throbber
Exhibit A (Curriculum Vitae for Katherine T. Dawson -------- pages 38 - 43
`
`Exhibit B (Kappos, L., el al., "Efficacy and safety of oral fumarate
`in patients with relapsing-remitting multiple sclerosis: a multicenter,
`randomised, double--blind, placebo--controlled phase IIIb study,"
`Lancet 372: 1463-72 (2008) ----------------------------------------- pages 44 - 54
`
`Exhibit C (Kappos, L., et al., "Efficacy of a novel oral single-agent
`fumarate, BG00012, in patients with relapsing-remitting
`multiple sclerosis: results of a phase 2 study* 16th Meeting
`of the European Neurological Society (May 30, 2006)
`(Slide Presentation)) -------------------------------------------------- pages 56 - 57
`
`Exhibit D (Kappos, L., et al., "Efficacy of a novel oral single-agent
`Fumarate, BG00012, in patients with relapsing-remitting multiple
`sclerosis: results of a phase II study," 16th Meeting of the European
`Neurological Society (May 30, 2006)
`(Abstract to the Presentation) --------------------------------------- pages 78 - 79
`
`Exhibit E ("Oral Compound BG-12 Achieves Primary Endpoint
`in Phase II Study of Relapsing-Remitting MS with BG-12 Led to
`Statistically Significant Reductions in MRI Measures,"
`Biogen Idec News Release (May 30, 2006)) ---------------------- pages 80 - 82
`
`Table of Contents For Ex. 1007A
`Amendment ------------------------------------------------------------------ pages 2 - 13
`Exhibit 1 (Declaration of Katherine T. Dawson,
`M.D. Under 37 C.F.R. § 1.132) ------------------------------------------- pages 14 – 35
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Exhibit 2 (Press Release Details) --------------------------------------------pages 83 - 86
`
`Transmittal letter -------------------------------------------------------------- page 87
`
`
`
`
`
`Page 1 of 87
`
`Biogen Exhibit 2015
`Mylan v. Biogen
`IPR2018-01403
`
`

`

`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re application of:
`
`LUKASHEV et al.
`
`Confirmation No.: To be assigned
`
`Art Unit: To be assigned
`
`Appl. No.: To be assigned
`
`(Continuation of Appl. No. 121526,296,
`
`§ 371 (c) Date: January 13, 2011)
`
`Examiner: To be assigned
`
`Filing Date: Herewith
`
`Atty. Docket: 2159.3210002/JMC/MRG/u-S
`
`For: Treatment for Multiple Sclerosis
`(As Amended)
`
`Prelhninary Ameruhnent Under 37 C.F.R. § 1.115
`
`Commissioner for Patents
`PO Box 1450
`Alexandria, VA 22313-1450
`
`Sir:
`
`In advance of prosecution, Applicants submit the following amendments and
`
`remarks.
`
`Amendments to the Specification begin on page 2 of this paper.
`
`Amendments to the Claims are reflected in the listing of claims which begins on
`
`page 3 of this paper.
`
`Remarks and Arguments begin on page 6 of this paper.
`
`It is not believed that extensions of time or fees for net addition of claims are
`
`required beyond those that may otherwise be provided for in documents accompanying
`
`this paper. However, if additional extensions of time are necessary to prevent
`
`abandonment of this application, then such extensions of time are hereby petitioned
`
`under 37 C.F.R. § 1.136(a), and any fees required therefor (including fees for net
`
`addition of claims) are hereby authorized to be charged to our Deposit Account No.
`
`19-0036.
`
`Page 2 of 87
`
`

`

`- 2-
`
`LUKASHEVet ai.
`Appl. No. To be assigned
`
`Amendments to the Specification
`
`Please amend the title as follows:
`
`eompositiOflS
`
`Please amend paragraph [0128], beginning on page 33, line 21, as follows:
`
`[0128]
`
`Immunohistochemistry was performed using the Dakoautostainer as
`
`follows. Endogenous peroxidase was quenched by a 10 minute incubation in 3% H202 1
`
`Methanol. The rabbit anti Nrf2 antibody C-20 (sc-722, Santa Cruz Biotechnology) was
`
`added at a 1 :250 dilution in Dako Diluent with Background Reducing Components
`
`(Dako # S3022) C-20 antibody was detected using the Envision anti rabbit labeled
`
`polymer-HRP (Dako #K4003) and DAB (Vector Labs #SK-4100) was used as the
`
`chromogenic substrate. Morphometric analysis of Nrf2 immunostaining was performed
`
`On page 1, below the title of the invention, please add the following new paragraph:
`
`CROSS REFERENCE TO RELATED APPLICATIONS
`
`This application is a continuation of U.S. Patent Application No. 12/526,296,
`
`§ 371(c) Date January 13, 2011, now pending, which is the U.S. National Phase of
`
`International Application No. PCTIUS2008/001602, filed February 7, 2008, which
`
`claims the benefit of U.S. Provisional Application 60/888,921, filed February 8,2007.
`
`Atty. Dkt. No. 21593210002/JMC/MRGIU-S
`
`Page 3 of 87
`
`

