Reply Under 37 C.F.R. § 1.116
`Prioritized Examination (Track 1) — Art Unit 1649
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`In re application of:
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`LUKASHEV et al.
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`Confirmation No.: 5998
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`Art Unit: 1649
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`Appl. No.: 13/3 72,426
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`Examiner: ULM, John D.
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`Filed: February 13, 2012
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`Atty. Docket: 2159.3210002/JMC/MRG/U-S
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`For: Treafiment for Multiple Sclerosis
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`Reply ta Finai Office Actian Under 3’? {1.31%. § mm
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`Mail Stop AF
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`Commissioner for Patents
`PO Box 1450
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`Alexandria, VA 22313 —1450
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`Commissioner:
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`In reply to the Final Office Action dated October 12, 2012 (“the Final Office
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`Action”), Applicants submit the following Remarks.
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`The Claims are listed beginning on page 2 of this paper.
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`Remarks and Arguments begin on page 6 of this paper.
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`It is not believed that extensions of time or fees for net addition of claims are
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`required beyond those that may otherwise be provided for in documents accompanying
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`this paper. However,
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`if additional extensions of time are necessary to prevent
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`abandonment of this application, then such extensions of time are hereby petitioned
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`under 37 C.F.R. § 1.136(a), and any fees required therefor (including fees for net
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`addition of claims) are hereby authorized to be charged to our Deposit Account
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`No. 19—0036.
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`Page 1 0f 27
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`Biogen Exhibit 2022
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`Mylan v. Biogen
`IPR2018-01403
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`Page 1 of 27
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`Biogen Exhibit 2022
`Mylan v. Biogen
`IPR2018-01403
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`Reply to Final Office Action of October 12, 2012
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`- 2 -
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`LUKASHEV et a].
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`Appl. No. 13/372,426
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`Listing of the Claims
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`The claims are listed below for the Examiner's convenience.
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`1—17.
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`(Cancelled)
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`18.
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`(Previously Presented) A method of treating a subject in need of treatment for
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`multiple sclerosis comprising orally administering to the subject in need thereof
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`a pharmaceutical composition consisting essentially of (a) a therapeutically
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`effective amount of dimethyl fumarate, monomethyl fumarate, or a combination
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`thereof, and (b) one or more pharmaceutically acceptable excipients, wherein the
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`therapeutically effective amount of dimethyl fumarate, monomethyl fumarate, or
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`a combination thereof is about 480 mg per day.
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`19.
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`(Previously Presented) The method of claim 18, wherein the pharmaceutical
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`composition is administered in the form of a tablet, a suspension, or a capsule.
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`20.
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`(Previously Presented) The method of claim 18, wherein the therapeutically
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`effective amount is administered in separate administrations of 2, 3, 4, or 6 equal
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`doses.
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`21.
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`(Previously Presented) The method of claim 20, wherein the therapeutically
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`effective amount is administered in separate administrations of 2 equal doses.
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`22.
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`(Previously Presented) The method of claim 20, wherein the therapeutically
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`effective amount is administered in separate administrations of 3 equal doses.
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`Reply to Final Office Action of October 12, 2012
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`LUKASHEV et al.
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`Appl. No. 13/372,426
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`23.
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`(Previously Presented) The method of claim 18, wherein the pharmaceutical
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`composition consists essentially of dimethyl
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`fumarate and one or more
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`pharmaceutically acceptable excipients.
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`24-.
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`(Previously Presented) The method of claim 18, wherein the pharmaceutical
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`composition consists essentially of monomethyl fumarate and one or more
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`pharmaceutically acceptable excipients.
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`25.
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`(Previously Presented) The method of claim 18, wherein the pharmaceutical
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`composition is administered to the subject for at least 12 weeks.
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`26.
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`(Previously Presented) The method of claim 23, wherein the therapeutically
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`effective amount is administered to the subject in 2 equal doses.
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`27.
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`(Previously Presented) The method of claim 26, wherein the therapeutically
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`effective amount is administered to the subject for at least 12 weeks.
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`28.
