MARSHAA. ROSE
`
`DIRECTOR
`(202)772—8692
`MROSE@SKGF.COM
`
`February 14, 2012
`
`Commissioner for Patents
`
`PO Box 1450
`Alexandria, VA 22313 -1450
`
`
`
`s:seem“ '\ mm“-
`\\
`‘
`w
`QSKSSM‘Q RUN
`\‘N
`3
`3
`s
`“
`VNSSMMS‘
`\\
`\.\\\
`‘
`\\
`ssmmmm
`.
`
`
`
`
`
`Confirmation No. 5998
`
`Art Unit To be assigned
`
`Re:
`
`US. Utility Patent Application
`Appl. No. 13/372,426; Filing Date: February 13, 2012
`For:
`Treatment for Multiple Sclerosis (As Amended)
`Inventors: LUKASHEV et al.
`
`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 (lPR2019-00789), Ex. 1053, p. 001
`
`Sawai (IPR2019-00789), Ex. 1053, p. 001
`
`

`

`Commissioner for Patents
`
`February 14, 22012
`Page 2
`
`The US: Patent and Trademark 0ffice is hereby authorézed to charge any fee deficiency,
`
`or credit any overpayment, to our Deposit Account No. E90036.
`
`Respectfufiy submitted,
`
`STERNE, KESSLER GOLDSTEEN & Fox P.L,}...C.
`
`
`
`Marsh
`
`Attorney for Applicants
`Registration N0. 58,403
`
`MRG/U-S:enm
`
`Enclosures
`
`1484850_1.DOCX
`
`
`
`V
`n _
`“,
`.‘c a;
`3:
`:\:s::.:‘..\::.~s\=§
`
`Sawai (IPR2019-00789), EX. 1053, p. 002
`
`Sawai (IPR2019-00789), Ex. 1053, p. 002
`
`

`

`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re application of:
`
`LUKASHEV et a1.
`
`Appl. No.: To be assigned
`
`(Continuation ofApp]. No. 12/526,296,
`
`2 Confirmation No.: T0 be assigned
`
`Art Unit: T0 be assigned
`
`§ 371(c) Date: January I 3, 2011)
`
`Examiner: T0 be assigned
`
`Filing Date: Herewith
`
`Atty. Docket: 2159.3210002/JMC/MRG/U-S
`
`For: Treatment for Multiple Sclerosis
`(As Amended)
`
`i
`i
`
`?reiiminary Amendmefet {finder 3‘7 {7..RR. § 1.115
`
`Commissioner for Patents
`PO Box 1450
`
`Alexandréa, 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 Claims are reflected in the listing of claims which begins on
`
`page 3 of this paper.
`
`Remarks and Arguments begin on page 6 of this 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—
`
`LUKASHEVet al.
`
`Appl. No. T0 be assigned
`
`Amendments to the Specification
`
`Please amend the title as follows:
`
`
`Treatment for Multimgle Sclerosis IVER?agzsenmgawawaud:eiar‘eémetiwaseiki
`.
`.
`
`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 (so-722, Santa Cruz Biotechnology) was
`
`added at a 1:250 dilution in Dako Diluent with Background Reducing Components
`
`(Dako # S3022) C—2O antibody was detected using the Envision anti rabbit labeled
`
`po’lymer-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
`
`.
`
`
`WE§}:§}=1:§€1§4§§1%.
`
`On page 1, below the title of the invention, please add the following new paragraph:
`
`CROSS REFERENCE TO RELATED APPLICATIONS
`
`This application is a continuation of US. Patent Application No. 12/526,296,
`
`§ 371(c) Date January 13, 2011, now pending, which is the US. National Phase of
`
`International Application No. PCT/US2008/001602, filed February 7, 2008, which
`
`claims the benefit of US. Provisional Application 60/888,921, filed February 8, 2007.
`
`Atty. Dkt. No. 2159i3210002/JMC/MRG/U-S
`
`Sawai (IPR2019-00789), EX. 1053, p. 004
`
`Sawai (IPR2019-00789), Ex. 1053, p. 004
`
`