`

`- 3-
`
`LUKASHEVet al.
`Appl. No. To be assigned
`
`Amendments to the Claims
`
`This listing of claims will replace all prior versions, and listings, of claims in the
`
`application.
`
`1-17.
`
`(Cancelled)
`
`18.
`
`(New) A method of treating a subject in need of treatment for multiple sclerosis
`
`comprising orally administering to the subject in need thereof a pharmaceutical
`
`composition consisting essentially of (a) a therapeutically effective amount of
`
`dimethyl fumarate, monomethyl fumarate, or a combination thereof, and (b) one
`
`or more pharmaceutically acceptable excipients, wherein the therapeutically
`
`effective amount of dimethyl fumarate, monomethyl fumarate, or a combination
`
`thereof is about 480 mg per day.
`
`19.
`
`(New) The method of claim i8, wherein the pharmaceutical composition is
`
`administered in the form of a tablet, a suspension, or a capsule.
`
`20.
`
`(New) The method of claim 18, wherein the therapeutically effective amount is
`
`administered in separate administrations of 2, 3, 4, or 6 equal doses.
`
`21.
`
`(New) The method of claim 20, wherein the therapeutically effective amount is
`
`administered in separate administrations of 2 equal doses.
`
`22.
`
`(New) The method of claim 20, wherein the therapeutically effective amount is
`
`administered in separate administrations of 3 equal doses.
`
`23.
`
`(New) The method of claim 18, wherein the pharmaceutical composition consists
`
`essentially of dimethyl fumarate and one or more pharmaceutically acceptable
`
`excipients.
`
`Atty. Dkt. No. 2159.3210002/JMCIMRGIU-S
`
`Page 4 of 87
`
`

`

`- 4-
`
`LUKASHEVet al.
`Appl. No. To be assigned
`
`24.
`
`(New) The method of claim 18, wherein the pharmaceutical composition consists
`
`essentially of monomethyI fumarate and one or more pharmaceutically acceptable
`
`excipients.
`
`25.
`
`(New) The method of claim 18, wherein the pharmaceutical composition IS
`
`administered to the subject for at least 12 weeks.
`
`26.
`
`(New) The method of claim 23, wherein the therapeutically effective amount is
`
`administered to the subject in 2 equal doses.
`
`27.
`
`(New) The method of claim 26, wherein the therapeutically effective amount is
`
`administered to the subject for at least 12 weeks.
`
`28.
`
`(New) A method of treating a subject in need of treatment for multiple sclerosis
`
`consisting essentially of orally administering to the subject about 480 mg per day
`
`of dimethyl fumarate, monomethyl fumarate, or a combination thereof.
`
`29.
`
`(New) The method of claim 28, wherein about 480 mg of dimethyl fumarate per
`
`day is administered to the subject.
`
`30.
`
`(New) The method of claim 29, wherein the dimethyl fumarate is administered in
`
`separate administrations of2 equal doses.
`
`31.
`
`(New) The method of claim 29, wherein the dimethyl fumarate is administered in
`
`separate administrations of 3 equal doses.
`
`32.
`
`(New) A method of treating a subject in need of treatment for multiple sclerosis
`
`comprising orally administering to the subject a pharmaceutical composition
`
`consisting essentially of (a) a therapeutically effective amount of dimethyl
`
`fumarate and (b) one or more pharmaceutically acceptable excipients, wherein
`
`Atty. Dkt. No. 2159.3210002/JMC/MRGIU-S
`
`Page 5 of 87
`
`

`

`- 5-
`
`LUKASHEVet al.
`Appl. No. To be assigned
`
`the therapeutically effective amount of dimethyl fumarate is about 480 mg per
`
`day.
`
`33.
`
`(New) The method of claim 32, wherein the dimethyl fumarate is administered in
`
`separate administrations of2 equal doses.
`
`34.
`
`(New) The method of claim 18, wherein the expression level of NQOl in the
`
`subject is elevated after administering to the subject the therapeutically effective
`
`amount of dimethyl fumarate, monomethyl fumarate, or a combination thereof.
`
`35.
`
`(New) The method of claim 28, wherein the expression level of NQOl in the
`
`subject is elevated after administering to the subject about 480 mg per day of
`
`dimethyl fumarate, monomethyl fumarate, or a combination thereof.
`
`36.
`
`(New) The method of claim 32, wherein the expression level of NQOl in the
`
`subject is elevated after administering to the subject the therapeutically effective
`
`amount of dimethyl fumarate.
`
`Atty. Dkt. No. 2159.3210002!JMCIMRGIU-S
`
`Page 6 of 87
`
`