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`(Previously Presented) A method of treating a subject in need of treatment for
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`multiple sclerosis consisting essentially of orally administering to the subject
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`about 480 mg per day of dimethyl fumarate, monomethyl fumarate, or a
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`combination thereofi
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`29.
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`(Previously Presented) The method of claim 28, wherein about 480 mg of
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`dimethyl fumarate per day is administered to the subject.
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`30.
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`QPreviously Presented) The method of claim 29, wherein the dimethyl fumarate
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`is administered in separate administrations of 2 equal doses.
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`Atty. Dkt. No. 2159.3210002/IMC/MRG/U-S
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`Reply to Final Office Action of October 12, 2012
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`LUKASHEV er a].
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`Appl. No. 13/3 72,426
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`31.
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`32.
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`33.
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`34.
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`35.
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`36.
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`(Previously Presented) The method of claim 29, wherein the dimethyl fumarate
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`is administered in separate administrations of 3 equal doses.
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`(Previously Presented) A method of treating a subject in need of treatment for
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`multiple
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`sclerosis
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`comprising
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`orally
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`administering
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`to
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`the
`
`subject
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`a
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`pharmaceutical composition consisting essentially of (a) a therapeutically
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`effective amount of dimethyl fumarate and (b) one or more pharmaceutically
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`acceptable excipients, wherein the therapeutically effective amount of dimethyl
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`fumarate is about 480 mg per day.
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`(Previously Presented) The method of claim 32, wherein the dimethyl fumarate
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`is administered in separate administrations of 2 equal doses.
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`(Previously Presented) The method of claim 18, wherein the expression level of
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`NQ01 in the subject
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`is elevated after administering to the subject
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`the
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`therapeutically effective amount of dimethyl fumarate, monomethyl fumarate, or
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`a combination thereof
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`(Previously Presented) The method of claim 28, wherein the expression level of
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`NQOl in the subject is elevated after administering to the subject about 480 mg
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`per day of dimethyl fumarate, monomethyl fumarate, or a combination thereof.
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`(Previously Presented) The method of claim 32, wherein the expression level of
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`NQOl
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`in the subject
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`is elevated after administering to the subject
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`the
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`therapeutically effective amount of dimethyl fumarate.
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`Reply to Final Office Action of October 12, 2012
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`LUKASHEV et al.
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`Appl. No. 13/372,426
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`37.
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`{Previcusly Presented) A methcd of treating a subject in need of treaimem. for
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`multiple sclerosis, ccn'lprising treafing the subject in need thereof with a therapeuticaiiy
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`effective antleum, of dimetbyl fumarate, mcncmethyi fumarate? or a, ccmbinmicn thereefi
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`wherein {he
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`therapeuticafiy effective anlcunt 0f dimeihyi
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`fumamte, monemethyi
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`fmnamte, m a mmabinafior; {herecf is abcut 480 mg per day.
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`Atty. Dkt. N0. 21593210002/JMC/MRG/U-S
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`Reply to Final Office Action of October 12, 2012
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`LUKASI-IEV er a].
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`Appl. No. 13/372,426
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`Remarks
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`Claims 18-37 are pending in the application, with claims 18, 28, 32, and 37 being
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`the independent claims. Based on the following remarks, Applicants respectfully
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`request that the Examiner reconsider all outstanding objections and rejections and that
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`they be withdrawn.
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`I.
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`Summing: of the Claimed Subject Matter
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`The claimed invention is directed to methods of treating multiple sclerosis
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`("MS") which involve the administration of, or treatment of a subject with, a specific
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`daily dose of about 480 mgfiday of dimethyl fumarate ("DMF") andfor monomethyl
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`fumarate ("MMF") (a biologically active metabolite of DMF).
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`As demonstrated in two phase 3 MS clinical studies,
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`the claimed methods
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`produced unexpectedly high efficacy,
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`i.e., 480 mg/day DMF showed very similar
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`My in treating MS as 720 tug/day of DMF.
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`The magnitude of the efficacy
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`demonstrated for the 480 mg/day dose was especially unexpected and quite surprising
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`given the results of an earlier Phase 2 clinical study in which 720 mg/day of DMF
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`showed statistically significant efficacy when compared to placebo while 120 rug/day
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`and 360 mg/day of DMF did pg: exhibit statistically significant efficacy versus placebo.
