mg/day dose is just_as effective in treating MS as a
`
`higher dose of 720 mg/day DMF. This is especially unexpected given the results of a
`
`Phase 2 clinical study in which a dose of 720 mg/day DMF, but not a 360 mg/day DMF
`
`dose, was found to beeffective.
`
`il.
`
`Patentability of the Claimed Invention
`
`The prior art teaches that certain autoimmune diseases (e.g., MS) can be treated
`
`with fumarates (e.g., DMF). See e.g., U.S. Patent Publication No. 2003/0018072 to Joshi
`
`et al. ("Joshi") and Schimrigk et al., European Journal of Neurology 2006, 13(6):604-
`
`610 ("Schimrigk"). However, the prior art does not teach or suggest a dose consisting
`
`essentially of about 480 mg/day of DMF and/or MMF. Needless to say, the prior art
`
`does not mention the efficacy of the 480 mg/day dose.
`
`As mentioned above, it is unexpected that the dose of about 480 mg/day DMF
`
`was similarly effective compared to the higher dose of about 720 mg/day. The evidence
`
`of these unexpected results are provided in a declaration under 37 CFR § 1.132 of
`
`Katherine T. Dawson, M.D. ("Declaration") previously filed on October 13, 2011, in
`
`U.S. Patent Application No. 12/526,296, submitted herewith as Exhibit 1.
`
`Biogen Idec MA Ine.("Biogen Idec"), the assignee of the current application,
`
`recently completed two pivotal Phase 3 placebo-controlled, double-blind, clinical
`studies,
`"the DEFINE study" and "the CONFIRM study", which evaluated the
`
`investigational oral drug candidate BG-12 (DMFasthe only active ingredient) to treat
`
`relapsing-remitting MS (RRMS).
`
`Atty. Dkt. No. 2159.3210002/JMC/MRG/U-S
`
`Sawai (IPR2019-00789), Ex. 1053, p. 011
`
`Sawai (IPR2019-00789), Ex. 1053, p. 011
`
`

`

`- 10-
`
`LUKASHEVetal.
`Appl. No. To be assigned
`
`Results of the DEFINE study are depicted in Figures 4-11 and Table 2 of the
`
`Declaration. The results of the DEFINE study indicate that the dose of 480 mg/day
`
`unexpectedly demonstrated significant efficacy on MS disease activity as measured by
`
`the key clinical and MRI disease activity endpoints.
`
`(Declaration, pages 11-18, Figures
`
`4-11; and page 20, Table 2.) Even more unexpected was the magnitude of the treatment
`
`effect. Given that the dose typically impacts the efficacy, it was quite surprising that the
`
`480 mg/day dose demonstrated similar efficacy to the higher 720 mg/day dose on both
`
`clinical and MRI measures of MS disease activity ~ with a high level ofstatistical
`
`significance. (Id. at page 19, paragraphs 13-15; and page 20, Table 2.)
`
`Furthermore, the results of the second Phase 3 study (CONFIRM) support the
`
`first Phase 3 study.
`
`See Exhibit 2, which states "[rJesults of the CONFIRM study
`
`showed that 240 mg of BG-12, administered either twice a day (BID) or three times a
`
`day (TID), demonstrated significant efficacy and favorable safety and_tolerability
`
`profiles. Further analyses of the CONFIRM study are ongoing... ."
`
`Therefore,:the results of the DEFINE and CONFIRM studiesindicate that the 480
`
`mg/day DMF dose demonstrates efficacy in the DEFINE study, meeting all measured
`
`endpoints with a high level of statistical significance.
`
`(See Declaration, page 16,
`
`paragraph 16; see Exhibit 2.) Not only was the 480 mg/day DMFdoseefficacious, but
`
`the480mz/daydosesurprisinglydemonstratedsimilareffectivenessonclinicalandMRI
`
`
`
`measuresofMSdiseaseactivityas720me/dayDMF. (See Declaration, page 15,
`
`paragraph 15.)
`
`Atty. Dkt. No. 2159.3210002/IMC/MRG/U-S
`
`Sawai (IPR2019-00789), Ex. 1053, p. 012
`
`Sawai (IPR2019-00789), Ex. 1053, p. 012
`
`

