IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re application of:
`
`LUKASHEV et al.
`
`Confirmation No.: 5998
`
`Art Unit: 1649
`
`Appl. No. 13/372,426
`
`Examiner: Ulm, John D.
`
`Filing Date: February 13,2012
`
`Atty. Docket: 2159.3210002/JMC/MRGIU-S
`
`For: Treatment for Multiple Sclerosis
`
`Amendment and Reply Under 37 C.ER. § 1.111
`
`Mail Stop Amendment
`
`Commissioner for Patents
`PO Box 1450
`Alexandria, VA 22313-1450
`
`Sir:
`
`In reply to the Office Action dated May 3, 2012, Applicants submit the following
`
`Amendments and Remarks.
`
`The Claims are listed beginning on page 2 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 abandorunent 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.
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`Page 1 of 35
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`Appl. No. 13/372,426
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`Listing of the Claims
`
`The claims are listed below for the Examiner's convenience.
`
`1-17.
`
`(Cancelled)
`
`18.
`
`(Previously Presented) 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.
`
`(Previously Presented) The method of claim 18, wherein the pharmaceutical
`
`composition is administered in the form of a tablet, a suspension, or a capsule.
`
`20.
`
`(Previously Presented) The method of claim 18, wherein the therapeutically effective
`
`amount is administered in separate administrations of2, 3,4, or 6 equal doses.
`
`21.
`
`(Previously Presented) The method of claim 20, wherein the therapeutically effective
`
`amount is administered in separate administrations of 2 equal doses.
`
`22.
`
`(Previously Presented) The method of claim 20, wherein the therapeutically effective
`
`amount is administered in separate administrations of 3 equal doses.
`
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`23.
`
`(Previously Presented) The method of claim 18, wherein the pharmaceutical
`
`composition consists essentially of dimethyl
`
`fumarate and one or more
`
`pharmaceutically acceptable excipients.
`
`24.
`
`(Previously Presented) The method of claim 18, wherein the pharmaceutical
`
`composition consists essentially of monomethyl fumarate and one or more
`
`pharmaceutically acceptable excipients.
`
`25.
`
`(Previously Presented) The method of claim 18, wherein the pharmaceutical
`
`composition is administered to the subject for at least 12 weeks.
`
`26.
`
`(Previously Presented) The method of claim 23, wherein the therapeutically effective
`
`amount is administered to the subject in 2 equal doses.
`
`27.
`
`(Previously Presented) The method of claim 26, wherein the therapeutically effective
`
`amount is administered to the subject for at least 12 weeks.
`
`28.
`
`(Previously Presented) 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.
`
`(Previously Presented) The method of claim 28, wherein about 480 mg of dimethyl
`
`fumarate per day is administered to the subject.
`
`30.
`
`(Previously Presented) The method of claim 29, wherein the dimethyl fumarate is
`
`administered in separate administrations of 2 equal doses.
`
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`Page 3 of 35
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`31.
`
`(Previously Presented) The method of claim 29, wherein the dimethyl fumarate is
`
`administered in separate administrations of 3 equal doses.
`
`32.
`
`(Previously Presented) 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 the therapeutically effective amount of dimethyl fumarate is about 480 mg
`
`per day.
`
`33.
`
`(Previously Presented) The method of claim 32, wherein the dimethyl fumarate is
`
`administered in separate administrations of 2 equal doses.
`
`34.
`
`(Previously Presented) 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.
`
`35.
`
`(Previously Presented) 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, mono methyl fumarate, or a combination thereof.
`
`36.
`
`(Previously Presented) 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.
`
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`37.
`
`(New) A method of treating a subject in need of treatment for multiple sclerosis
`
`comprising treating the subject in m.~ed thereof with a therapeutically effective
`
`amount of dimethyl fumarate, monomethyl fumarate, or a combination thereof,
`
`wherein the therapeutically effective arnount of dimet.hyl fumarate, monomethyl
`
`fumarate, or a combination thereof is about 480 mg per day.
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`Page 5 of 35
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`Remarks
`
`LUKASHEVef al.
`Appl. No. 13/372,426
`
`Reconsideration of this Application is respectfully requested.
