IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`hJ re application of:
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`LUKASHEV et a!.
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`Confinnation No.: 5998
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`Art Unit:
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`1649
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`Appl. No. 13/372,426
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`Examiner:
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`Ulm, JohnD.
`
`Filing Date: February 13, 2012
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`Atty. Docket: 2159.3210002/JMC/MRG/U-S
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`For: Treatment for Multiple Sclerosis
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`Declaration of Richard A. Rudick, M.D. U nder 37 C.F.R. § 1.132
`
`US Patent and Trademark Office
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`POBox 1450
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`Alexandria, Virginia 22313-1450
`
`Dear Sir:
`
`I, the undersigned, Rkhard A. Rudick, M.D., residing at 5067 Boulder Creek
`
`Drive, Solon, Ohio 44139-1379, declare and state as follows:
`
`I.
`
`My Background
`
`1.
`
`I am a physician (neurologist), professor and clinical investigator with
`
`a focus on treating patients with neurological diseases. During the last 30 years,
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`much of my clinical research has focused on multiple sclerosis ("MS"). I am Director
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`of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland
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`Cl.inic (since 1987), the Vice Chairman for Research and Development at the
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`Neurological Institute at the Cleveland Clinic (since 2007), and a Professor of
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`Medicine in the Cleveland Clinic Lerner College of Medicine at Case Western
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`Reserve University (since 2003). I served on the Editorial Board of the journal
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`Multiple Sclerosis - Clinical Issues from 1992 to 2010, and as a member of the
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`Research Program Advisory Committee at the National Multiple Sclerosis Society
`
`since 2006 (chair of the committee since 2009). I am an author or co-author of about
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`200 peer-reviewed scientific articles, nine (9) books, and more than 40 book chapters
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`related to MS. A copy of my curriculum vitae accompanies this declaration as
`
`Exhibit A.
`
`2.
`
`I have extensive educational and research experience in the field of
`
`neurologic disorders. 1 currently focus on therapeutic aspects of MS, including
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`clinical and MRI outcome measures forMS patient care and research. I conducted
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`pivotal clinical trials involving MS treatments that are now approved by the Food and
`
`Drug Administration. For example, I was an investigator for the Phase 3 clinical
`
`trials involving interferon beta (IFNP-1 a), now marketed as A vonex® . I conducted
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`MS clinical trials on behalf ofBiogen Idee Inc. ("Biogen Idee") in connection with
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`natalizumab, a parenteral therapy for relapsing-remitting MS ("RRMS"), now
`
`marketed as Tysabri®.
`
`3.
`
`l am familiar with U.S. Patent Application No. 13/372,426 (filed
`
`February 13, 20 12) enti tied "Treatment for Multiple Sclerosis" and the current claims
`
`in that application, which are directed to methods of treating MS by administering
`
`480 mg/day of dimethyl fumarate ("DMF") and/or monomethyl fumarate ("MMF"). I
`
`am also familiar with the two references cited by the Examiner: U.S. Patent
`
`Publication No. US 2003/0018072 to Joshi et al. ("Joshi"), and Scbimrigk et a/.,
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`"Oral fumaric acid esters for the treatment of active multiple sclerosis: an open-label
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`baseline-controlled pilot study," European Journal ofNeurology2006, 13(6):604-610
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`("Scbimrigk").
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`4.
`
`The Cleveland Clinic (my employer) is being compensated by Biogeo
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`Idee for my services related to this declaration at a rate in accordance with my
`
`standard consu]tation fee. In the past, the Cleveland Clinic (my employer) received
`
`two research grants from Biogen Idee for research studies for which I served as
`
`principal investigator (Exhibit A).
`
`5.
`
`As a physician and an expert in the field of MS, and further as a
`
`clinical investigator, I am qualified to provide an opinion as to what a person of
`
`ordinary skill in the art would have known and concluded as of February 8, 2007, the
`
`priority date for U.S. Patent Application No. 13/372,426 ("the time of the invention").
`
`6.
`
`I have been asked by Applicants' attorneys to comment on two areas of
`
`interest in connection with Biogeo Idee's investigational drug BG-12, which contains
`
`dimethyl fumarate ("DMF") as the only active ingredient. First, I was asked to
`
`comment on wlhether or not a person of ordinary skill in the art at the time of the
`
`invention would have reasonably expected a 480 mg/day dose of DMF to be as
`
`e fficacious as a 720 mg/day dose of DMF. Second, I was asked to comment on
`
`whether there was a long-felt, but unmet need for oral MS therapi.es at the time of the
`
`invention.
`
`II.
`
`It is unexpected that 480 mg/day of DMF is as efficacious .as 720 mg/day
`
`of DMF in treating MS
`
`7.