`

`-11-
`
`LUKASHEVetal.
`Appl. No. To be assigned
`
`WT.
`
`The Unexpected Results Must Be Given Substantial Weight: There is a
`Nexus Between the Suggorted Claims 18-36 and the Unexgected Results of
`the DEFINE and CONFIRM Studies
`
`Unexpected results of the claimed invention do not need to be included in the
`
`specification for an Examiner to consider them. The MPEP at 716.01(b) states that "[t]o
`
`be given substantial weight in the determination of obviousness or nonobviousness,
`
`evidence of secondary considerations must be relevant to the subject matter as claimed,
`
`and therefore the examiner must determine whether there is a nexus between the merits
`
`of the claimed invention and the evidence of secondary considerations." (emphasis
`
`added). Thus, according to the MPEP, the Examiner must consider whether there is a
`
`nexus between the claimed invention and the unexpectedresults.
`
`As mentioned above, the application teaches and fully supports the claimed
`
`invention of treating MS using DMFand/or MMFat a dose of 480 mg/day. Thus, the
`
`data from the DEFINE and CONFIRM clinical studies, which flow inherently from the
`
`claimed invention, must be given substantial weight when considering the patentability
`
`of claims 18-36.
`
`IV.
`
`Summary
`
`Based on the reasons set forth above, Applicants respectfully submit that the
`
`present claimsare patentable.
`
`Atty. Dkt. No. 2159.3210002/JMC/MRG/U-S
`
`Sawai (IPR2019-00789), Ex. 1053, p. 013
`
`Sawai (IPR2019-00789), Ex. 1053, p. 013
`
`

`

`- 12-
`
`LUKASHEVetal.
`Appl. No. To be assigned
`
`Conclusion
`
`Prompt
`
`and favorable
`
`consideration of
`
`this Preliminary Amendment
`
`is
`
`respectfully requested. Applicants believe the present application is in condition for
`
`allowance.
`
`If the Examiner believes, for any reason, that personal communication will
`
`expedite prosecution of this application,
`
`the Examiner is invited to telephone the
`
`undersigned at the number provided.
`
`Respectfully submitted,
`
`STERNE, KESSLER, GOLDSTEIN & FOX P.L.L.C.
`
`
`
`“Se &
`
`Marsha A. Rose
`Attorney for Applicants
`Registration No. 58,403
`
`XX
`<
`Date: &
`1100 New York Avenue, N.W.
`Washington, D.C.20005-3934
`(202) 371-2600
`
`1481215_1.DOCX
`
`Atty. Dkt. No. 2159.3210002/JIMC/MRG/U-S
`
`Sawai (IPR2019-00789), Ex. 1053, p. 014
`
`Sawai (IPR2019-00789), Ex. 1053, p. 014
`
`

`

`
`
`Sawai (IPR2019-00789), Ex. 1053, p. 015
`
`Sawai (IPR2019-00789), Ex. 1053, p. 015
`
`

`

`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re application of:
`
`Confirmation No.: 3197
`
`LUEASHEV, MatveyE.
`
`Art Unit:
`
`1649
`
`Appl. No. 12/526,296
`
`Examiner:
`
`Ulm, John D.
`
`§ 37 itc) Date: January 13, 2011
`
`Atty. Docket: 2159.32106GLJIMC/M-R/U-S
`
`Por. Treatment for Multiple Sclerosis
`(ds Amended}
`
`Declaration of Katherine T. Dawson, M.D. Under 37 C.P.R. § 1.132
`
`US Patent and Trademark Office
`PO Box 1450
`Alexandria, Virginia 223 13-1456
`
`Dear Sir:
`
`1, the undersigned, Katherine T. Dawson, M.D. residing at 561 Canton Street, Westwood,
`
`MA 92690 declare and state as follows:
`
`i
`
`MyBackground
`
`1.
`
`Lam a Senior Director of Medical Research at Biogen Idec MA inc. ("Biogen
`
`Idec"), the assignee of the currently pending application. [have seven years of experiencein the
`
`clinical development of MS drug products,
`
`I was involved in the development of Tysabri® and
`
`was the medical director of the Avonex” program. Tysabri? and Avonex®, both parenteral
`
`therapies, are among the few currently-approvedtreatment options for MS patients. Lam currently
`
`responsible for developing BG-12, a new oral MS therapy. A copy of mycurriculum vitae
`
`accompanies this declaration as Exhibit A.
`
`Sawai (IPR2019-00789), Ex. 1053, p. 016
`
`Sawai (IPR2019-00789), Ex. 1053, p. 016
`
`