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`See Applicants’ prior responses in connection with US. Patent Application No.
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`12/526,296, and the response to the first Office Action filed August 3, 2012 in the
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`instant application (collectively “the prior responses”).
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`Reply to Final Office Action of October 12, 2012
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`LUKASHEV er a1.
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`Appl. No. 13/372,426
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`II.
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`A Primer Facie Case of Obviousness Has Not Been Established
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`The Examiner maintains his obviousness rejections of claims 18-37 over U.S.
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`Patent Publication No. US 2003/0018072 to Joshi er al. (“Joshi”) and over Schirnrigk et
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`4:11., European Journal of Neurologid3:604-610 (2006) (“Schimrigk”). Applicants
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`respectfully traverse both rejections on the grounds that a prima facie case of
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`obviousness has not been adequately established. See Applicants' prior responses (see,
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`in particular, response dated August 3, 2012, page 7, line 10 to page 12, line 7).
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`As appreciated by the Examiner, neither Joshi nor Schimrigk teaches or suggests
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`using a 480 mg/day dose to treat MS. It is the Examiner’s position that a skilled person
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`in the art, based on either Joshi or Schimrigk, would have engaged in routine
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`experimentation to arrive at
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`the 480 mg/day dose as claimed,
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`thus rendering it
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`prima facie obviousness.
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`It is well established that obviousness cannot be based on
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`selectively picking and choosing from diverse teachings of references, but must be based
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`on the teachings of the prior art as a whole. See In re Dow Chemical Co., 837 F.2d 469,
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`473 (Fed. Cir. 1988) (“In determining Whether such a suggestion can fairly be gleaned
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`from the prior art, the full field of the invention must be considered; for the person of
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`ordinary skill is charged with knowledge of the entire body of technological literature,
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`including that which might
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`lead away from the claimed invention”) However,
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`considering the total knowledge available to the skilled person as of the filing date of the
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`present application, the results of the Phase 2 clinical study would not have motivated
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`the skilled person to use the 480 mg/day dose since the 720 mg/day was the dose a
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`skilled person would have expected to be most effective.
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`In light of the lack of prior art
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`Reply to Final Office Action of October 12, 2012
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`LUKASHEV et a1.
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`Appl. No. 13/372,426
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`teachings directing a skilled person to the claimed dosage (and indeed directing to a
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`higher dosage), a primafacie case of obviousness has not been established.
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`In addition, Applicants would like to address the Examiner’s understanding of
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`Schimrigk.
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`In the Final Office Action (the paragraph bridging pages 7 and 8), the
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`Examiner justifies disregarding Applicants’ remarks concerning Schimrigk’s teaching of
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`using 1290 mg/day of finnaric acid esters (FAE) because the abstract recites a “target
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`dose of 720 mg/day” in connection with the main treatment phase and a “target dose of
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`360 mg/day” in connection with the second treatment phase. The abstract does not
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`reveal to what the term “target dose” refers. The Examiner seems to be under the
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`impression that
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`the term “target dose” refers to the total daily amount of FAEs
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`administered to the MS patients. However, this conclusion is incorrect.
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`In the Schimrigk study, scientists used Fumaderm®, a medication that contains
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`DMF as well as three different monoethyl fumarate (“MEF”) salts, also referred to as
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`ethylhydrogen fumarates in the study. This is clearly stated in the paragraph under
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`“Study Drug” on page 605 with Fumaderm forte® containing 120 mg of DMF and 95
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`mg of MEF. Schimrigk further states that patients were administered up to 6 tablets of
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`Fumaderm forte® in the main treatment phase and up to 3 tablets of Furnaderm forte®
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`in the second treatment phase. See page 605, left column, last sentence of the last full
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`paragraph. Simple additions of the FAE amounts in 6 tablets of Fumaderm forte® lead
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`to 720 mg/day of DMF and 570 mg/day of MEF - a total of 1290 mg/day of FAE.
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`Schimrigk may have referred to the DMF dose in the abstract as “the target dose” as a
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`short hand notation since there was more DMF (120 mg) than MEF (95 mg) in a
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`Reply to Final Office Action of October 12, 2012
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`‘
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`LUKASI-IEV er a].