`
`Claims 18-37 are pending in the application, with claims 18,28,32, and 37 being the
`
`independent claims. Support for new claim 37 can be found at least in paragraphs [0009],
`
`[0010], [0062-0063], and [0116] of the specification. Based on the above amendment and
`
`the following remarks, Applicants respectfully request that the Examiner reconsider all
`
`outstanding objections and rejections and that they be withdrawn.
`
`I.
`
`Summar"v of the Claime,~,Subiect M,~t~~r
`
`The claimed invention is generally directed to methods of treating multiple sclerosis
`
`("MS") which involve the administration of, or treatment of a su~ject with, a specifJ.c daily
`
`dose of about 480 mg/day of dimethyl fumarate ("DMF") andlor monomethyl fumarate
`
`("MMF") (a biologically active metabolite of DtvlF).
`
`The claimed method demonstrated surprising efficacy in two large-scale Phase 3 MS
`
`clinical studies (further discussed herein below) These clinical studies demonstrated that
`
`480 mg/day of DMF was unexpectedly just as efficacious in treating MS as 720 mg/day of
`
`DMF, This result was especially unexpected given the results of an earlier Phase 2 clinical
`
`study in which 720 mg/day of DMF was the only dose found to be efficacious, while the
`
`other tested doses, i.e., 120 mg/day and 360 mg/day ofDMF did not show any statistically
`
`significant efficacy when compared to placebo. Since the dose response was not linear, the
`
`magnitude of the efficacy demonstrated by the 480 mg/day dose (that it is just as efficacious
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`as the 720 mg/day dose) is surprising and unexpected. Moreover, knowledge available to a
`
`person or ordinary skill in the art as of the priority date of the instant application (i. e.,
`
`February 8, 2007) (referred to "at the time of the invention" here) would have led the person
`
`of ordinary skill in the art to use a higher dose to treat MS, effectively teaching away from
`
`the claimed invention of using the 480 mg/day dose ofDMF.
`
`As will be discussed in more detail below, the 480 mg/day DMF dose is preferred
`
`over the 720 mg/day or an even higher dose. One reason 480 mg/day DMF is preferred is
`
`because side effects associated with chronic, lifelong treatment are generally dose-related, so
`
`the 480 mg/day dose naturally would be expected to have fewer side effects in the long run.
`
`II.
`
`No Prima Facie Case of Obviousn,~,~~
`
`Claims 18 to 36 are rejected under 35 U.S.C. § 103(a) as being unpatentable over
`
`U.S. Patent Publication No. US 2003/0018072 to Joshi ef al. ("Joshi"). Claims 18 to 36 are
`
`further rejected under 35 U.S.C. § 103(a) as being unpatentable over Schimrigk ef al.,
`
`European Journal of Neurology 2006, 13(6):604-610 ("Schimrigk").
`
`Applicants
`
`respectfully traverse both rejections.
`
`The Examiner acknowledges that neither Joshi nor Schimrigk anticipate the pending
`
`claims because neither reference teaches the specific treatment protocol recited in the
`
`claims. (Office Action of May 3, 2012, page 3, last sentence, and page 5, lines 14-16).
`
`However, the Examiner alleges that "merely determining the optimal conditions for
`
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`Page 7 of 35
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`patentable inventive contribution."
`
`(Id. at page 4, lines 5-7 and page 5, lines 18-20
`
`(emphasis added».
`
`The current claims are not prima facie obvious over the cited art because neither
`
`Joshi nor Schirnrigk teaches or suggests the treatment of MS with a pharmaceutical
`
`composition consisting essentially of about 480 mg/day of DMF and/or MMF. Moreover,
`
`the cited references, especially Schimrigk, together with the knowledge available at the time
`
`of the invention, direct a person of ordinary skill in the art toward using higher doses of MS
`
`to treat MS than the claimed 480 mg/day dose.
`
`A.
`
`Joshi does not teach or suggest using a 480 mg/day dose of DMF and/or
`MMF to treat MS
`
`Joshi teaches oral administration of dialkyl fumarates (e.g., DMF) to treat MS.
`
`However, as appreciated by the Examiner, Joshi does not teach or suggest a 480 mg/day
`
`dose of DMF and/or MMF. Furthermore, there is nothing in Joshi that would motivate a
`
`person of ordinary skill in the art to select the particular dosing regimen involving 480
`
`mg/day of DMF and/or MMF to effectively treat MS as required in the claims.