`

`- 6-
`
`Remarks
`
`LUKASHEVet al.
`Appl. No. To be assigned
`
`Upon entry of the foregoing amendment, claims 18-36 are pending III the
`
`application, with claims 18,28, and 32 being the independent claims.
`
`Claims 1-17 are sought to be cancelled without prejudice or disclaimer thereof.
`
`New claims 18-36 are sought to be added. Support for claims 18-36 is set forth in
`
`Section I below.
`
`I.
`
`Summan' of the Claimed Subiect Matter
`
`The claimed invention is generally directed to methods of orally treating multiple
`
`sclerosis (MS). MS is a chronic disease for which only a limited number of disease-
`
`modifying treatment options are currently available, most of which are administered by
`
`injection. Only one disease-modifying oral drug has been approved in the United States
`
`and that has only recently been approved. In addition, not all MS drugs are indicated for
`
`every MS patient. Furthermore, patients must carefully weigh the risks associated with
`
`each drug at a given disease state. It is very clear that additional medications are needed
`
`to provide better life quality and reduced risk of disability for MS patients. Oral MS
`
`medications with favorable safety profiles are particularly desired. Applicants' invention
`
`satisfies this desire.
`
`Applicants disclose a method for treating a neurological disease with at least one
`
`fumaric acid derivative, including dimethyl fumarate (DMF) or mono methyl fumarate
`
`(MMF), as "method 4" in paragraph [0009], lines 9-11 and paragraphs [0062-0063] of
`
`the specification.
`
`The application discloses that "[Un some embodiments
`
`the
`
`neurological disease
`
`is MS or another demyelinating neurological disease."
`
`Atty. Dkt. No. 21593210002/JMC/MRG/u-S
`
`Page 7 of 87
`
`

`

`- 7-
`
`LUKASHEVet ai.
`Appl. No. To be assigned
`
`(Specification, p. 4, paragraph [0010D (emphasis added). Applicants also discussed a
`
`MS animal model, Experimental Autoimmune Encephalomyelitis (EAE), in paragraphs
`
`[0108] and [0109J, as well as Example 3. Therefore, MS is supported in the application.
`
`Additionally, Applicants disclose that DMF and/or MMF are effective in treating
`
`MS. For example, DMF and MMF are listed as specific examples of neuroprotective
`
`compounds.
`
`(Specification, p. 13, paragraph [0063 j.) 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
`
`neuroproiective compound which has Formula I, II, III, or
`
`IV, e.g., a fumaric acid derivative (e.g., DMF or MMF).
`
`(Jd.) As such, DMF and MMF are specifically named in the application as compounds
`
`effective in treating neurological diseases such as MS. Furthermore, the dosages
`
`disclosed in paragraph [0116] of the application refer to the specific compounds "DMF"
`
`and "MMF". Accordingly, Applicants teach that DMF and MMF are effective in treating
`
`MS.
`
`Applicants also disclose that orally administering 480 mg per day of DMF and/or
`
`MMF is effective in treating MS. (Specification, p. 30, paragraph [0116].) Specifically,
`
`the specification discloses that
`
`[a]n effective dose of DMF or MMR [sic]
`
`to be
`
`administered to a subject orally can be from about 0.1 g to
`
`1 g per pay [sic], 200 mg to about 800 mg per day (e.g.,
`
`Atty. Dkt. No. 21593210002IJMC/MRG/U-S
`
`Page 8 of 87
`
`