`Appl. No. 13/372,426
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`Fumaderm® tablet. But a skilled person in the art reading the entire Schimrigk
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`reference would have realized that the reference taught administration of 1290 mg/day
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`FAB.
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`Indeed, a skilled person in the art would have been aware that Fumaderm®
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`contains four active ingredients, i.e., DMF + 3 MEF salts.
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`See, ag. "Summary of
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`Product Characteristics" for Fumaderm® (also referred to herein as Furnaderm forte®,
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`"Fumaderrn") and Fumadenn® Initial, which is submitted herewith as Exhibit A. The
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`Examiner clearly acknowledges that Schimrigk teaches the use of a mixture of fumaric
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`acid esters. See, e.g., Final Office Action, page 7, lines 1-4.1 Importantly, Schimrigk
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`does not teach that the MEF salts were inert in this study. The Examiner’s conclusion
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`that the predominant active ingredient in Furnaderm is DMF appears to be unsupported
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`based on the teaching of Schirnrigk alone.
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`See Final Office Action, page 8, lines 3-5.
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`2
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`No evidence was presented as to why a skilled person in the art would have ignored the
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`presence of MEF in the Furnaderm tablets and used only DMF.
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`In summary, the Examiner has provided no rationale as to why a person of
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`ordinary skill in the art, based on Schimrigk in its entirety, would have made the
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`changes necessary to arrive at the instant invention, i.e., (l) DMF+MEF to DMF only
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`and (2) 1290 mg/day fumarates to 480 rug/day of DMF or MMF.
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`lApplicants would like to point out that Fumaderm (as used in the study described in Schimrigk)
`contains DMF and 3 different MEF (monoethylfumarate) salts, and not “methyl ethyl furnarate and diethyl
`fumarate” as stated in the Final Office Action, page 7, lines 3-4.
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`2The two most abundant active ingredients in Fumaderm are DMF and MEF, Ca salt. The ratio
`of the amount of DMF vs. MEF, Ca salt is 58% ( 120 mg) vs. 40% (87 mg). Applicants disagree that DMF
`can be considered the predominant active ingredient in a Fumaderin tablet.
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`Reply to Final Office Action of October 12, 2012
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`— 10 -
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`LUKASHEV at a].
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`Appl. No. 13/372,426
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`Contrary to the Examiner’s position and for at least the reasons stated here, as
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`well as those set forth in the prior responses, the claimed method is not prima facie
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`obvious in view of either Joshi or Schimrigk.
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`III.
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`Even if A Prima Facie Case Of Obviousness Had Been Established,
`Applicants’ Evidence of Unexneeted Results Would Overcome it
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`The Examiner acknowledges
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`"[t]he unexpected and advantageous results
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`demonstrated for the claimed method relative to the other embodiments that are
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`disclosed in the instant specification are not in dispute." See Final Office Action, page
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`3, lines 3-5. However, the Examiner continues to maintain that because “neither those
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`unexpected and allegedly advantageous results nor the particular combination now
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`claimed are described in the specification as filed” (see Final Office Action, page 3,
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`lines 5—7; emphasis original), the unexpected results cannot be used to overcome the
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`obviousness rejection. Thus, it appears that the following two issues must be addressed
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`in determining whether the unexpected results must be considered for overcoming the
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`prima facie obviousness rejections (assuming they have been established, which
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`Applicants disagree): (1) does the specification describe or reasonably convey the
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`claimed invention to a skilled person in the art? and (2) do the unexpected results have
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`to be described in the specification as filed for them to be considered?
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`A.
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`The Claimed Invention Is Described In The Specification As Filed —
`The Specification Directs a Person Of Ordinary Skill To The
`Claimed Invention
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`AS summarized below, the Specification contains ample teachings directing a
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`person of ordinary skill in the art to the claimed invention (treating MS with DMF/MMF
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`using a 480 mg/day dose).
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`It is well settled that when considering whether a claimed
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`Reply to Final Office Action of October 12, 2012
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`- 11 -
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`LUKASHEV et a].
