IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re application of:
`
`Confirmation No.: 5998
`
`LUKASHEV et al.
`
`Art Unit: 1649
`
`App1.No. 13/372,426
`
`Examiner: Ulm, John D.
`
`Filing Date: February 13, 2012
`
`Atty. Docket: 2159.3210002/JMC/MRG/U-S
`
`For: Treatment for Multiple Sclerosis
`
`Amendment and Reply Under 37 {EYE § iii}
`
`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 abandonment of
`
`this application,
`
`then such extensions of time are hereby petitioned under 37 CPR.
`
`§ 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 0f 35
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`Biogen Exhibit 2107
`Mylan v. Biogen
`IPR 2018-01403
`
`Biogen Exhibit 2107
`Mylan v. Biogen
`IPR 2018-01403
`
`Page 1 of 35
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`LUKASHEVet al.
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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 furnarate, 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 of 2, 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
`
`pharrnaceutically 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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`31.
`
`32.
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`33.
`
`34.
`
`35.
`
`36.
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`- 4-
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`LUKASHEVet al.
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`Appl. No. 13/3 72,426
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`(Previously Presented) The method of claim 29, wherein the dimethyl fumarate is
`
`administered in separate administrations of 3 equal doses.
`
`(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.
`
`(Previously Presented) The method of claim 32, wherein the dimethyl fumarate is
`
`administered in separate administrations of 2 equal doses.
`
`(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.
`
`(Previously Presented) The method of claim 28, wherein the expression level of
`
`NQ01 in the subject is elevated after administering to the subject about 480 mg per
`
`day of dimethyl fumarate, monomethyl fumarate, or a combination thereof.
`
`(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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`Appl. No. 13/372,426
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`37.
`
`(New) A method of treating a subject in need of treatment for multiple sclerosis
`
`comprieing treating the subject
`
`in need thereof with a therapeuticafiy effective
`
`amount of dimethyi funaarate, monomethyl mitigate? or a, combination thereof,
`
`wherein the therapeutically effective amount of din'iethyi
`
`thmarate, monomethyi
`
`filmarate, or a combination thereof is about 489 mg per day.
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`w 6*
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`Remarks
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`LUKASHEVet al.
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`Appl. No. 13/372,426
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`Reconsideration of this Application is respectfully requested.
`
`Claims 18-37 are pending in the application, WEth 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.
`
`1.
`
`Summas‘rr of the Claimexd‘Subiect Matter
`
`The claimed invention is generally directed to methods of treating multiple sclerosis
`
`("MS") which inveive the administration ef, or treatment of a subject with, a specific- daily
`
`dose of about 480 mg/day of dimethyl fumarate ("DMF") and/or monomethyl fumarate
`
`("MMF") (a biologically active metabolite of DMF).
`
`The claimed method demonstrated surprising efficacy in two large—scale Phase 3 MS
`
`clinical studies (further discussed herein below). These eiinieai 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 elinicai
`
`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 of DMF did n_ot 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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`LUKASHEVet al.
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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 of DMF.
`
`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 wéth 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‘ObViousness
`
`Claims 18 to 36 are rejected under 35 U.S.C. § 103(a) as being unpatentable over
`
`US. Patent Publication No. US 2003/0018072 to Joshi et al. ("Joshi"). Claims 18 to 36 are
`
`further rejected under 35 U.S.C. § 103(a) as being unpatentable over Schimrigk et al.,
`
`European Journal of Neurology 2006,
`
`l3(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
`
`practicing a prior art process, inwtheAabsenceuofuunwexggected,“results, does not constitute a
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`Appl. No. 13/372,426
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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 Schimrigk teaches or suggests the treatment of MS with a pharmaceutical
`
`composition consisting essentially of about 480 mg/day of DMF and/or MME’. 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/0r
`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 of BG-12 (DMF). In light of those results, a person of
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`Appl. No. 13/372,426
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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 enrolled 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 not primafacz'e 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 Idec 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 (.11., 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 LMF anti/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 g); tablets of Fumaderm forte® during the 18-week
`
`main treatment phase. Six tablets of Fumaderm forte® correspond to 720 mg of DMF and
`
`570 mg of MEF salts, a total of 1290mgoffumaratesyerdavadosfle‘that is much higher
`
`tInerttthe,4,30maidenretmredmtheg‘xesentelalms Subsequent to the main treatment phase,
`
`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 of MEF-Ca salt, 5 mg of MEF-Mg salt, 30 mg of DMF,
`and 3 mg of MEF-Zn salt, was administered to patients during up-titration, which lasted 9 weeks, and the final
`dose was reached after the up-titration period.
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`- 1 in
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`LUKASHEVet al.
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`Appl. No. 13/372,426
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`However, nothing in Schimrigk teaches or suggests replacing Fumaderrn 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 Schimrégk does not teach or suggest the specific
`
`dose as required in the present claims, i.e., about 480 mg/day of DMF 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 of DMF.
`
`In summary, neither Joshi nor Schimrigk teaches or suggests administering about
`
`480 mg/day of DMF and/or MMF to effectively treat MS. With the knowledge of the Phase
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`— 12—
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`2 clinical study, one would not have engaged in routine experémentation 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.
`
`m\\m\
`Qnegpected Results Overcome the Alleged Prima Facie {Ease 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.
`
`Resuits of the Phase 3 ciinical 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 studies
`
`evaluated the investigational oral drug candidate BG—lZ, which contains DMF as
`
`substantially the only active ingredient, at two doses, 480 mg/day and 720 mg/day, for the
`
`treatment of RRMS. As mentioned above, MMF is the active metabolite of DMF.