`
`Still, it is the Examiner's view that the skilled person would have engaged in routine
`
`experimentation needed to determine the optimal effective dose. See the Office Action,
`
`page 4, lines 1-5. Applicants disagree because a person of ordinary skill in the art at the
`
`time of the invention would have been aware of the results of the Phase 2 clinical study
`
`described herein that involved the use ofBG-12 (DMF). In light of those results, a person of
`
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`ordinary skill in the art would have been motivated to treat a patient having MS by
`
`administering 720 mg/day DMF, not a DMF dose less than 720 mg/day (e.g., 480 mg/day).
`
`In 2006, Biogen Idec completed a six-month Phase 2 placebo controlled clinical
`
`study of BG-12 (DMF), which emolled 257 patients with relapsing-remitting MS
`
`("RRMS"). Three doses, 120 mg, 360 mg, and 720 mg/day of DMF, were tested and
`
`compared to placebo. The Phase 2 endpoints included MRI endpoints such as the number of
`
`Gd+ lesions (primary endpoint), the number of new or newly enlarging T2-hyperintense
`
`lesions, and the number of new T1 hypointense lesions, endpoints commonly used in MS
`
`clinical studies. The results of the Phase 2 clinical study, which were available as of June
`
`2006, showed that only the 720 mg/day DMF dose had a statistically significant effect
`
`compared to placebo and the 120 mg/day dose and the 360 mg/day dose both failed to
`
`achieve statistically significant results. 1 Thus, the results of the Phase 2 clinical study would
`
`have led one of ordinary skill in the art to use a different, higher dose (i.e., 720 mg/day)
`
`rather than the dose required by the claimed invention (i.e., 480 mg/day). Because the
`
`results of the Phase 2 clinical study were available before the priority date of the present
`
`application, the skilled person would have used the 720 mg/day dose rather than engaging in
`
`experimentation as suggested by the Examiner. Thus, Applicants respectfully submit that
`
`the claimed invention is notprimajacie obvious over Joshi.
`
`1 See, e.g., Kappos, L., et al., 16th Meeting of the European Neurological Society (May 30, 2006)
`(Abstract); Kappos, L., et al., 16th Meeting of the European Neurological Society (May 30, 2006)
`(presentation given on May 30, 2006); and Biogen Idee News Release of May 30, 2006 (submitted herewith as
`Exhibits B, C, and D to Exhibit 1 - the Rudick Declaration (discussed below), respectively), as well as Kappos,
`L., et al., Lancet 372:1463-72 (2008), submitted as Exhibit B to the Dawson Declaration.
`
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`B.
`
`Schimrigk does not teach or suggest using a pharmaceutical composition
`consisting essentially of DMF and/or MMF to treat MS, let alone a dose
`of about 480 mg/day of DMF and/or MMF
`
`Schimrigk teaches the administration of Fumaderm forte®, a pharmaceutical
`
`preparation which contains a mixture of DMF and monoethyl fumarate ("MEF") salts (also
`
`known as ethylhydrogen salts). One tablet of Fumaderm forte® contains 120 mg of DMF
`
`plus 87 mg of MEF-Ca salt, 5 mg of MEF-Mg salt, and 3 mg of MEF-Zn salt.2 See
`
`Schimrigk, page 605, right column, paragraph entitled "Study drug." Specifically, in
`
`Schimrigk, patients were administered six tablets of Fumaderm forte® during the 18-week
`
`main treatment phase. Six tablets of Fumaderm forte® correspond to 720 mg of DMF and
`
`the patients in Schimrigk were administered three tablets of Fumaderm forte® during a 48-
`
`week second treatment phase (a total of 645 mg/day of fumarates). See Schimrigk, page
`
`605, "Study design and assessments" and "Study drug." According to Schimrigk, this high
`
`dosing regimen showed promise with respect to certain MS parameters, such as reduction of
`
`the mean number of Gd+ lesions, and the positive effects from the first treatment phase were
`
`maintained in the second treatment phase. See, e.g., Schimrigk at page 607, third paragraph
`
`"Clinical outcomes", Figures 1 and 2, and page 608, last paragraph "Discussion." As a
`
`whole, Schimrigk teaches the use of a dosing regimen that uses high doses of fumarates (i. e.,
`
`1,290 mg/day followed by 645 mg/day).