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`Appl. No. 13/372,426
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`invention is described in the specification, the totality of the teaching of the application
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`must be considered (see, e. g., In re Dow Chemical Co., supra).
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`1.
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`The Sgecitzjcation Focuses 0n Treating MS with DMF and/0r
`MMF
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`The Examiner indicates that MS is disclosed in the description only in the
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`context of a long list of neurological diseases and that the description does not disclose
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`"a particular advantage to applying the method described therein to MS." See Final
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`Office Action, the paragraph bridging pages 3-4. Contrary to the Examiner's assertion,
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`MS is singled out throughout the specification and is clearly not just one of many
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`diseases in a long laundry list of diseases.
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`In fact, paragraphs [0001] to [0004] of the background section are explicitly
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`directed to MS, as well as treatments of MS available as of the filing date. Additionally,
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`the abstract lists MS as the sole exemplary disease to be treated. The application also
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`specifically discloses that the neurological disease can be MS.
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`See, e. 5;, page 4,
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`paragraph [0010] and page 25, paragraph [0104].
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`Furthermore, paragraph [0032]
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`explains DMF’s neuroprotective nature and activation of Nrf2 pathway help form the
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`rationale for its effective treatment of neurological disorders such as MS. Additionally,
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`the one animal disease model disclosed in the specification to test the effect of DMF and
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`MMF is a generally accepted mouse model ofm, known as Experimental Autoimmune
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`Encephalomyelitis (EAE). See, e.g., pages 26-27, paragraphs [1081-[0110] and Example
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`3.
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`There is well—established case law holding that guidance or so-called “blaze
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`marks” contained in the originally filed disclosure, which direct the skilled artisan t0 the
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`Reply to Final Office Action of October 12, 2012
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`- 12 —
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`LUKASHEV er 01.
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`Appl. No. 13/372,426
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`claimed invention, are sufficient to describe the claimed invention and to reasonably
`
`convey to a person of skill in the art that Applicants had possession of the invention.
`
`See, 3.3., In re Ruschig, 379 F.2d 990, 154 U.S.P.Q. 118 (C.C.P.A. 1967) and Purdue
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`Pharma LP. v. Faulding Inc, 230 F.3d 1320, 56 U.S.P.Q. 2d 1481 (Fed. Cir. 2000).
`
`The Court in Purdue notes that “[t]he blaze marks directing the skilled artisan to [the
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`claimed invention] must be in the originally filed disclosure.” Purdue, 230 F.3d at
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`1326-1327.
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`There are a number of blaze marks in the instant specification which clearly
`
`direct a person of ordinary skill in the art to use DMF and/or MMF in treating MS. For
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`example, Applicants disclose (i) a method (method 4) comprising administering to a
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`mammal a therapeutically effective amount of at least one neuroprotective compound,
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`e.g., DMF or MMF (see, page 13, paragraph [0063]) and (ii) a specific embodiment of
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`neurological disease being MS (see, page 4, paragraph [0010]).
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`Therefore, Applicants respectfully submit
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`that, contrary to the Examiner’s
`
`contention, treatment of MS with DMF and/or MMF is specifically singled out and
`
`described in the present application.
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`2.
`
`The Specification Teaches The Claimed Dose of 480 mgdag
`DMF and/or MMF
`
`The Examiner asserts that "the specification, as filed, fails to demonstrate, or
`
`even predict, any particular advantage to be realized from the administration of a dosage
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`of 480 mg/day of DMF .
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`.
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`. to an individual suffering from MS." See Final Office
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`Action, page 4, lines 18—21. The Examiner further states that "the instant specification,
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`as filed, fails to suggest any specific daily dosage of DMF or MMF that had been shown
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`LUKASHEV et a].
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`Appl. No. 13/372,426
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`or could reasonably be predicted to be effective in the treatment of MS in particular. Id.
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`at page 5, lines 12-14. Applicants respectfully disagree with the Examiner and submit
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`that the specific dose of 480 mg/day is clearly conveyed in the specification to a skilled
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`person in the art.