`

`- 8-
`
`LUKASHEVet al.
`Appl. No. To be assigned
`
`from about 240 mg to about 720 mg per day; or from
`
`about 480 mg to about 720 mg per day; or about 720 mg
`
`per day).
`
`(Id.) (emphasis added). Because Applicants teach 480 to 720 mg/day, and further
`
`disclose this dosage range as the most narrow range, it is clear that Applicants describe
`
`orally administering 480 mg DMF daily to treat MS. See, e.g., In re Wertheim, 541 F.2d
`
`257, 191 U.S.P.Q. 90 (C.C.P.A. 1976).
`
`The specification further discloses that the daily dose of DMF and/or MMF can
`
`be administered in 2,3,4, or 6 equal doses. See, e.g., Specification, pp. 29-30, paragraph
`
`[0116] ("[FJor example, the 720 mg per day may be administered in separate
`
`administrations of2, 3, 4, or 6 equal doses.") It is clear from the entire paragraph [0116]
`
`that, although the above citation from the specification refers to 720 mg/day as an
`
`example, the disclosure of multiple separate administrations equally applies to other
`
`dosages, e.g., the 480 mg/day dose.
`
`The specification further discloses that the expression level of NQO 1 is elevated
`
`in vivo after administration ofDMF or MMF. See, e.g., original claims 1, 5, and 11; p. 2,
`
`paragraph [0006]; pp. 4-5, paragraph [0012]; pp. 22-23, paragraph [0092]; p. 31,
`
`paragraph [0122], Example 1, Figure 1; p. 31-32, paragraph [0123], Example 2, Figure 2.
`
`Accordingly, Applicants disclose
`
`treating a subject with MS by orally
`
`administering 480 mg/day DMF and/or MMF to the subject.
`
`Applicants' claimed method involves the oral administration of a specific daily
`
`dose of about 480 mg/day of dimethyl fumarate (DMF) and/or monomethyl fumarate
`
`(MMF) (the physiologically active metabolite of DMF). The claimed method has been
`
`Atty. Dkt. No. 2159.3210002/JMC/MRGIU-S
`
`Page 9 of 87
`
`

`

`- 9-
`
`LUKASHEVet al.
`Appl. No. To be assigned
`
`proven effective for the treatment of MS in human patients in two large-scale Phase 3
`
`clinical studies (further discussed herein below). Quite surprisingly, it was found in
`
`those clinical studies that the 480 mg/day dose is just as effective in treating MS as a
`
`higher dose of 720 mg/day DMF. This is especially unexpected given the results of a
`
`Phase 2 clinical study in which a dose of 720 mg/day DMF, but not a 360 mg/day DMF
`
`dose, was found to be effective.
`
`II.
`
`Patentabilitv of the Claimed Invention
`
`The prior art teaches that certain autoimmune diseases (e.g., MS) can be treated
`
`with fumarates (e.g., DMF). See e.g., U.S. Patent Publication No. 2003/0018072 to Joshi
`
`et al. ("Joshi") and Schimrigk et al., European Journal of Neurology 2006, 13(6):604-
`
`610 ("Schimrigk"). However, the prior art does not teach or suggest a dose consisting
`
`essentially of about 480 mg/day of DMF and/or MMF. Needless to say, the prior art
`
`does not mention the efficacy of the 480 mg/day dose.
`
`As mentioned above, it is unexpected that the dose of about 480 mg/day DMF
`
`was similarly effective compared to the higher dose of about 720 mg/day. The evidence
`
`of these unexpected results are provided in a declaration under 37 CFR § 1.132 of
`
`Katherine T. Dawson, M.D. ("Declaration") previously filed on October 13, 2011, in
`
`U.S. Patent Application No. 12/526,296, submitted herewith as Exhibit 1.
`
`Biogen Idec MA Inc. ("Biogen Idec"), the assignee of the current application,
`
`recently completed two pivotal Phase 3 placebo-controlled, double-blind, clinical
`
`studies, "the DEFINE study" and "the CONFIRM study", which evaluated the
`
`investigational oral drug candidate BG-12 (DMF as the only active ingredient) to treat
`
`relapsing-remitting MS (RRMS).
`
`Atty. Dkt. No. 21593210002/JMC/MRG/u-S
`
`Page 10 of 87
`
`

`

`- 10-
`
`LUKASHEVet al.
`Appl. No. To be assigned
`
`Results of the DEFINE study are depicted in Figures 4-11 and Table 2 of the
`
`Declaration. The results of the DEFINE study indicate that the dose of 480 mg/day
`
`unexpectedly demonstrated significant efficacy on MS disease activity as measured by
`
`the key clinical and MRI disease activity endpoints. (Declaration, pages 11-18, Figures
`
`4-11; and page 20, Table 2.) Even more unexpected was the magnitude of the treatment
`
`effect. Given that the dose typically impacts the efficacy, it was quite surprising that the
`
`480 mg/day dose demonstrated similar efficacy to the higher 720 mg/day dose on both
`
`clinical and MRI measures of MS disease activity·" with a high level of statistical
`
`significance. (Id. at page 19, paragraphs 13-15; and page 20, Table 2.)
`
`Furthermore, the results of the second Phase 3 study (CONFI~) support the
`
`first Phase 3 study. See Exhibit 2, which states "[ r Jesuits of the CONFIRM study
`
`showed that 240 mg of BG-12, administered either twice a day (BID) or three times a
`
`day (TID), demonstrated significant efficacy and favorable safety and tolerability
`
`profiles. Further analyses of the CONFIRM study are ongoing .... "
`
`Therefore, the results of the DEFINE and CONFIRM studies indicate that the 480
`
`mg/day DMF dose demonstrates efficacy in the DEFINE study, meeting all measured
`
`endpoints with a high level of statistical significance.
`
`(See Declaration, page 16,
`
`paragraph 16; see Exhibit 2.) Not only was the 480 mg/day DMF dose efficacious, but
`
`measures of Mp disease activitI .. J!§._2.2.Q .. _Qlg::g~jLJ2ME. (See Declaration, page 15,
`
`paragraph 15.)
`
`Atty_ Dkt. No. 21593210002/JMCIMRGIU-S
`
`Page 11 of 87
`
`