`
`2 Fumaderm initial®, which contains 67 mg ofMEF-Ca salt, 5 mg ofMEF-Mg salt, 30 mg ofDMF,
`and 3 mg of MEF -Zn salt, was administered to patients during up-titration, which lasted 9 weeks, and the fmal
`dose was reached after the up-titration period.
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`However, nothing in Schimrigk teaches or suggests replacing Fumaderm Forte®, i.e.,
`
`a mixture of four active ingredients, with a pharmaceutical composition consisting
`
`essentially of DMF and/or MMF or that such a composition could be efficacious for treating
`
`MS.
`
`Furthermore, even if Schimrigk had suggested a pharmaceutical composition
`
`consisting essentially of DMF and/or MMF, which it did not, one would still not arrive at
`
`the instantly claimed invention because Schimrigk does not teach or suggest the specific
`
`dose as required in the present claims, i.e., about 480 mg/day ofDMF and/or MMF, to treat
`
`MS.
`
`In fact, Schimrigk directs a person of ordinary skill in the art toward using much
`
`higher doses of fumarates than the claimed invention, which uses 480 mg/day of DMF,
`
`effectively teaching away from the claimed invention. Based on the teaching of Schimrigk,
`
`a person of ordinary skill in the art would have expected a dose that is much higher than 480
`
`mg/day to be required to effectively treat MS. After all, the promising results described in
`
`Schimrigk were generated by using the dosing regimen of 1,290 mg/day followed by a dose
`
`of 645 mg/day. In contrast to the claimed invention which requires the use of DMF and/or
`
`MMF, Schimrigk teaches the use of a mixture of four fumarates (i.e., DMF and three MEF
`
`salts). Taking together the teaching of high fumarate doses and the use of the four
`
`fumarates, Schimrigk clearly leads a person of ordinary skill in the art away from the
`
`claimed invention of using a dose of 480 mg/day ofDMF.
`
`In summary, neither Joshi nor Schimrigk teaches or suggests administering about
`
`480 mg/day ofDMF and/or MMF to effectively treat MS. With the knowledge of the Phase
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`2 clinical study, one would not have engaged in routine experimentation to arrive at the
`
`claimed invention in view of either reference. Applicants respectfully submit that the
`
`present claims are not prima facie obvious in view of the cited references. However, even
`
`assuming arguendo that prima facie obviousness has been established, Applicants submit
`
`that it is rebutted by (1) the unexpected results obtained from practicing the claimed
`
`invention and (2) evidence that the claimed invention satisfies a long-felt but unsolved need
`
`as set forth below.
`
`III.
`
`Un.e~l)e~te<J Results Overcome the Allefred Prima Facie Case of Obviousness
`
`A.
`
`The claimed invention demonstrates unexpected results
`
`The unexpected results, which flow inherently from the claimed invention, are based
`
`on results of two large-scale Phase 3 MS clinical studies.
`
`1.
`
`Results of the Phase 3 clinical studies
`
`Biogen Idec MA Inc. ("Biogen Idec"), the assignee of the current application,
`
`recently completed two pivotal Phase 3 placebo-controlled, double-blind, clinical studies
`
`(DEFINE and CONFIRM) ("the Phase 3 clinical studies!!), The Phase 3 clinical studi(:s
`
`evaluated the investigational oral drug candidate BG-12, which contains DlVIF as
`
`substantially the only active ingredient, at two doses, 480 mg/day and 720 mg/day, for the
`
`treatment ofRRMS. As mentioned above, MMF is the active metabolite ofDMF.