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`The specification discloses a limited number of progressively narrowing
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`effective dose ranges of DMF or MMF and discloses the 480 to 720 mg/day dosage
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`range as the narrowest range for the treatment of a patient with a neurodegenerative
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`disease (see page 30, paragraph [0116]). As set forth above, MS is a neurodegenerative
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`disease that is specifically singled out in the specification. Therefore, for at least these
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`reasons and those discussed above, it is clear that the specification describes and directs
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`a skilled person in the art to the claimed combination (i.e., using 480 mg/day DMF
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`and/or MMF to treat MS). See, e.g., In re Wertheim, 541 F.2d 257, 191 U.S.P.Q. 90
`
`(C.C.P.A. 1976).
`
`B. Unexpected Results or Advantages That Inherently Flow From A
`Claimed Invention Must Be Given Significant Weight
`
`As mentioned above, even though the Examiner acknowledges the unexpected
`
`and advantageous results demonstrated for the claimed method, he nevertheless
`
`maintains the obviousness rejections on the basis that such unexpected results are not
`
`described in the specification as filed (see Final Office Action, page 3,
`
`lines 3-5).
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`Contrary to the Examiner’s position,
`
`the law is clear that unexpected results or
`
`advantages need not be disclosed in the specification as filed. So long as the advantages
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`or unexpected results inherently flow from the claimed invention described in the
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`Reply to Final Office Action of October 12, 2012
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`LUKASHEV 92‘ al.
`Appl. No. 13/372,426
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`specification,
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`substantial weight must be given to them in the obviousncss
`
`determination.
`
`In support of his position, the Examiner relied on two cases, In re Lundberg, 253
`
`F.2d 244, 117 U.S.P.Q. 190 (C.C.P.A. 1958) and In re Chu, 66 F.3d 292, 36 U.S.P.Q.Zd
`
`1089 (Fed. Cir. 1995). However, neither case supports the Examiner’s position that
`
`unexpected results or advantages of a claimed invention must be found in the
`
`specification to be considered.
`
`In the Lundberg case, While it is true that the asserted advantages or unexpected
`
`results were not disclosed in the specification and they were not given weight, the reason
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`they were not given weight was that they did not flow from the claimed invention as
`
`disclosed in the specification. Rather, they flowed from a feature of an invention that
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`was not described in the specification.
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`In re Lundberg, 253 F.2d at 247.
`
`In marked
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`contrast, the unexpected results or advantages of the instant invention inherently flow
`
`from an invention that was disclosed in the specification as filed, i.e., 480 mg/day DMF
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`to treat MS. As such, the unexpected results or advantages presented in the instant case
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`must be considered. The Lundberg case is clearly distinguishable from the present case.
`
`The Examiner’s reliance on the Char case is equally misplaced.
`
`In Chu, to
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`overcome an obviousncss rejection, the applicant presented advantages that had not been
`
`disclosed in the specification that were based on the location of the catalyst. The Board
`
`in Chu, like the Examiner in the present case, justified its rejection by stating Chu’s
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`“specification is virtually silent on the matter of any purported advantage to locating the
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`catalyst within the bag retainer” and “does not state that the claimed location of the
`
`Atty. Dkt. N0. 2159.3210002/JMC/MRG/U—S
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`Reply to Final Office Action of October 12, 2012
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`LUKASHEV et al.
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`Appl. No. 13/372,426
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`catalyst “inside the bag retainer” solves any particular problem or produces any
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`unexpected result.” While the location of the catalyst in In re Chu was disclosed, its
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`“criticality” was not disclosed. Both the examiner and Board in that case found the
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`location to be a “design choice.” The Board concluded that the specification was
`
`“virtually silent on the matter of any purported advantage” of the location. In re Chu, 66
`
`F.3d 292, 298 (Fed. Cir. 1995). The Federal Circuit, however, rejected the Board’s
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`holding that advantages must be contained Within the specification in order for them to
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`be considered.
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`In the instant case, the Examiner distinguishes the present case and justifies not
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`giving weight to the unexpected results submitted by the Applicants post-filing by
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`stating that “the instant
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`specification does not disclose the criticality of the
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`limitations...nor does
`
`it
`
`identify the claimed combination as being particularly
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`advantageous...” (see Final Office Action, page 6, lines 9-13). First, nowhere in Chu
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`did the Court state that criticality of a claimed feature must be contained in the
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`specification.