`

`- 3-
`
`LUKASHEVet al.
`
`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, whereir’: the therapeutically effective amount is
`
`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 amount is
`
`administered in separate administrations of 3 equal doses.
`
`23.
`
`(New) The method of claim 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-
`
`LUKASHEVet al.
`
`Appl. No. T0 be assigned
`
`24.
`
`25.
`
`26.
`
`27.
`
`28.
`
`29.
`
`30.
`
`31.
`
`32.
`
`(New) The method of claim 18., wherein the pharmaceutical composition consists
`
`essentially of monomethyl fumarate and one or more pharmaceutically acceptable
`
`excipients.
`
`(New) The method of claim 18, wherein the pharmaceutical composition is
`
`administered to the subject for at least 12 weeks.
`
`(New) The method of claim 23, wherein the therapeutically effective amount is
`
`administered to the subject in 2 equal doses.
`
`(New) The method of claim 26, wherein the therapeutically effective amount is
`
`administered to the subject for at least 12 weeks.
`
`(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.
`
`(New) The method of claim 28, wherein about 480 mg of dimethyl fumarate per
`
`day is administered to the subject.
`
`(New) The method of claim 29, wherein the dimethyl fumarate is administered in
`
`separate administrations of 2 equal doses.
`
`(New) The method of claim 29, wherein the dimethyl fumarate is administered in
`
`separate administrations of 3 equal doses.
`
`(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—
`
`LUKASHEVet al.
`
`Appl. No. T0 be assigned
`
`the therapeutically effective amount of dimethyl fumarate is about 480 mg per
`
`day.
`
`33.
`
`34.
`
`35.
`
`36.
`
`(New) The method of claim 32, wherein the dimethyl fumarate is administered in
`
`separate administrations of 2 equal doses.
`
`(New) The method of claim 18, wherein the expression level of NQOl
`
`in the
`
`subject is elevated after administering to the subject the therapeutically effective
`
`amount of dimethyl fumarate, monomethyl fumarate, or a combination thereof.
`
`(New) The method of claim 28, wherein the expression level of NQOl
`
`in the
`
`subject is elevated after administering to the subject about 480 mg per day of
`
`dimethyl fumarate, monomethyl fumarate, or a combination thereof.
`
`(New) The method of claim 32, wherein the expression level of NQOl 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
`
`LUKASHEVet al.
`
`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.
`
`I.
`
`Summary of the Claimed Sfibg'ect Matter
`
`The claimed invention is generally directed to methods ofm treating multiple
`
`sclerosis (MS). MS is 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 @ 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
`
`QMMF), as "method 4" in paragraph [0009], lines 9-11 and paragraphs [0062-0063] of
`
`the specification.
`
`The application discloses
`
`that
`
`”[i]n 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-
`
`LUKASHEVet al.
`
`Appl. No. T0 be assigned
`
`(Specification, p. 4, paragraph [0010]) (emphasis added). Applicants also discussed a
`
`MS animal 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 MMF are effective in treating
`
`MS. For example, DMF and MMF are listed as specific examples of neuroprotective
`
`compounds.
`
`(Specification, p. 13, paragraph [0063].) Specifically, the specification
`
`indicates that
`
`[i]n some embodiments of method 4, a method of treating a
`
`mammal who has or is at risk for a neurological disease is
`
`provided. The methods comprises administering to the
`
`mammal a therapeutically effective amount of at least one
`
`neuroprotective compound which has Formula I, 11, 111, or
`
`IV, e.g., a fumaric acid derivative (e.g., DMF or MMF).
`
`(161.) As such, DMF and MMF are 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 MMF are effective in treating
`
`MS.
`
`Applicants also disclose that orally administering 480 mg per day of DMF and/or
`
`MMF is effective in treating MS. (Specification, p. 30, paragraph [0116].) Specifically,
`
`the specification discloses that
`
`[a]n 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/JMC/MRG/U-S
`
`Sawai (IPR2019-00789), Ex. 1053, p. 009
`
`Sawai (IPR2019-00789), Ex. 1053, p. 009
`
`