`
`In both Phase 3 clinical studies, the magnitude of the efficacy demonstrated by the
`
`480 mg/day dose was quite surprising. Specifically, the lower 480 mg/day dose of DMF
`
`was shown to be just as efficacious as the higher 720 mg/day dose of DMF in almost every
`
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`endpoint of the Phase 3 clinical studies including annualized relapse rate, proportion of
`
`subjects relapsed, number of Gd+ lesions, and disability progression at two years. These
`
`endpoints are standard endpoints, commonly used in MS clinical studies. The unexpected
`
`results from the DEFINE study Wf..~re previously presented in the fom} of a declaration under
`
`37 CFR § 1.132 by Katherine T. Dawson, M.D. ("the Dawson Declaration") in U.S. Patent
`
`Application No. 12/526,296, and submitted herewith as Exhibit 2. The unexpected results
`
`from both Phase 3 clinical studies are presented in a separate declaration under 37 CFR §
`
`1.132 by Richard A. Rudick, M.D} which is submitted herewith as Exhibit 1 ("the Rudick
`
`Declaration,,).4
`
`Graphical representations of the Phase 3 clinical study results related to the
`
`Annualized Relapse Rate ("ARR") and disability progression, and a summary of the pooled
`
`DEFINE and CONFIRM data are shown in Figures 3-5 of the Rudick Declaration. Table 1
`
`below summarizes some of the results of the Phase 3 clinical studies.
`
`3 Richard A. Rudick, M.D., is a physician, professor and clinical investigator who focuses on treating
`patients with neurological diseases. During the last 30 years, much of his clinical research has focused on MS.
`He is the Director of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic,
`the Vice Chairman for Research and Development at Cleveland Clinic's Neurological Institute, and a Professor
`of Medicine in the Cleveland Clinic Lerner College of Medicine at Case Western Reserve University. As a
`physician and an expert in the MS field, and further as a clinical investigator, Dr. Rudick is qualified to provide
`an opinion as to what a person of ordinary skill in the art would have known and concluded at the time of the
`invention.
`
`4 Results of the Phase 3 clinical studies (DEFINE and CONFIRM) are summarized in Biogen Idec
`press releases of April 11,2011 and October 26,2011, respectively (submitted herewith as Exhibits E and F to
`the Rudick Declaration).
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`Table 1
`Comparison ofBG-12 at 480 mg/day and 720 mg/days
`r-----------------------------------------------------------------·····················l:::::::::::::::::::::~:~!~~~~"""'~~"~~,
`CON~IRM
`
`,
`
`57%C l 65%d
`
`! 480 mg/day ! 720 mg/day !! 480 mg/day ! 720 mg/day
`~
`i
`ii
`t~~~~···················································································r······················~·~t···
`I Reduction of Annualized
`ii
`i
`i
`i
`I
`I
`53%
`48%
`44%
`51%
`i
`!i
`!
`I Relapse Rate
`I.
`I
`i.
`ii
`'-"""""'r"""";'~~_"m"rm"""~'~~"--"""-l"--------~-~-~m--mmr----m--.~~~--....... ml
`I Disability
`.. ~.~~~.~.~~.~~~~.~ __ ~~ .. : .. ~~~'~'~~mmmm"mm" I
`I
`I
`!
`'
`I
`!
`73<)1(
`71<)1(
`74<)1(
`85<)1(
`RcductionofMeanNumberof
`It
`o!
`NewfNcwlvEnlarging T2 I,eslons !
`0
`0
`0
`____________ . ______________ ~~ ________ ~ ___________________________________________________ ... 1 ................................................................ ~ .................................... ~ ..... m~_~
`~ed~ctiol1 of~1ean Nnm?er of
`73%a
`63%b
`New _fl Hvpomtense LesIOns
`1 - - - - - " - - " ' - -...... ---------------------------,,-----.-.-.-.--.------------------------ ----................. --........ - ................................................... ,,"""""""
`Reduction in Number of Gd+
`Lesions
`
`90%
`
`73%
`
`74%
`
`65%
`
`The 480 mg/day DMF dose and the 720 mg/day DMF dose similarly reduced ARR
`
`compared to placebo by 53% and 48%, respectively, in the DEFINE trial, and by 44% and
`
`51 %, respectively, in the CONFIRM trial with high statistical significance (p<0.0001 vs.
`
`placebo). Disability progression was also similarly reduced compared to placebo by the 480
`
`mg/day and 720 mg/day doses (38% and 34%, respectively for the DEFINE trial and 21 %
`
`and 24% for the CONFIRM trial). See, e.g., Rudick Declaration, Figures 3 and 4. The
`
`similarity of the efficacy obtained with the 480 mg/day and 720 mg/day doses of DMF is
`
`further demonstrated by the largely overlapping "activity ratios" depicted in Figure 5 of the
`
`Rudick Declaration.