`
`In view of what was publicly known aboutlreatingMS with fumarates
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`at the time ofthe invention (e.g. , the teaching in Schimrigk and the DMF doses used
`
`in the Phase 2 BG-12 clinical study), based on my knowledge and experience, I
`
`believe that a person of ordinary skill in the art would have found the magnitude of
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`the efficacy of the 480 mg/day dose ofDMF, as observed in two recently completed
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`Phase 3 MS clinical studies, to be unexpected (i.e. , the 480 mg/day dose was found to
`
`be similarly efficacious as the higher dose of 720 mg/day). The observations
`
`described below form the basis of my opinion.
`
`(tl)
`
`The 480 mgldav dose wtJS unexpectedly e(fiCllcious based on
`results trom the Phase 2 clinical studv
`
`8.
`
`In 2004, Biogen Idee initiated a Phase 2 placebo controlled clinical
`
`study of BG-12 (DMF), which emolled 257 patients with RRMS ("the Phase 2
`
`clinical study"). Three doses, ] 20 mg, 360 mg, and 720 mg/day ofDMF, were tested.
`
`See, e.g. , Kappes, L. , et al. , "Efficacy of a novel oral single-agent fumarate,
`
`BGOOO 12, in patients with relapsing-remitting multip le sclerosis: results of a phase 2
`
`study," 16th Meeting of the European Neurological Society (May 30, 2006) (Abstracl)
`
`(Exhibit B); 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 IT
`
`study," 16th Meeting of the European Neurological Society (May 30, 2006) (Slide
`
`Presentation) (Exhibit C); 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," Biogeo Idee News Release (May 30, 2006)
`
`(Exhibit D). I am familiar with the results of the Phase 2 study. The study results
`
`show that the 120 mg/day and 360 mg/day doses did not exhibit a statistically
`
`significant difference compared to placebo with respect to the clinical endpoints
`
`measured in the trial (i.e., the mean total number of Gd+ lesions, and the munber of
`
`new and enlarging T-2 hyperin~ense lesions). The 720 mg/daydose was the on ly dose
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`found Lo have a slatislically significant effect wmpared lo placebo. See figures below
`
`which are reproduced from the slide presentation of May 30, 2006 (Exhibit C):
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`Figure 1:
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`LUKASHEV et al.
`Appl. No. 13/372,426
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`Mean Total Number of Gd+ Lesions at Weeks 12, 16, 20, and 24
`Combined in the Phase 2 Trial
`
`+
`"0
`(9
`
`~ z
`
`....
`IJ)
`0 c:
`~ 0
`~ ·~ 3
`
`6
`
`5
`
`4
`
`2
`
`P<0.001 169%
`
`E_~
`:J
`z
`c
`ro
`<ll
`~
`
`n=56
`n=59
`n=54
`n=54
`o ~~~--~----~--~----~--~----~--~---
`120 mg/day
`360 mg/day
`720 mg/day
`Placebo
`Treatment Group
`
`N ote: The mean number of new Gd+ lesions was measured in comparison to the placebo.
`
`Figure 2:
`
`Mean Number of New and Enlarging T2-Hyperintense Lesions
`(Week 24) in the Phase 2 Trial
`
`6
`
`IJ) c
`0
`'iii
`<ll
`_I 5
`N
`I-
`~ 4
`z
`0
`3
`Q5
`.0 2
`E
`:J z
`c:
`ro
`<ll
`~ 0
`
`- 1-
`
`1-f-
`
`r - -
`
`P<0.001 48
`
`r-1-
`
`n=54
`
`n=59
`
`n=56
`
`n=54
`
`Placebo
`
`120 mg/day
`
`360 mg/day
`
`720 mg/day
`
`Treatment Group
`
`Note: The mean number of new and enlarging T2-hyperintense lesions was measured in comparison to
`the placebo.
`
`9.
`
`As one can tell from the figures above, the effects seen for different
`
`doses of BG-12 were not clearly dose-proportional (i.e. , no suggestion of linear
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`response). Based on the Phase 2 clinical study results, I believe a person of ordinary
`
`skill in the art at the time of the invention would not have reasonably expected a 480
`
`mg/day dose ofDMF to have similar efficacy as the 720 mg/day dose ofDMF for the
`
`treatment of MS. The person of ordinary skill would have expected that the efficacy
`
`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), were found to be similarly efficacious is surprising.
`
`10.