`

`Atty. Dkt. No. 2159.32 10001
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`2,
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`Thave personal knowledge ofthe matters in this declaration — knowledge whichis
`
`either first-hand, or derived from my experience in this ficid and from interacting with others on
`
`the BG-12 development team at Biogen Idec.
`
`i.
`
`Long Felt Need for Oral Treatment of Multiple Sclerosis
`
`3.
`
`Maltiple sclerosis CMS")is an autotmimime disease characterized by inflammation,
`
`myelin desiruction, axonal damage and neuronal floss in the central nervous system and affects
`
`about 2.5 million people worldwide.
`
`4,
`
`Patients with MS are typically treated with injectable medications. Despite the
`
`recent approval of one oral MS therapy, a substantial challenge remains to develop efficacious yet
`
`safe oral therapies to treat MS patients. As such, there is a high, unmet, long-felt need for oral
`
`therapies that are effective in treating MS.
`
`8.
`
`In an atternpt to address this high, unmet, long-telt need, Biogen Idec has completed
`
`Phase 2? and Phase 3 clinical trials to investigate BG-12 as an oral treatment for MS. The only
`
`active ingredient of BG-12 is dimethyl fumarate (DMEP").
`
`in,«=Phe 486 mg DMEFPer Day Dose is Unexpectedly Efficacious
`
`A.
`
`6,
`
`Phase 2 Clinical Trial
`
`In 2004, Biogen idec initiated a Phase 2 six-month placebo controlled clinical trial
`
`of BG-12 in 16 countries and enrolled 257 patients with relapsing remitting MS (RRM). The
`
`clinical trial included an additional six-monthsafety extension. Overall, nmety-one percent ofthe
`
`patients completed the placebo-controlled part of the Phase 2 clinical trial.
`
`Sawai (IPR2019-00789), Ex. 1053, p. 017
`
`Sawai (IPR2019-00789), Ex. 1053, p. 017
`
`

`

`iad ha i—
`Atty, Dkt. No. 2159.32
`10601
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`a.
`
`Men and women 18 to 35 years of age were eligible for the study if they had a
`
`diagnosis of RRMS and an Expanded Insabiltty Status Scale ("EDSS") score (a
`
`well-known measure of the disabilities suffered by MS patients) between 6.0 and
`
`5.0. Additionally, the patients had to have had at least | relapse within 12 months
`
`prior to randomization or gadolintum-enhancing (Gd+) lesions (Gd-+ lesions im the
`
`brain are a well-known marker of M5} on brain MRI within six weeks of
`
`randomization.
`
`b.
`
`The patients were randomlyassignedto one of four treatrnent groups for 24 weeks:
`
`(a) 120 mg BG-12 once daily (120 mag/day); (b} 120 mg BG-12 three times daily
`
`(360 me/day); (c) 240 mg BG-12 threetimes daily (720 mp/day}; and (d) placebo.
`
`%
`
`The primary end point of the Phase ? clmical trial was the sam of all new Gd+
`
`lesions from four brain MRI seans obtained at Weeks 12, 16, 20, and 24. The
`
`number of Gd+ lesions is considered a surrogate end pointfor clinical efficacyand
`
`as such is accepted as a primary end point for a proof of concept stady.
`
`a.
`
`The secondary end points of the Phase 2 clinical trial inchided the cumulative
`
`numiber of new Gd+ lesions on scans from Weeks 4 and 24, the number of newor
`
`newly enlargingT?-hyperintense lesions at Week 24, and the number of new Tl
`
`hypointense lesions at week 24.
`
`a.
`
`7.
`
`Additional end points inchided annualized relapse rate ("ARR") and disability
`
`progression as measured by EDSS.
`
`The results ofthe Phase 2 clinicaltrial are reported in the peer-reviewed publication
`
`of Kappos, L., ef al, "Efficacy and safety of oral fumarate in patients with relapsing-remuitting
`
`multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase Ub study,”
`
`Sawai (IPR2019-00789), Ex. 1053, p. 018
`
`Sawai (IPR2019-00789), Ex. 1053, p. 018
`
`