`
`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 ammalized relapse rate, propertion 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 were previously presented in the fern} of a declaration under
`
`37 CFR § 1.132 by Katherine T. Dawson, MD. ("the Dawson Declaration") in US. 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.,3 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 summarézes 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 Peofessor
`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
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`LUKASHEVet al.
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`Appl. No. 13/372,426
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`Comparison ofBG;12 at 480 mg/day and 720 mg/day5
`
`‘
`EEFFENE
`CONFIRM
`480 mg/day 72G mg/day
`480 mg/day%E 720 mg/day
`
`
`
`Reduction of Annualized
`
`g Relapse Rate
`
`
`‘
`
`l
`
`53%
`
`48%
`
`E
`
`1
`
`51%
`
`38%
`
`34%
`
`21%
`
`24%
`
`Bisabifiit v
`3
`ngressmn at’5 Years
`g
`..
`m“ ““WW
`Reduction of Mean Numme of
`o
`0
`E
`o
`o
`Ne‘w'NewEv Emiaigmg E‘E Lawnsi
`85 A)
`74A)
`§
`71 /°
`73 A)
`_.
`77777
`___ . “g...
`57<y°
`Reductioa of Mean NumE-Eer3E
`73%,
`63‘Vb
`65y
`
`o
`New E1 83'pointense“Eesiens
`o
`0
`0
`
`74%
`Reductionm Numbei0EEEEE+
`90%
`73%
`65%
`
`
`
`
`
`
`Lesions
`
`3
`
`m -
`
`{
`
`'
`
`3
`
`
`
`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
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`51%, respectively, in the CONFIRM trial wéth high statistical significance (p<0.0001 VS.
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`placebo). Disability progression was also similarly reduced compared to placebo by the 480
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`mg/day and 720 mg/day doses (38% and 34%, respectively for the DEFINE trial and 21%
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`and 24% for the CONFERM trial). See, e. g., Rudick Declaration, Figures 3 and 4. The
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`similarity of the efficacy obtained with the 480 mg/day and 720 mg/day doses of DMF is
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`further demonstrated by the largely overlapping "activity ratios" depicted in Figure 5 of the
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`Rudick Declaration.
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`5 Except for disability progression (21 p=0.0050; 1’ p=0.0128; ° p=0.2536; d p=0.2041), all data points
`are statistically significant versus placebo (p<0.0001 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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`studies (i-e-a the480mw/daxdosewasustaseffectlveasthe720ma/daidosem
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`m), 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 trig/day
`dose is unexpected based on results from a Phase 2 study
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`As mentioned above, Biogen l‘dec completed the six-month Phase 2 clinical study
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`involving the use of BG-l2 (DMF) in 2006. Tne 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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`effectiveness 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 efi’ects seen for the different doses ofBG—I 2 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 efiicacy" (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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`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
`
`. a person of
`.
`.
`based on the Phase 2 clinical study results,
`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:
`
`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.
`
`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
`
`as efficacious as the 720 mg/day dose.
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`(b)
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`The 720 mg/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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`At the time of the invention, Schimrigk was the only other clinical study (other than
`
`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
`
`teaching that three other MEF salts were required), a person of ordinary skill in the art
`
`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.
`
`Taking the Phase 2 clinical study results and the teaching of Schimrigk together, the
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`720 mg/day dose of DMF (or an even higher dose of fumarates) was clearly expected to be
`
`required for clinical effectiveness. As Dr. Rudick concluded:
`
`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.
`
`Rudick Declaration, page 9, paragraph 12.
`
`Importantly, consideréng the Phase 2 clinical study results and Schimrigk as a Whole,
`
`the references both teach or suggest a dose higher than 480 mg/day DMF is required to
`
`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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`claimed invention, which demonstrated the unexpected results (that the 480 mg/day dose of
`
`DMF met all measured endpoints Wéth 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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`primafacz'e case of obviousness, had one been established, has been overcome.
`
`IV.
`
`The Uneszected Result‘sé‘wWEich Inherentl‘tr Flow From the Claimed Invention2
`Must Be Given Substantial Weight,
`
`It is well settled that unexpected results or advantages of the claimed invention (in
`
`this case, Applicants‘ clinical study results) do not need to be included in the specification
`
`for an Examiner to consider them. MPEP 716.02(f) states that:
`
`[t]he totality of the record must be considered when
`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.
`
`(emphasis added). So long as the undisclosed property would inherently flow from the
`
`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
`
`is fully supported in the specification.
`
`A.
`
`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
`
`following key claim limitations:
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`(i) A method of treating muitiple seiemsis
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`(ii) ()rally administering (or treating. . .with). .. dimethyl fumarate, monomethyl
`fumarate, or a combination thereaf,’ . ..
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`...\
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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
`
`(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 "[zjn 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
`
`[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
`
`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, 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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`- 20—
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`Appl. No. 13/372,426
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`(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".
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`Accordingly, Applicants teach that DMF and MMF are effective in treating MS.
`
`For the dose “480 mg per day,” Applicants disclose in the specification 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
`
`[3111 effective dose of DMF or MMR. {sic} to be administered
`to a subject. orally can be from about 0.1 g to l g per pay {sic},
`2200 mg to about 890 mg per day (e.g., from about 240 mg to
`about 72% mg per day; or from about 48% mg to abeu