`
`BG-12 was subsequently evaluated in two placebo-controlled, double-
`
`blind Phase 3 clinical studies (DEFINE and CONFIRM) ("the Phase 3 clinical
`
`studies"). Inboth of these Phase 3 clinical studies, it was unexpectedly found that the
`
`480 mg/day dose of DMF has similar efficacy as the 720 mg/day dose of DMF in
`
`treating MS in almost every endpoint measured (i. e., annualized relapse rate,
`
`proportion of subjects relapsed, number ofGd+ lesions, and progression of disability
`
`at two years). See, e.g., results of the DEFINE study summarized in a Biogen Idee
`
`press release of April 11 , 2011 (Exhibit E), results of the CONFIRM study
`
`summarized in a Biogen Idee press release of October 26, 2011 (Exhibit F), and a
`
`recent Biogen Idee slide presentation (Exhibit G). See figures 3-5 below which are
`
`reproduced from Exhibit G.
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`Figure 3:
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`LUKASHEV et al.
`Appl. No. 13/372,426
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`Annualized Relapse Rate (ARRf>
`
`DEFINE
`(SECONDARY ENDPOINT!
`
`CONFIRM
`!PRIMARY ENDPOINT)
`
`0.6
`
`0.5
`
`0.4
`
`u
`...
`"' 0.3
`e
`"'
`"'
`
`<(
`
`0.2
`
`0.1
`
`0
`
`48%
`reduction
`
`53%
`reduction
`vs placebo
`P<0.0001
`
`0.364
`
`o.e
`
`0.5
`
`0.4
`
`..
`u
`... 0.3
`e
`"'
`"'
`<( 0.2
`
`0.1
`
`OA01
`
`29%
`reduc~on
`vs placebo
`P=00128
`
`51%
`
`44%
`reducbon
`vs placebo
`/'<;0.0001
`
`Placebo
`(n=408)
`
`BG-12 BID
`(n=410)
`
`BG-12 TID
`(n=416)
`
`Placebo
`~n=363)
`
`BG·12 BID BG·12 TID
`(n=359)
`(n=345)
`
`GA
`(n=350)
`
`•
`
`Figure 4:
`
`Disabilitv Progression at Two (2) Yearsa)
`
`DEFINE
`IS[COI<OARY El'IDPOINTl
`
`CONFIRM
`!SECONDARY ENOPO,NT)
`
`(/) 0.3
`"'
`..
`~
`>-
`<
`2:
`Q 0.2
`;z
`w
`"'
`"
`0
`"'
`a.
`:r
`....
`~
`z
`0
`i=
`"'
`0
`a.
`0
`"'
`0..
`
`0.1
`
`0
`
`38%
`re<iucbon
`vs placebo
`P=O OO!JO
`
`34%
`reduc~on
`vs placebo
`p--Q 0128
`
`0.271
`
`Placebo
`(n=408)
`
`BG-12 BID
`(n=410)
`
`BG-12TID
`(n=416)
`
`II)
`
`N
`
`<(
`
`"'
`,.
`~
`...
`z
`~
`w
`"'
`1!1
`0
`"'
`0..
`J:
`i
`z
`0
`i=
`0:
`0
`..
`0..
`0
`"'
`
`21%
`
`24%
`
`7%
`reductiO~'
`vspiacebo
`P=0.7036
`
`0.3
`
`0.2
`
`0.1
`
`0.
`
`0
`
`Placebo
`(n= 363)
`
`BG-12 BID BG-12TID
`(n=359)
`(n=345)
`
`GA
`(n=350)
`
`a) BID = 480 mglday ofDMl"; TID= 720 mglday ofDMF; GA = glatiramer acetate
`t = not statistically significant against placebo
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`Figure 5:
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`Appl. No. 13/372,426
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`Summary of Key E fficacy E ndpoints (Ratio and 95% Cl)
`DEFINE and CONFIRM (Pooled)
`
`e BG-12 240 mg BID
`Favors BG-12
`
`.a. BG-12 240 mg TID
`Favors Placebo
`
`P<0.0001
`
`P<0.0001
`
`P<0.0001
`
`P<0.0001
`
`P<0.0001
`
`P<0.0001
`
`P<0.0001
`
`P<0.0001
`
`P<0.0001
`
`P<0.0001
`
`PRIMARY ENDPOINT 1
`ARR (RR)
`
`PRIMARY. ENDPOINT 2
`Proportion of subJects relapsed (HR)
`
`SECONDARY ENDPOINTS
`Number of new or newly enlargmg T2-
`hypenntense les1ons (LMR: MRI cohort)
`
`Number of new T1-hypointense
`lesions (LMR: MRI cohort)
`
`Number of Gd+ lesions
`(OR; MRI cohort)
`
`Disability progress1on {HR)
`
`•
`
`*
`
`I
`0.1
`
`I
`0.2 0.3
`
`I I I
`
`I I
`0.5
`Ratio (95% CI)
`
`I
`2
`
`3
`
`P=0.0034
`
`P=0.0059
`
`I I I I.,
`
`5 7 10
`
`K ey: CJ (Confidence Interval), RR (Rate Ratio), HR (Hazard Ratio), LMR (Lesion Mean Ratio), and
`OR (Odds Ratio)
`
`(b)
`
`Basetl on past clinical studies, 720 mgltlav of DMF was
`expectetl to be required dose (or efficttcv
`
`ll. Results fTom an earlier MS clinical study were reported by Scbimrigk.