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`In fact, the Court in Chu simply stated that evidence andfor arguments to
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`rebut an obviousness rejection do not need to be disclosed in the specification.
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`Id. at
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`299. Further, the Court explicitly rejected the Board’s requirement that the specification
`
`must disclose an advantage of the claimed feature to be considered.
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`Thus,
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`the
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`Examiner’s justification for requiring the specification to disclose criticality or to
`
`identify advantageous features of the claimed invention is unsupported.
`
`In fact,
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`Applicants emphasize the guidance outlined in the MPEP 716.02(fl: “[t]he Specification
`
`need not disclose progertions or values as critical for applicants to present evidence
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`Atty. Dkt. No. 2159.3210002/11VlC/MRG/U—S
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`Reply to Final Office Action of October 12, 2012
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`- 16 —
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`LUKASHEV et (1!.
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`Appl. No. 13/372,426
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`showing the proportions or values to be critical. In re Saunders, 444 F.2d 599, 607, 170
`
`USPQ 213, 220 (CCPA 1971 ),, (emphasis added).
`
`Based on the relevant section in the MPEP and the case law discussed above, it is
`
`clear that unexpected results or advantages or criticality of a claimed feature do not need
`
`to be disclosed in the specification to be considered. The Examiner must therefore give
`
`substantial weight to the unexpected results, which flow inherently from the claimed
`
`invention of using the 480 mg/day of DMF to treat MS.
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`IV.
`
`Addressing the Examiner’s Remaining Reasons For Maintaining The
`Obviousness Rejection
`
`In the Final Office Action,
`
`the Examiner states that
`
`in his View the true
`
`unexpectedness of the instant rejection resides in the inoperability of a majority of
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`embodiments disclosed in the specification. See Final Office Action, page 3, lines 3-10.
`
`As discussed in the Applicants’ response to the Office Action filed August 3, 2.012, the
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`Examiner’s position is unsupported and no evidence or argument was presented in the
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`Finai Office Action to address Applicants’ rebuttal. As pointed out in Applicants
`
`previous response, the unexpectedness of the instant invention is the magnitude of the
`
`effect of the 480 trig/day dose and not simply that the dose is efficacious as expressed by
`
`the Examiner (see Final Office Action, page 3, lines 7-8). Further, no reason was given
`
`as to Why the operability of an unclaimed species would be relevant to the patentability
`
`of the claimed invention.
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`In the instant case, the unexpected results flow inherently
`
`from the claimed invention, and that should be the focal point in determining whether
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`the obviousness rejection has been overcome.
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`Reply to Final Office Action of October 12, 2012
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`LUKASI-IEV et a].
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`Appl. No. 13/372,426
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`V.
`
`Summary
`
`Based on the reasons set forth above and those presented in Applicants” prior
`
`responses, Applicants submit that the present claims are patentable over the art of
`
`record. Applicants respectfully request the Examiner reconsider the rejections in the
`
`Final Office Action.
`
`Conclusion
`
`All of the stated grounds of objection and rejection have been properly traversed,
`
`accommodated, or rendered moot. Applicants therefore respectfully request that the
`
`Examiner reconsider all presently outstanding objections and rejections and that they be
`
`Withdrawn. Applicants believe that a full and complete reply has been made to the
`
`outstanding Office Action and, as such,
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`the present application is in condition for
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`allowance.
`
`If the Examiner believes, for any reason, that personal communication will
`
`expedite prosecution of this application,
`
`the Examiner is invited to telephone the
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`undersigned at the number provided.
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`Prompt and favorable consideration of this Amendment and Reply is respectfiilly
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`requested.
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`Atty. Dkt. No. 2159.3210002/JMC/MRG/U—S
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`Reply to Final Office Action of October 12, 2012
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`LUKASHEV et a1.
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`Appl. No. 13/372,426
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`Respectfully submitted,
`
`STERNE, KESSLER, GOLDSTEIN & Fox P.L.L.C.