`

`- 11-
`
`LUKASHEVet al.
`Appl. No. To be assigned
`
`III.
`
`The Unexliected Jtesults ~ust_Be Given Substantial Weight: There is a
`Nexus Between the Supported Claims 18-36 and the Unexpected Results of
`the DEFINE and CONFIRM Studies
`
`Unexpected results of the claimed invention do not need to be included in the
`
`specification for an Examiner to consider them. The MPEP at 716.01(b) states that "[t]o
`
`be given substantial weight in the determination of obviousness or nonobviousness,
`
`evidence of secondary considerations must be relevant to the subject matter as claimed,
`
`and therefore the examiner must determine whether there is a nexus between the merits
`
`of the claimed invention and the evidence of secondary considerations." (emphasis
`
`added). Thus, according to the MPEP, the Examiner must consider whether there is a
`
`nexus between the claimed invention and the unexpected results.
`
`As mentioned above, the application teaches and fully supports the claimed
`
`invention of treating MS using DMF and/or MMF at a dose of 480 mg/day. Thus, the
`
`data from the DEFINE and CONFIRM clinical studies, which flow inherently from the
`
`claimed invention, must be given substantial weight when considering the patentability
`
`of claims 18-36.
`
`IV.
`
`Summary
`
`Based on the reasons set forth above, Applicants respectfully submit that the
`
`present claims are patentable.
`
`Atty. Dkt. No. 2159.3210002/JMCIMRG/U-S
`
`Page 12 of 87
`
`

`

`- 12-
`
`LUKASHEVet at.
`Appl. No. To be assigned
`
`Conclusion
`
`Prompt and favorable consideration of this Preliminary Amendment
`
`is
`
`respectfully requested. Applicants believe the present application is in condition for
`
`allowance. If the Examiner believes, for any reason, that personal communication will
`
`expedite prosecution of this application, the Examiner is invited to telephone the
`
`undersigned at the number provided.
`
`Respectfully submitted,
`STERNE, KESSLER, GOLDSTEIN & Fox P.L.L.C.
`(l~~~t:;,,·""t"'-..
`
`~
`
`Marsha A. Rose
`Attorney for Applicants
`Registration No. 58,403
`
`1100 New York Avenue, N.W.
`Washington, D.C.20005-3934
`(202) 371-2600
`
`1481215_l.DOCX
`
`Atty. Dkt. No. 2159.3210002/JMCIMRG/U-S
`
`Page 13 of 87
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`

`

`Exhibit 1
`
`Page 14 0f 87
`
`Page 14 of 87
`
`

`

`IN THE UNITED STATES PATENT AND TRADEl\'1ARK OFFICE
`
`In re application of:
`
`ConfirmationNo,: 5197
`
`LUKASHEV, Matvey E.
`
`Art Unit
`
`1649
`
`Appl. No. 12/526,296
`
`Examiner:
`
`l.Hm, John D.
`
`§ 37l(c) Date: January 13, 2011
`
`Atty. Docket: 2159.321000l/JMCiM-RJU-S
`
`For: Treatment for .Multiple Sclerosis
`(As Amended)
`
`Declaration of Katherine T. Dawson, lVLD. Under 37 C.:F.R. § 1.132
`
`US Patent and Trademark Office
`PO Box 1450
`Alexandria, Virginia 22313-1450
`
`Dear Sir:
`
`I, the undersigned, Katherine T. Dawson, M.D. residing at 561 Canton Street, Westwood,
`
`MA 02090 declare and state as follows:
`
`I.
`
`My Background
`
`1.
`
`I am a Senior Director of Medical Research at Biogen Idec MA Inc. ("Biogen
`
`Idec"), the assignee of the cUlTently pending application. I have seven years of experience in the
`
`clinical development ofMS dmg products. I vvas involved in the development ofTysabri@ and
`
`was the medical director of the Avonex@ program. Tysabri@ and A vonex ID
`
`, both parenterai
`
`therapies, are among the few currently-approved treatment options for MS patients. I am cUlTently
`
`responsible for developing BG-12, a new oral JVrS tberapy. A copy of my curriculum vitae
`
`accompanies tbis declaration as Exhibit A.
`
`Page 15 of 87
`
`