`
`5 Except for disability progression (" p=O.0050; b p=O.0128; C p=0.2536; d p=O.2041), all data points
`are statistically significant versus placebo (p<O.OOO 1 vs. placebo).
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`Given what was known about the use of DMF to treat MS at the time of the
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`invention (see discussion below), the person of ordinary skill in the art would have been
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`quite surprised by the unexpected results demonstrated by the DEFINE and CONFIRM
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`MS), not to mention that the skilled person would have been taught away from using the 480
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`mg/day dose based on the knowledge available at the time of the invention.
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`(a)
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`The 480 mg/day dose having similar efficacy as the 720 mg/day
`dose is unexpected based on results from a Phase 2 study
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`As mentioned above, Biogen Idec completed the six-month Phase 2 clinical study
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`involving the use of BG-12 (DMF) in 2006. The results, which were available as of June
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`2006, found that the 720 mg/day DMF dose was the only dose tested that was clinically
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`effective, whereas both 120 mg/day dose and the 360 mg/day failed to show clinical
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`efIectiveness when compared to placebo.6 Accordingly, the Phase 2 results did not indicate
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`a dose-proportional relationship for the three DMF doses investigated. See, e.g., Rudick
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`Declaration, paragraph 9: "the effects seenfor the different doses ofBG-12 were not clearly
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`dose-proportional" (emphasis added). Similarly, Dr. Dawson notes in her Declaration at
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`page 19, paragraph 14: "the Phase 2 results do not demonstrate a linear dose response
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`between the DMF dose and the efficacy" (emphasis added). Thus, there is no expectation as
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`to whether the 480 mg/day dose would be efficacious when compared to placebo (and
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`6 See, e.g., Rudick Declaration page 4, paragraph 8, and Figures 1 and 2, and Dawson Declaration,
`page 9, paragraph 10, Figures 1-3).
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`Appl. No. 13/372,426
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`certainly no expectation the 480 mg/day dose would have similar efficacy as the 720 mg/day
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`dose). Indeed, Dr. Rudick states that
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`based on the Phase 2 clinical study results, . , . a person of
`ordinary skill in the art at the time of the invention would not
`have reasonably expected a 480 mg/day dose of DMF to have
`similar efficacy as the 720 mg/day dose of DMF for the
`treatment of MS.
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`Rudick Declaration, page 6, paragraph 9. In other words, the level of efficacy demonstrated
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`by the 480 mg/day dose is unexpected and quite surprising.
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`If a person of ordinary skill in the art had any expectation, the person would have
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`expected a lower dose (i.e., 480 mg/day) to have lower efficacy when compared to a higher
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`dose (i.e., a 720 mg/day). See, e.g., Rudick Declaration, page 6, paragraph 9:
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`The person of ordinary skill would have expected that the
`efficacy of the of the 480 mg/day dose to be less than that of
`the 720 mg/day dose. The fact that the 480 mg/day dose and
`the 720 mg/day dose, as tested in the Phase 3 clinical studies
`(see below), are found to be similarly efficacious is surprising.
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`To reiterate, based on the earlier phase 2 clinical study results, the results of the
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`phase 3 clinical studies demonstrated quite unexpectedly that the 480 mg/day dose was just
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`as efficacious as the 720 mg/day dose.
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`(b)
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`The 720 rug/day dose was expected to be required for clinical
`effectiveness
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`As discussed above, the Phase 2 clinical study results teach a person of ordinary skill
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`in the art to orally administer the only dose effective in the study, namely 720 mg/day of
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`DMF, to treat patients with MS.
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`Appl. No. 13/372,426
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`At the time of the invention, Schimrigk was the only other clinical study (other than
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`the Phase 2 clinical study) known to a person of ordinary skill in the art that disclosed using
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`fumarates to treat MS. Schimrigk administered 1,290 mg/day of a mixture of four fumarates
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`(six tablets of Fumaderm Forte®) to MS patients in the main treatment phase to achieve
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`positive clinical results. Based on the high fumarate dose taught by Schimrigk (and its
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`teaching that three other MEF salts were required), a person of ordinary skill in the art
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`would not have reasonably expected that 480 mg/day of DMF alone would be as efficacious
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`as seen in the Phase 3 clinical studies.