`
`7AM
`
`Jo
`
`. Covert
`
`A omey for Applicants
`Registration No. 38,759
`
`Date: December 12 2012
`
`l 100 New York Avenue, N.W.
`
`Washington, D.C. 20005—3934
`(202) 3 71-2600
`
`1621047_1.DOCX
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`Atty. Dkt. No. 2159.3210002/JMC/MRGfU-S
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`

`

`EXHEBIT A
`
`Page 19 of 27
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`Page 19 of 27
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`

`

`Summary of Product Characteristics
`
`Fumaderm® Initial
`
`Fumaderm®
`
`1.
`
`2.
`
`Name of the medicinal product
`Fumaderm Initial
`Fumaderm
`
`Qualitative and quantitative composition
`The active ingredients of Fumaderm Initial and Fumaderm are:
`Dimethyl fumarate;
`Ethyl hydrogen fumarate, calcium salt;
`Ethyl hydrogen fumarate, magnesium salt;
`Ethyl hydrogen fumarate, zinc salt.
`
`‘I gastro—resistant tablet contains:
`
`
`
`
`
`
`
`
`——_
`
`
`———Zinc salt
`
`Calcium salt
`
`Ma-nesium salt
`
`67 m
`
`5 m-
`
`3 m-
`
`87 m
`
`-
`
`3 m-
`
`3.
`
`4.
`
`4.1
`
`For excipients, see section 6.1
`
`Pharmaceutical Form
`Gastro-resistant tablet for oral use.
`
`Clinical Particulars
`
`Therapeutic Indications
`Fumaderm initial:
`
`Indicated to improve patient tolerability to Fumaderm therapy during the start-up phase.
`
`Fumaderm:
`
`Indicated for the treatment of severe forms of plaque psoriasis (Psoriasis vuigaris), in cases where
`previous, externally applied, stand-alone treatments have failed. Prior to administration, patient
`tolerability must firstly be reinforced by treatment with Fumaderm Initial (q.v.).
`
`4.2
`
`Posology and method of administration
`Fumaderm Initial:
`
`Unless otherwise prescribed, dosage instructions are as follows:
`
`In reaching the optimal efficacy and tolerability profile, dose escalation should be gradual. During
`the first week of treatment,
`1 gastro-resistant Fumaderm Initial tablet should be taken once daily
`(evenings). During Week 2, this daily dose should be increased to 2 gastro—resistant Fumaderm
`Initial tablets (1 x mornings and 1 x evenings). During Week 3 (daily dose = 3 gastro—resistant
`
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`

`

`tablets has finished,
`tablets), as soon as the course of Fumaderm Initial
`Fumaderm Initial
`treatment should be immediately switched over to Fumaderm, viz. at an initial daily dose of ‘l
`gastro-resistant Fumaderm tablet once daily (evenings).
`
`i(
`
`DW
`
` M
`
`
`
`LONA
`
`
`
`Unless otherwise prescribed, dosage instructions are as follows:
`Following pre-treatment with Fumaderm Initial to increase tolerability, treatment should be switched over
`to Fumaderm during the third week of treatment.
`During the first week of treatment with Fumaderm, 1 gastro-resistant Fumaderm tablet should be taken
`once daily (evenings). Depending on individual
`tolerability,
`this daily dosage should be increased in
`weekly increments (i.e. by one gastro-resistant Fumaderm tablet per week), according to the following
`chart:
`
`
`
`venin-s
`
`E 1 1 1 2 2 2
`
`Lunchtimes
`
`The maximum daily dosage of 3 x 2 gastro-resistant Fumaderm tablets must not be exceeded. However,
`in most cases, administration of this maximum daily dosage is not needed. Clinical experience has shown
`that the initial therapeutic effects are noticed within 4 — 6 weeks of treatment.
`When skin reactions subside, daily dosage should be reduced gradually until the individual maintenance
`dose is reached. Fumaderm gastro—resistant tablets should be swallowed whole (not chewed) with plenty
`of liquid during or immediately after a meal. Patients should be advised to drink sufficient amounts of
`water during the day (11/5 - 2 litres). Duration of treatment is left up to the discretion of the treating
`physician. Adequate experience gained during clinical
`trials would suggest a treatment