`

`- 8—
`
`LUKASHEVet al.
`
`Appl. No. T0 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).
`
`(Id) (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 DMF daily to treat MS. See, e. g, In re 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 MMF can
`
`be administered in 2, 3, 4, or 6 equal doses. See, e. g, Specification, pp. 29-30, paragraph
`
`[0116]
`
`("[F]or 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 filrther discloses that the expression level of NQOl 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 MMF to 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 monomethyl fumarate
`
`(MMF) (the physiologically active metabolite of DMF). The claimed method has been
`
`Atty. Dkt. No. 2159.3210002/JMC/MRG/U-S
`
`Sawai (IPR2019-00789), EX. 1053, p. 010
`
`Sawai (IPR2019-00789), Ex. 1053, p. 010
`
`

`

`— 9—
`
`LUKASHEVet al.
`
`Appl. No. T0 be assigned
`
`proven effective for the treatment of MS in human patients 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 be effective.
`
`II.
`
`Patentabilik‘fi: 0f 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., US. 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
`
`US. Patent Application No. 12/526,296, submitted herewith as Exhibit 1.
`
`Biogen Idec MA Inc. ("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 (DMF as the 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-
`
`LUKASHEVei al.
`
`Appl. No. T0 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 magnitade 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 of statistical
`
`significance.
`
`(1d. 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 "[r]esu1ts 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 studies indicate 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 DMF dose efficacious, but
`
`
`the4L80ma/dwdosesuirrlsmrlademonstratedsmilareffectivenessoncllnlcalandMRI
`
`WswiamtasnOmedaaDMF (See Declaration, page 15,
`
`paragraph 15.)
`
`Atty. Dkt. No. 2159.3210002/JMC/MRG/U—S
`
`Sawai (IPR2019-00789), Ex. 1053, p. 012
`
`Sawai (IPR2019-00789), Ex. 1053, p. 012
`
`

`

`— ll-
`
`LUKASHEVet al.
`
`Appl. No. To be assigned
`
`III.
`
`The Unexpected Results Must Be Given Substantial Weight: There is a
`Nexus Between the Suggggorted Claims 18-36 and the Unexpected Results of
`the DEFINE and CONFIRMStuliieS
`
`Unexpected results of the claimed invention do not need to be included in the
`
`specification for an Examiner to consider them. The MPEP at 71 6.01 (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 unexpected results.
`
`As mentioned above, the application teaches and fully supports the claimed
`
`invention of treating MS using DMF and/or MMF at 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.
`
`Sammafl
`
`Based on the reasons set forth above, Applicants respectfully submit that the
`
`present claims are 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-
`
`LUKASHEVet al.
`
`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.
`
` w
`
`Marsha A. Rose
`
`Attorney for Applicants
`Registration No. 58,403
`
`,2
`3
`Date: s>\
`
`1””1111,1 ,m
`
`~~‘\
`‘
`t
`\
`w
`\\ EQ‘\\\‘ 3‘
`”/11”,
`_\
`
`1100 New York Avenue, NW.
`Washington, D.C.20005—3934
`(202) 3 71-2600
`
`1481215_1.DOCX
`
`Atty. Dkt. N0. 2159.3210002/JMC/MES‘EG/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
`
`