`

`Atty. Dkt. No. 2[59.3210001
`
`- 2 -
`
`LUKASHEV
`AppL No. 12/526,296
`
`2.
`
`I have personal knowledge of the matters in this declaration - knowledge which is
`
`either first-hand, or derived from my experience in this field and from interacting I;vith others on
`
`the 80-12 development team at Biogen Idee.
`
`H.
`
`Long Felt Need for Oral Treatment of Multiple Sclerosis
`
`3.
`
`Multiple sclerosis ("MS") is an autoimnnme disease characterized by inflammation,
`
`myelin destmction, axonal damage and neuronal loss in the central nervous system and aflects
`
`about 2.5 million people worldwide.
`
`4.
`
`Patients with JVrS are tYl)lcally treated \-vith injectable medications. Despite the
`
`recent approval of one oral MS therapy, a substantial challenge remains to develop efficacious yet
`
`safe oral therapies to treat MS patients. As such, there is a high, unmet, long-felt need for oral
`
`therapies that are effective in treating MS.
`
`5.
`
`In an attempt to address this high, umnet, long-felt need, 8iogen Idee bas completed
`
`Phase 2 and Phase 3 clinical trials to investigate BG-12 as an oral treatment for MS. The only
`
`active ingredient of 8G-12 is dimethyl fumarate ("Dl'vlF").
`
`HI.
`
`The 480 mg DI\fF Per Day Dose is Unexpectedly Efficacious
`
`A.
`
`6.
`
`Ph.ase 2 Clinkal Trial
`
`In 2004, 8iogen Idee initiated a Phase 2 six-month placebo controlled clinical trial
`
`of 80··12 in 10 countries and enrolled 257 patients with relapsing remitting MS (Rl:tMS). The
`
`clinical trial included an additional six-month safety extension. Overall, ninety-one percent of the
`
`patients completed the placebo-controlled part of the Phase 2 clinical trial.
`
`Page 16 of 87
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`a.
`
`Men and \-vomen 18 to 55 years of age were eligible for the study if they had a
`
`diagnosis of RRMS and an Expanded Disability Status Scale ("EDSS") score (a
`
`wen-known measure of the disabilities suiTered by IvIS patients) between 0.0 and
`
`5.0. Additionally, the patients had to have had at least 1 relapse within 12 months
`
`prior to randomization or gadolinium-enhancing (Gd+) lesions (Gd+ lesions in the
`
`brain are a well-known rnarker of MS) on brain MRT within six weeks of
`
`randomization.
`
`b.
`
`The patients were randomly assigned to one of four treatment groups for 24 weeks:
`
`(a) 120 mg BG-12 once daily (120 mg/day); (b) 120 mg BG-12 three times daily
`
`(360 mg/day); (c) 240 mgBG-12 three times daily (720 mg/day); and (d) placebo.
`
`c.
`
`The primary end point of the Phase 2 clinical tria! was the sum of ail new (ld+-
`
`lesions from four brain MRI scans obtained at Weeks 12, 16, 20, and 24. The
`
`number ofGd+ lesions is considered a surrogate end point for clinical efficacy and
`
`as such is accepted as a primary end point f"()f a proof of concept study.
`
`d.
`
`The secondary end points of the Phase 2 clinical trial included the cumulative
`
`number of new Gd+ lesions on scans from Weeks 4 and 24, the number of new or
`
`newly enlargingT2-hyperintense lesions at Week 24, and the number of new Tl
`
`h)1)ointense lesions at \-veek 24.
`
`e.
`
`Additional end points included annualized relapse rate ("ARR") and disability
`
`progression as measured by FDSS.
`
`7.
`
`The results of the Phase 2 clinical trial are reported in the peer-reviewed publication
`
`of Kappos, L., et aZ., "Efficacy and safety of oral fumarate in patients with relapsing-remitting
`
`multiple sclerosis: a multlcentre, randomised, double-blind, placebo-controlled phase IIb study,"
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`Page 17 of 87
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`Atty. Dkt. No. 2[59.3210001
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`AppL No. 12/526,296
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`Lancet 372:1463-72 (2008) (Exhibit B); as well as in Kappos, L, et al., "Efficacy of a novel oral
`
`single-agent fumarate, BGOOO 12, in patients with relapsing-remitting multiple sclerosis: results of
`
`a phase 2 study," 16th Meeting of the European Neurological Society (presentation given on May
`
`30, 2006) (Exhibit C); Kappos, L., et aI., "Efficacy of a novel oral single-agent Fumarate,