`

`Atty. Dkt. No. 2159.32 10001
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`Lancet 372:1463-72 2008) (Exhibit B), as well as in Kappos, L., etal, "Efficacy of a novel oral
`
`singlo-agont fumarate, BGOOOL2, in pationts with rclapsing-remitting onultiple sclerosis: resulta of
`
`a phase 2 study,” 16th Meeting of the European Neurological Society (presentation given on May
`
`30, 2006) (Exhibit C): Kappos, L., et af, “Efficacy of a novel oral single-agent Purnarate,
`
`BGCOGl2, in patients with relapsing-remitting multiple sclerosis: results ofa phase I study,” 16th
`
`Meeting of the Earopean Neurological Society (abstract to presentation given on May 30, 2006)
`
`(Exhibit D}; and “Oral Compound BG-12 Achieves Primery Endpoint in Phase IT Study of
`
`Relapsing-Remitting MS with BG-12 Led to Statistically Significant Reductions in MRI
`
`Measures,” Biogen Idec News Release (May30, 2006) (Exhibit E).
`
`a.
`
`Onlythe patients who were administered 720 me/day DMF exhibited a statistically
`
`significant effect on the primary endpoint vs. placebo. Patients in this dose group
`
`showed a 69%decrease (P<0.0013 in the mean number of new Gdt lesions over
`
`MRI scans Weeks 12 to 24 as shown in Figure | below.
`
`Sawai (IPR2019-00789), Ex. 1053, p. 019
`
`Sawai (IPR2019-00789), Ex. 1053, p. 019
`
`

`

`Atty. Dkt. No. 2159.32 10001
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`Appl No. 12/526,296
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`Figure
`
`Mean Total Number of Gd+ Lesions at Weeks 12, 16, 20, and 24
`Combined in the Phase 2 Trial
`
`
`
`MeanNumberofNewGd+ Lesions
`
`oe
`
`i
`
`
`
`P<0.004
`
`BO%
`
`Placebo
`
`360 mg/day
`120 mg/day
`Treatment Group
`
`720 malday
`
`Sawai (IPR2019-00789), Ex. 1053, p. 020
`
`Sawai (IPR2019-00789), Ex. 1053, p. 020
`
`

`

`Atty. Dkt. No. 2159.32 10001
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`b.
`
`Additionally, patients administered 720 mg/day DMFexhibited a 48%decrease
`
`(p<G.9001) in the mean number of new and enlarging T2-hyporintenac lesions at
`
`Week 24, compared to placebo as shown in Figure 2 below.
`
`Figure2:
`
`Mean Number of New and Enlarging T2-Hyperintense Lesions
`(Week 24) in the Phase 2 Trial
`
`
`
`MeanNumberofNewT2Lesions
`
`
`
`
`
`Paget 48%
`-t
`
`
`
`
`Placebo
`
`120 mg/day
`
`S00 ma/day
`
`720 mo/day
`
`Treatment Group
`
`Sawai (IPR2019-00789), Ex. 1053, p. 021
`
`Sawai (IPR2019-00789), Ex. 1053, p. 021
`
`

`

`Atty. Dkt. No. 2159.32 10001
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`c.
`
`Patients administered 720 mg/day DMFalso exhibited a $3%decrease (p=0.014)
`
`m the moan mumber of new Ti-hypointonse lesions at Week 24 vs. placcho as
`
`shown in Figure 3 below.
`
`Figure3:
`
`Mean Number of New T1-Hypointense Lesions (Week 24) in the
`Phase 2 Trial
`
`
`
` P=O.014|53a, MeanNumberofNewT1Lesions
`
`
`
`
`Placebo
`
`{20 magiday
`
`360 melday
`
`720 mg/day
`
`Treatment Group
`
`Sawai (IPR2019-00789), Ex. 1053, p. 022
`
`Sawai (IPR2019-00789), Ex. 1053, p. 022
`
`