`

`1N THE [NEED STATES PATENT AND TRADEMARK OFFICE
`
`In re appiieation of:
`
`Cmafirmatien N3; 5197'
`
`LUKASHEV, Matvey E
`
`Art Unit:
`
`1649
`
`Appl. No. 12/526,296
`
`Examiner:
`
`U Ern. John D.
`
`§ 3 71(6) Date: .1anuary 13, 201 1
`
`Atty. Becket: 2159.3 211.100 11"31‘viC/1v1-R/U- S
`
`For: Treatment fer Mnitipie Seiernsis
`{HES Amen deaf)
`
`Rentarntinn nf Katherine '1‘. Between, REE). tinder 3‘? {EELR § 1.132
`
`U S Patent and Trademark Office
`PO: BOX 1450
`
`Aiexandria Virginia 22313-1451}
`
`Dear Sir:
`
`I. the undersigned. Katherine '1‘. Dawson, MD. residing at 561 Canton Street. Westwood.
`
`MA 02090 declare and sta ,e as fniiows:
`
`1.
`
`My Raekgrnnné
`
`1.
`
`1 am a Senior Dh‘eeter of Mediea1 Research at Biegen 1dee MA inc. (”Biegen
`
`Wee”), the assignee of the eun‘entiy pending application. Ihave seven years 01" experience in the
`
`e1iniea1 deveioprnent ethis dmg preducts.
`
`1 was inve1ve€1 in the development 01‘ Tysahri® and
`
`was the medical director of the Avenex® pregrarn. Tysahri® and Avenex‘ig. 130th parenterai
`
`therapies, are among the few current1y-—approved treatment options- for MS patients. 1am enrrent1y
`
`respensihie fer deve10ping 136—12., a new Oral MS the'apy. A eepy of n y curriculum vitae
`
`aeem’npanies this deeiaratien as Exhibit A.
`
`Sawai (IPR2019-00789), EX. 1053, p. 016
`
`Sawai (IPR2019-00789), Ex. 1053, p. 016
`
`

`

`Atty. Diet. No. 2159330001
`
`— 2 —
`
`LUKASl-ll-EV
`
`Appl, No. l2/526,296
`
`3
`
`I have personal knowledge ofth e matters in this declaration — knowledge which is
`
`either first—hand, or derived from my experience in this lield and from interacting with others on
`
`the BG—lZ development team at Biogen ldec.
`
`ll.
`
`Lang; Felt Need for Ural Treatment of Multiple Sclerosis
`
`3.
`
`Multiple sclerosis ("MS“) is an atitoii‘nintine disease characterized by in tlan'irn ation,
`
`myelin destruction, axonal darnage and neuronal loss in the central nervous system and ailects
`
`about 2.5 million people worldwide.
`
`4-,
`
`Patients with h/lS are typically treated with injeetable 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, longd’elt need for oral
`
`therapies that are effective in treating MS.
`
`5.
`
`in an attempt to address this hi git, unmet, long—felt nee-Ll, Biogen id ec has completed
`
`Phase 2 and Fliase 3 clinical trials to investigate BG—lZ as an oral treatment for MS, The only
`
`active ingredient of Bil—l2 is dirnethyl funiarate ("EMF").
`
`ill.
`
`The 48% mg DMF Per Day Base is Unexpectedly Et‘t‘leacious
`
`A
`
`Phase 2 Clinical Trial
`
`6.
`
`in 2004, Biogen ldec initiated a Phase 2 six—month placebo controlled clinical trial
`
`of 8(3an in 10 countries and enrolled 257 patients with relapsing remitting MS (RRMS), The
`
`clinical trial included an additional six—m ontlt safety extension. Overall, ninety—one peree it ofthe
`
`patients completed the placebo—et‘introlled part of the Phase 2 clinical trial.
`
`Sawai (IPR2019-00789), EX. 1053, p. 017
`
`Sawai (IPR2019-00789), Ex. 1053, p. 017
`
`