`
`BG00012, in patients witb relapsing-remitting multiple sclerosis: results ofaphase n study," 16th
`
`Meeting oftbe European Neurological Society (abstract to presentation given on May 30,2006)
`
`(Exhibit D); and "Oral Compound BG-12 Achieves Primary Endpoint in Phase II Study of
`
`Relapsing-Remitting MS with BG-12 Led to Statistically Significant Reductions in MRI
`
`Measures," Biogen Idec News ReJease (May 30, 2006) (Exhibit E),
`
`a.
`
`Only the patients who were administered 720 mg/day DMF exhibited a statistically
`
`significant effect on the primary endpoint vs. placebo. Patients in this dose group
`
`showed a 69% decrease (P<O.OOl) in the mean number of new Gd+ lesions over
`
`lv1R1 scans Weeks 12 to 24 as shown in Figure 1 below.
`
`Page 18 of 87
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`Atty. Dkt. No. 2[59.3210001
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`Figure 1:
`
`Mean Total Number of Gd+ Lesions at Weeks 12, 16, 20, and 24
`Combined in the Phase 2 Trial
`
`(}
`
`5
`
`4
`
`-+
`'C
`C9
`~
`Q)
`z
`o@
`... 0 3
`Q) .-
`.o~
`E......I
`::::>
`z
`C
`ttl
`<D
`~
`
`2
`
`0
`
`Placebo
`
`360 mg/day
`120 mg/day
`Treatment Group
`
`720 rng/day
`
`Page 19 of 87
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`Atty. Dkt. No. 2[59.3210001
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`b.
`
`Additionally, patients administered 720 mg/day DMF exhibited a 48% decrease
`
`(p<O.OO 1) in the mean nmnber of nel;v and enlarging T2-hyperintense lesions at
`
`Week 24, compared to placebo as shown in Figure 2 below.
`
`Mean Number of New and Enlarging T2-Hyperintense Lesions
`(Week 24) in the Phase 2 Trial
`
`(/)
`
`6
`
`5
`
`c
`0
`'iI)
`<U
`.....J
`~
`~ 4
`z .......
`3
`0
`iii
`.0 2
`E
`::J
`Z
`c
`!\:l
`<l)
`::?!
`
`1
`
`0
`
`001148%
`
`1'<0,
`
`Placebo
`
`'120 mg/day
`
`360 rng/day
`
`720 mg/day
`
`Treatment Group
`
`Page 20 of 87
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`Atty. Dkt. No. 2[59.3210001
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`Co
`
`Patients administered 720 mg/day DJVfF also exhibited a 53°/~) decrease (p=0,014)
`
`in the mean number of new Tl-hypointense lesions at Week 24 VSo placebo as
`
`shown in Figure 3 below.
`
`Mean Number of New T1-Hypolntense Lesions (Week 24) in the
`Phase 2 Trial
`
`2
`
`2
`
`l'? o
`]
`
`Placebo
`
`i 20 mg/day 360 mg/day 720 mg/day
`
`Treatment Group
`
`Page 21 of 87
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`Atty. Dkt. No. 2[59.3210001
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`d.
`
`Finally, patients administered 720 mg/day DlvlF exhibited an ARR of 0.44, as
`
`compared to an ARR of 0.65 in patients administered placebo as shown in Table 1
`
`below, resulting in a clinically meaningfu132~~ reduction in ARR, which is similar
`
`to the treatment effect on ARR of the approved interferon -beta and glatiramer
`
`acetate treatments for MS. The reduction in ARR was not statistically significant]
`
`and has to be viewed in the context of the study being powered to achieve
`
`statistical significance for MRI endpoints and not for an evaluation of ARR.
`
`Treatment Group
`720 mg/day
`120 mg/day
`360 mg/day
`Placebo
`N"'63
`,N'''64
`N"64
`N"'65
`--------------------------------------------------------------------------------------+---------------------------------------- ---------------------------------------- -----------------------------------------------
`!
`0.65
`0.42
`0.78
`0.44
`Annualized relapse
`__ I~~~ __ (2~~~ __ QD_~ ___________________ (Q_:~;?,2 __ L:QD ___ L ____ (Q:_~_~LQ:.7}1 __________ JQ:_~_~J __ J_:_L91 _______________ (Q_:~§2 __ Q:~Z!:D ________ __
`CI = confidence interval
`
`8.
`
`In comparison, treatment with 120 mg/day and 360 mg!day DMF did not provide
`
`results that were statistically significant versus placebo on any endpoint. (See, e.g., Exhibit E).
`
`9.
`
`The Phase 2 clinical trials results indicated 720 mg/ day DMF significantly reduced
`
`the cumulative nurnber of new Gd+ lesions, the number of nevv or enlarging T2-hyperintense
`
`lesions, and the number of new Tl-hypointense lesions compared with placebo. (See, e.g., Exhibit
`
`C).
`