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`Taking the Phase 2 clinical study results and the teaching of Schimrigk together, the
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`720 mg/day dose ofDMF (or an even higher dose offumarates) was clearly expected to be
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`required for clinical effectiveness. As Dr. Rudick concluded:
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`In summary, given that Schimrigk does not provide any
`teaching or expectation with regard to DMF dosing and that
`the results of the Phase 2 clinical study provides the
`expectation that 720 mg/day of DMF is the effective dose for
`MS treatment, it would have been highly unexpected by a
`person of ordinary skill in the art that 480 mg/day of DMF is
`as effective for the treatment of MS as 720 mg/day of DMF.
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`Rudick Declaration, page 9, paragraph 12.
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`Importantly, considering the Phase 2 clinical study results and Schimrigk as a whole,
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`the references both teach or suggest a dose higher than 480 mg/day DMF is required to
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`effectively treat MS. In other words, the references effectively teach away from the claimed
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`invention. Because Applicants proceeded contrary to the accepted wisdom to arrive at the
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`Appl. No. 13/372,426
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`claimed invention, which demonstrated the unexpected results (that the 480 mg/day dose of
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`DMF met all measured endpoints with a high level of statistical significance and that this
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`dose was shown to be just as efficacious as the 720 mg/day dose), Applicants submit that a
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`primafacie case of obviousness, had one been established, has been overcome.
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`IV.
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`The Unexpected Result§J,,"':!~Jsh Inherentlv Flow From th~ {:Jaimed Inven!i9,~
`My,~'!Jle Given Substantial Weight
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`It is well settled that unexpected results or advantages of the claimed invention (in
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`this case, Applicants' clinical study results) do not need to be included in the specification
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`for an Examiner to consider them. MPEP 716.02(f) states that:
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`totality of the record must be considered when
`[t]he
`determining whether a claimed invention would have been
`obvious to one of ordinary skill in the art at the time the
`invention was made. Therefore, evidence and arguments
`directed to advantages not disclosed in the specification cannot
`be disregarded.
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`(emphasis added). So long as the undisclosed property would inherently flow from the
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`claimed invention, which is well supported by the specification, such property must be given
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`substantial weight in determining obviousness. As discussed below, the claimed invention
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`is fully supported in the specification.
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`A.
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`Every claimed limitation is described in the specification
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`Each of the independent claims (i.e., claims 18, 28, 32, and 37) contains the
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`following key claim limitations:
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`Appl. No. 13/372,426
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`(i) A method of treating , .. multiple sclerosis
`(Ii) OraHy administering (or treating. «with) ... dimethyl fumarate, monomethyl
`fumarate~ or a combination thereof,? 0'
`(iii)The therapeutically etTective amount .. .is about 480 mg per day.
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`For "treating MS," Applicants disclose in the specification a method for treating a
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`neurological disease with at least one fumaric acid derivative, including dimethyl fumarate
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`(DMF) or monomethyl fumarate (MMF), as "method 4" in paragraph [0009], lines 9-11 and
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`paragraphs [0062-0063] of the specification. The application discloses that 'TUn some
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`embodiments the neurological disease is MS or another demyelinating neurological
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`disease." Specification, p. 4, paragraph [0010] (emphasis added). Applicants also discussed
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`a MS animal model, Experimental Autoimmune Encephalomyelitis (EAE) , in paragraphs
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`[0108] and [0109], as well as Example 3. Therefore, MS is supported in the application.
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`For using "DMF and/or MMF," Applicants disclose in the specification that DMF
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`and/or MMF are effective in treating MS. For example, DMF and MMF are listed as
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`specific examples of neuroprotective compounds. Specification, p. 13, paragraph [0063].
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`Specifically, the specification indicates that
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`[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, II, III, or IV,
`e.g., a fumaric acid derivative (e.g., DMF or MMF).
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`7 Claim 32 covers the use of a pharmaceutical composition consisting essentially of DMF (and not
`DMF, MMF, or combination thereof).
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`LUKASHEVet ai.
`Appl. No. 13/372,426
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`(Jd.) As such, DMF and MMF are specifically named in the application as compounds
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`effective in treating neurological diseases such as MS. Furthermore, the dosages disclosed
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`in paragraph [0116] of the application refer to the specific compounds "DMF" and "MMF".
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`Accordingly, Applicants teach that DMF and MMF are effectiv