`

`Any. Dht. No. 21593210001
`
`— 3 —
`
`LUKASE—ll—E‘v’
`
`Appl. No. l2/526,296
`
`an
`
`Men and women l8 to 55 years of age were eligible for the study if they had a
`
`diagnosis ot'RRMS and an Expanded Disability Status Scale (”EDSS") snore (a
`
`well—ltnown measure of the disabilities: suffered by MS patients) between 0.0 and
`
`5f). Additionally, the patients had to have had at least l relapse Within l2. months
`
`prior to randomization or gadoliniuni—enhancing (th+) lesions (Gd+ lesions in the
`
`brain are a y 'ell-lmoyv'n marker of MS) on brain MRl within six weeks of
`
`randomization.
`
`b.
`
`The patients were randomly assigned to one of four treatment groups for 24 weeks:
`
`(a) lle mg BG—l 21 once daily ( l2l) ing/day}; (l3) l20 mg BGwl2 three tirnes daily
`
`(366 n‘ig/day); (e) 246 mg BG—l 2 three times daily (720 trig/day); and (d) placebo
`
`ll
`
`The primary end point of the Phase 2 clinical trial was the sum of all new Gil-+-
`
`lesions fern four brain MRI scans obtained at Weeks 12, 16, 20» and 24. The
`
`number ode+ lesions is considered a surrogate end point for clinical efficacy and
`
`as such is accepted as a primary endpoint for a proof of concept study.
`
`d.
`
`The secondary end points of the Phase 2 clinical trial included the cumulative
`
`number of new Gd+ lesions on scans from Weeks 4 and 24,” the number of new or
`
`newly enlarging’l‘E—hflaerintense lesions at Week 1243, and the numher of new "l‘l
`
`hypointense lesions at week 24.
`
`e.
`
`Additional end points included annualized relapse rate (”ARR") and disability
`
`progression as, measured by EDSS.
`
`7.
`
`The results oftlie Phase ‘2 clinical trial are reported in the eer~reyiewed publication
`
`of Kappos, L, 61' air, "Efficacy and safety of oral lurnarate in patients with relapsing—renrltting
`
`multiple sclerosis: a rnultieentre; randomised, double—blind, placebo—controlled phase lib study,"
`
`Sawai (IPR2019-00789), EX. 1053, p. 018
`
`Sawai (IPR2019-00789), Ex. 1053, p. 018
`
`

`

`Atty. Dkt. No. 2159330001
`
`— 4 —
`
`L’UKASE—ii—EV
`
`Appl. No. t2/526,296
`
`Lancet 3 72:1463w72 (2008) (Exhibit B); as weii as in Kappesg L“, at (2]., "Efficacy of a mwei orai
`
`siiigie—ageiit fivimatate, BGOGGE 2, iii patients with teiapsirig-remitting muiiipie sclerosis: resuits of
`
`a phase 2 study,” 16th Meeting et‘tiie Eurepean Neureiegieai Society (presentation given on May
`
`30., 2906) ifExhibit C); Kappos, L7 61 at,” "Efficacy 0f a novei ei‘ai singlet-agent Fumarate,
`
`BGOGOiZH in patients with reiapsing—remittiug muitipie seleresis: results of aphase 11 study” téth
`
`Meeting oft/he Eui‘epeaii Neurological Society (abstract to preseiitatiei‘i giveii on May 30, 2006)
`
`(Exhibit D); and ”Oral Cempeuud 363—12 Achieves Pi‘imaiy Endpeim in Phase 11 Study of
`
`Retapsiug—Remitting MS with BG-iZ Led to Statistically Significant Reductions in Miii
`
`iii/teastuesi" Biegeu Ides News Reiease (ix/fay 3Q, 2006) (Exhibit, E)
`
`a“
`
`01’in the patients who were administered 720 trig/dayDMF exhibited a statistieaiiy
`
`significant effect on the primary endpoint vs. ptacebe. Patients in this dose group
`
`shewed a 69% decrease (P<ti.t)t)1) in the mean number et‘new Gd+ iesiens over
`
`MRI scans Weeks 13?. it) 24 as shown in Figure 1 beiow.
`
`Sawai (IPR2019-00789), EX. 1053, p. 019
`
`Sawai (IPR2019-00789), Ex. 1053, p. 019
`
`

`

`Atty. Din. N0. 21593210001
`
`— S —
`
`LUKASE-EEV
`
`Appl. No. E2/526,296
`
`Figure 1 :
`
`Mean Tate! Number of GM Lesians at Weeks 12$ 16, 20‘, and 24
`Combined in the Phase 2 Triai
`
`MeanMumbarofNew(SCH Lesions w
`
`l
`
`
`
`69%
`
`P<0.001
`
`\
`
`P¥aceb0
`
`350 mgiday
`120 mglday
`Treatment Group
`
`720 mgr’day
`
`Sawai (IPR2019-00789), EX. 1053, p. 020
`
`Sawai (IPR2019-00789), Ex. 1053, p. 020
`
`