`

`iad ha i—
`Atty, Dkt. No. 2159.
`OGOL
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`a.
`
`Finally, patients administered 720 mg/day DMFexhibited an ARR of 0.44, as
`
`compared to an ARR of 6.65 im pationts administered placebo as shown in Table |
`
`below, resulting in a clinically meaningful 32%reduction in ARR, which is similar
`
`io the treatment effect on ARR of the approved interferon-Jeta and glatiramer
`
`acetate treatments for MS. The reduction in ARR. was notstatisticallysignificant!
`
`and has to be viewed m the context of the study being powered to achieve
`
`statistical significance for MRI endpoints and not for an evaluation of ARR.
`
`Table|:
`
`
`
`120 me /day
`Placebo
`366 mg/day
`720 me/day
`
`
`
`
`
`
`N=64
`65
`N=64
`N=63
`
`
`
`
`
`0.42
`“Amualizedrelapse|0.65
`O7850.44
`
`
`
`TateO3%CD"|(0.45,100)|(0.24,078)1(G52,116)|(0.26,0.76)
`
`
`Cl = confidence interval
`
`
`
`&.
`
`Tn comparison, treatment with 120 mg/day and 366 mg/dey DMF did not provide
`
`results that were statistically significant versus placebo on any endpoint.
`
`(See, e.g., Exhibit BE).
`
`G,
`
`The Phase 2 clinical trials results indicated 720 me/day DMFsignificantly reduced
`
`the cumulative number of new Gdt lesions, the number of new or enlarging T2-hyperintense
`
`lesions, and the number of new Tl-hypointense lesions compared with placebo. (See, 2.g., Exhibit
`~
`C}Bs
`
`‘ Que could attempt io draw a conclusionthat the relapseefficacy endpoint ofthe Phase2 clinical trial suggests that
`patients administered 120 mg/day DMFexhibit essensaythe same annualized relapse rate as patients administered
`
`720 mg/day DMF. However, the study was not designed to achievestatistical sgmficance for thisendpaint. (See, ¢.g.,
`Exhibit ).
`
`Sawai (IPR2019-00789), Ex. 1053, p. 023
`
`Sawai (IPR2019-00789), Ex. 1053, p. 023
`
`

`

`Atty. Dkt. No. 2159.32 10001
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`Appl No, 12/526,296
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`10.
`
`Therefore, the results of the Phase 2 clinical trial demonstrated that 720 mg/day
`
`DMF was an cfficacious dose for treating patients with MS. Additionally, because the 120 mg/day
`
`DMFand the 360 mg/day DMF groups were not statistically significant cormpared to placebo and
`
`the magnitude of effect on MRI lesions was not dose proportional, the results of the Phase 2 study
`
`did not suggest that DMFexhibited a linear dose response.
`
`BL
`
`Phase 3 DEFINE Clinical Trial Results”
`
`ii.
`
`The BG-12 Phase 3 placebo-controlied, double-blind clinical trial, named the
`
`"DEFINE" trial, was completed earlier this year and its top-line results were announced in April
`
`2011. The trial inchided over 1200 patients, in 28 different countries, on 5 different continents.
`
`Seventy-seven percent ofthe patients commpleted the clinical trial.
`
`a.
`
`Men and women 14 to 85 years of age were eligible for the studyif they had a
`
`diagnosis of RRMS and EDSS score between 0.0 and 8.0. Additionally, the
`
`patients mast have had at least one clinically confirmed relapse within 12 months
`
`prior to randomization and a brain MRI scan at any time that was consistent with
`
`MS or that showed evidence of at least one Gd+ enhancing lesion within 6 weeks
`
`of randomization.
`
`b.
`
`Patients were randomly assigned to one of three treatment groups: (2) 240 mg BG-
`
`12 twice daily (480 me/day); (b) 240 mg BG-12 three times daily (720 mg/day);
`
`and (c} placebo.
`
`c.
`
`The primary end point of the Phase 3 clinical trial was the proportion of relapsing
`
`patients at 2 years. A relapse was defined as new or recurrent neurologic
`
`* DEFINE is one ofthe two Phase3 clinical trials conducted by Biogen Idec. Theresults of the other Phase 3
`
`Sawai (IPR2019-00789), Ex. 1053, p. 024
`
`Sawai (IPR2019-00789), Ex. 1053, p. 024
`
`

`

`Atty. Dkt. No. 2159.32 10001
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`synipioms lasting for at least 24 hours that were not associated with fever or
`
`mifoction but wore accompanicd by now, objective neurological findings.
`
`a.
`
`Secondary end points of the Phase 3 clinical trial included the number of Gd+
`
`lesions, new or newly enlarging T2-hyperintense lesions, ARR, and sustained 12-
`
`week disability progression. Disability progression was defined as an increase in
`
`EDSS of(a) at least 1.0 point in patients with a baseline EDSS of > 1.0 or (b) at
`
`least 1.5 point increase in patients with a baselme EDSS of 0.6, sustained for 12
`
`weeks and confirmed by an independent neurologic evaluation committee (NEC).
`
`Additional MRI endpoints inchided the mumber ofnew TL hypointense lesions, and
`
`the mean-percentage change from baseline in Gd+, T2 hyperintense and Tl
`
`hypointense lesion volumes.
`
`i2.
`
`Asshown below, the results at 2 yoars of ine Phase 3 clinical trial demonstrated that
`
`both the 480 me/day

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