`lOne could attempt to draw a conclusion that the relapse efficacy endpoint ofthe Pha5e 2 clinical trial suggests that
`patients administered l20 mg/day DMF exhibit essentially the same annualized reJapse rate as patients administered
`no mg/day DMF. However, the study \vas not desigl1(~d to achiev(~ statistical significance fi:)rthis endpoint. (See, e.g.,
`Exhibit E).
`
`Page 22 of 87
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`Atty. Dkt. No. 2[59.3210001
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`10.
`
`Therefore, the results of the Phase 2 clinical trial demonstrated that no mg/day
`
`DMF was an efIi.cacious dose for treating patients with MS. Additionally, because the 120 mg/day
`
`DrvlF and the 360 mg/day DMF groups were not statistically significant compared to placebo and
`
`the magnitude of effect on MRlleslons was not dose prop01iional, the results of the Phase 2 study
`
`did not suggest that DMF exhibited a linear dose response.
`
`B.
`
`Phase:; DEFINE Clinical Trial ResuHs2
`
`11.
`
`The BG--12 Phase 3 placebo-controlled, double .. blind clinical trial, named the
`
`"DEFINE" trial, vvas completed earlier this year and its top-line results were announced in April
`
`2011. The trial included over 1200 patients, in 28 different countries, on 5 different continents.
`
`Seventy-seven percent of the patients completed the clinical trial.
`
`a.
`
`Men and women 18 to 55 years of age were eligible for the study if they had a
`
`diagnosis of RRMS and EDSS score between 0.0 and 5.0. Additionally, the
`
`patients must have had at least one clinically confirmed relapse I;vithin 12 months
`
`prior to randomization and a brain MRI scan at any time that was consistent with
`
`MS or that showed evidence of at least one Gd+ enhancing lesion within 6 weeks
`
`of randomization.
`
`b.
`
`Patients were random ly assigned to one ofthree treatment groups: (a) 240 mg BG-
`
`12 twice daily (480 mg/day); (b) 240 mg BG-12 three times daily (720 mg/day);
`
`and (c) placebo.
`
`c.
`
`The primary end point of the Phase 3 clinical trial was the proportion of relapsing
`
`patients at 2 years. A relapse was defined as nel;v or recurrent neurologic
`
`2 DEFINE is one ofthe tv,,'O Phase 3 clinical trials conducted by Biogen Idee. The results of the other Phase 3
`
`Page 23 of 87
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`Atty. Dkt. No. 2[59.3210001
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`AppL No. 12/526,296
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`symptoms lasting for at least 24 hours that ,vere not associated with fever or
`
`infection but were accornpanied by new, objective neurological findings.
`
`d.
`
`Secondary end points of the Phase 3 clinical tria! included the number of (ld+
`
`lesions, new or newly enlarging T2-hyverintense lesions, ARR, and sustained 12·-
`
`week disability progression. Disability progression was defined as an increase in
`
`EDSS of (a) at least LO point in patients with a baseline EDSS of 2~ 1.0 or (b) at
`
`least 1.5 point increase in patients with a baseline EDSS of 0.0, sustained for 12
`
`weeks and con:l:1nned by an independent neurologic evaluation committee (lNEC).
`
`Additional MRI endpoints included the number of new T 1 hyl)ointense lesions, and
`
`the mean-percentage change from baseline in Gd+, T2 hyverintense and Tl
`
`hy·pointense lesion volumes.
`
`12.
`
`As shown below, the results at 2 years of the Phase 3 clinical trial demonstrated that
`
`both the 480 mg/day dose and the 720 mg/day dose regimens versus placebo met all primary and
`
`secondary endpoints with a high level of statistical significance and that both doses demonstrate
`
`efHcacy in the DEFINE trial.
`
`clinical trial, CONFIRM, are expected to be released by the end of 20 11.
`
`Page 24 of 87
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`Atty. Dkt. No. 2[59.3210001
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`AppL No. 12/526,296
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`a.
`
`Compared to placebo (n= 165), patients administered 480 mg/day (n= 152) or no
`
`mg/day DMF (n=152) exhibited a 90% or 73% (p<O.OOOl fo

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