`

`Atty. Din. N0. 21593210001
`
`— 6 —
`
`LUKASE-EEV
`
`Appl. No. E2/526,296
`
`b,
`
`Additionally: patients administered 720 nag/day EMF fixhibited a, 48% dccreasa:
`
`(p<0~0€}i)
`
`in the mean number of new and cniarging T2~hypcrintcnnc lesions :1”:
`
`Week 24, compared in pincebo as shown in Figure 2 beiow.
`
`Rigging;
`
`Mean Number of New and Eniarging TEaHyperintense Lesions
`(Week 24) in the Phase 2 Triai
`
`
`
`
`
`MeanNumber:31“NewT2Lesicns
`
`
`
`
`
`
`
`Placebo
`
`120 mg/day
`
`360 mgr’dsy
`
`“(’23 mgfday
`
`Treatment: Group
`
`Sawai (IPR2019-00789), EX. 1053, p. 021
`
`Sawai (IPR2019-00789), Ex. 1053, p. 021
`
`

`

`Atty. Din. N0. 21593210001
`
`— 7 —
`
`LUKASE-iEV
`
`Appl. No. E2/526,296
`
`cc
`
`Patientg administemd 720 Eng/day DMF aise exhibimd a 53% decrease (13:03014)
`
`in the mean mambcr 03“ new TE—hypointcnsc icsims at Week 24 vs. piaccbo as
`
`shown in Fig’urs 3‘ below.
`
`Eiguxgég
`
`Mean Number a? New T1-Hypointense Lesions (Week 24) in the
`Phase 2 Trial
`
`
`
` P=O.GM 53% MeanNumberofNewT1Lesions
`
`
`
`
`Piacebo
`
`“120 mgfday
`
`350 mglday
`
`720 mgr‘day
`
`Treatment Group
`
`Sawai (IPR2019-00789), EX. 1053, p. 022
`
`Sawai (IPR2019-00789), Ex. 1053, p. 022
`
`

`

`A::V. 121:: 110.2159 521111191
`
`— 8 —
`
`LUKASE—ii—E‘v’
`
`Appl. No. 12/526,296
`
`11.
`
`F111:i11y, 1111151111115 311111111131611,11 720 mtg/111,13; EMF 3x11111113V1 an ARR of Cir-'14. as:
`
`00111111110610 11:11ARR 010.65 111 1211111311111 11111111111 511311311 1111115131212 as shown 111 "1211111: 1
`
`8...
`beluw 16211111119111a011111121111'1113211111112111 32% reductioniiiARR,VV'1iichis simiEai‘
`
`to the 1113311116111 effect :31: ARR of the approved interferon-[mm 211111 giatimmer
`
`3.11131311111‘11211111311‘15 £01" MS.
`
`"1111: reduction: 111 ARR. was 1101,111.21115111:1111y51351:“111‘1112111‘11
`
`211111 has 111 ha flawed 111 1111: 13111118211 011111: study 13131113); povered ’11”) achieva
`
`statistical 51 32111119311116 for MRI 61111111111115 2111111101 11112111 131’3111311011 01‘ ARR.
`
`
`
`16311113116
`A1’11‘11iai1zc11
`111113195xi: C1111
`C1—— 61111111111111311 1111mm}
`
`.
`
`..
`
`,.
`
`'
`'
`
`.
`
`.
`
`114
`
`(1 IS
`(11.52. i 16)
`
`1026,13'61
`
`8.
`
`111 C0filpfii‘1S0fi, 11131111116111 with 1211 111 g/‘day 211111 3611 111 gfday DMF did 1101 1110171111:
`
`113511115 that were 51211151103113! significant versus 1321;11:6130 011 any e1111110i111.
`
`(See, 11g, Exhibit E).
`
`9.
`
`T111) Phase 2 11111110111 triais 195111111: 11111111211611 7’20 111 g/day DMF significz 111137 16111101311
`
`1113 cumulative 111111111131 of 11va C1111 1621110115, the 1111111111131 111‘ 11159.1 01 enlarging T2—11yperiritensa
`
`1135101151, 2111111118 11111111181 of 116w Ti ~11ypoiiitense 18810115: compared with placebo. (See, ana , Exhibit
`“A
`L1,1.
`
`1 0.1113 131311111 2111131111121 10 draw 31 90111311151011 111211 11113 1131211359131):'ficacv 131111110111:‘ 11f 11:13 P111158 2 13111111331 11151 suggesis-11131
`152111611.5 21111111111511311311 127(3- 1:111:11aV 13M}. 6211111111 138513111 ial‘iy1116 same 11111113111161} raiapsa 12111: as 131111121111; 11111211111151.6161}
`i20111g/11ayi):V1F. Howevm, 11185411111ywas 1112111135Lb1g1181.111 2113111ch”. \taiixt-Vai\:g111awn-3:: toitnwndpunt (.8121? (5x5:
`Exnibit E)
`
`Sawai (IPR2019-00789), EX. 1053, p. 023
`
`Sawai (IPR2019-00789), Ex. 1053, p. 023
`
`

`

`Atty. Diet. No. 21593210001
`
`— 9 —
`
`LUKASl—lEV
`
`Appl. No. l2/526,296
`
`ll).
`
`rl‘lléircftjl'é), the results of the Phase 2 clinical trial demonstrated that 7210 nag/day
`
`DMF was an ctllcacio us close for treating patients with l‘vlS. Additionally? because the l 20 rng/day
`
`Dr‘s/ll7 and the Still ling/day DMF groups were not statistically significant compared to placebo and
`
`the magnitude of effect on MRl lesions was not dose proportional, the results of the Phase ‘2 study
`
`did not suggest that DMF exhibited a li ear dose response
`
`B.
`
`Phase 3 BEFINE Clinical Trial Results2
`
`ll.
`
`'l‘lie Bill-12 l’hase 3 placebo-controlled, double-blind clinical trial, named the
`
`"DEFlNE" trialfi was completed earlier this year and its top—line results were announced in April
`
`2m l. The trial included ever llell patients, in 28 different countries, on 5 different continents.
`
`Seventy—seven percent of the patients completed the clinical trial.
`
`a.
`
`Men and women l8 to 55 years of age were eligible for the study if they had a
`
`diagnosis of RRMS and 38088 score between ill) and 5.0. Additionally; the
`
`patients rnust have had at least one clinically continned relapse within 12 months
`
`prior to randomization and a brain MRl scan at any time that was consistent with
`
`MS or that showed evidence of at least one th+ enhancing lesion within 6 weeks
`
`of randomization.
`
`h.
`
`G17
`Patients were randomly assi ned to one ottltree treatment groups: (a) 240 rng BG—
`
`12 twice daily {480 ntg/day); (‘0) 24d mg BG~l 2 three times daily {720 mgr/day);
`
`and to) 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 neuroloeie
`
`2 DEFINE is one of the two Phase 3 clinical trials conducted by Biogen Idec, The results of the other Phase 3
`
`Sawai (IPR2019-00789), EX. 1053, p. 024
`
`Sawai (IPR2019-00789), Ex. 1053, p. 024
`
`

`

`Atty. Dln. No. 2159330001
`
`~ 10 ~
`
`LUKASE-ll—EV
`
`Appl. No. £2,626,296
`
`symptoms lasting for at least 2-4 hours that were not associated with fever or
`
`infection but were accompanied by new, objective neurological findings.
`
`at.
`
`Secondary end points of the Phase 3 clinical trial included the number of Cid-+-
`
`lesions, new or newly enlarging 'I‘ZK-hyperintense lesions, ARR, and