`
`In Schimrigk, investigators administered 1,290 mg/day of a mixture of four
`
`fumarates (six tablets of Fumaderm Forte®) toMS patients in the main treatment
`
`phase.1 According to Schimrigk, the administered fbmarate mixture at this dose was
`
`associated with promising results with respect to certain MS parameters. Even
`
`though DMF is one of the four fumarates in the mixture, the remaining three
`
`fumarates are each an active ingredient Thus, in my opinion, a person of ordinary
`
`skill in the art would not have reasonably expected DMF by itself to have similar
`
`efficacy in treating MS as four active fumarates (including DMF) together. The
`
`1 Schimrigk also disclosed administration of three tablets of Fumadem1 forte® during a second treatment
`phase (a total of 645 mg/day of fumarates) and that the effects from the first treatment phase were maintained.
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`person of ordinary skill would have even less expectation that 480 mg/day ofDMF
`
`wouJd have similar efficacy as 1,290 mg/day of a mixture of fumarates.
`
`12.
`
`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 ofDMF is the effective dose forMS
`
`treatment, it would have been highly unexpected by a person of ordinary skill in the
`
`art that 480 mg/day ofDMF is as effective for the treatment ofMS as 720 mg/day of
`
`DMF.
`
`III.
`
`BG-12 satisfies a long felt but unsolved need for oral treatment of MS
`
`13.
`
`Over the many years l have been treating MS patients and conducting
`
`clinical research on MS, I have seen the devastation the disease can bring. MS is a
`
`chronic autoimmune disease requiring lifelong therapy. The disease affects about 2.5
`
`million people worldwide and bas a prevalence that ranges between 2 and 150 per
`
`1 OO,OOOpeople (see e.g. , Rosati, G., Neurol. Sci. 2001, 22(2): 117-39; Nicholas, R. el
`
`al. , Drug Design, Developmenl and Therapy20Il , 5:255-274). MS is characterized
`
`by inflanunation, myelin destruction, axonal damage and neuronal loss in the central
`
`nervous system. See, e.g. , Killestein, J., eta!., "Oral treatment for multiple sclerosis.''
`
`Lancet Neurology 2011, 10:1026-34 ("Killestein") (Exhibit H). Physical and
`
`cognitive impairments of varying degrees are common in MS. The disease is one of
`
`the primary causes for neurological disability in young adults.
`
`A.
`
`There is currently no cure for MS - Lifelong treatment is required
`
`14. Not only isMS treatable by only a handful ofMS drugs, but all but
`
`one of the current disease-modifying drugs for MS require regular injections or
`
`monthly parenteral infusions. I have observed in my patients that administration of
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`these medications is often associated with injection anxiety and/or injection-related
`
`adverse effects and limited long-term adherence to treatment. See, e.g., Klauer T.,
`
`and Zettl, U.K., "Compliance, adherence, and the treatment of multiple sclerosis," J.
`
`Neurol. 2008, 255 Suppl 6: 87-92 (Exhibit I); Devonshire, V. et aL. , "The Global
`
`Adherence Project (GAP): a multicenter observational study on adherence to disease-
`
`modifying therapies in patients with relapsing-remi tting multiple sclerosis," Eur. J.
`
`Neurol. 2011, 18(1): 69-77 (Exhibit J); M iller, A.E. and Rhoades, R.W., "Treatment
`
`ofrelapsing-remittingmultiple sclerosis: current approaches and unmetneeds," Curr.
`
`Opin. Neural. 2012, 25 (suppl 1 ):S4-S I 0 (Exhibit K) , Gold, R., "Oral therapies for
`
`multiple scleroris: a review of agents in phase m development or recently approved,"
`
`CNS Drugs 2011, 25(1): 37-52 (Exhibit L), and Exhibit H. From my personal
`
`experience over many years, it is clear that maintaining adherence to the treatment
`
`regimens is a challenge when providing care forMS patients. Oral MS medications
`
`not only bring significant convenience for patients, but are also expected to greatly
`
`enhance patient compliance and thus are expected to improve long-tenn treatment
`
`benefits compared to injectable MS medications.
`
`15.
`
`A long-felt but unmet need for disease-modifYing oral MS medications
`
`has existed for decades. However, at the time of the invention not a single oral drug
`
`for the treatment ofMS was available. See, e.g. , "FDA approves first oral drug to
`
`reduce MS relapses," Food and Drug Administration News Release (September 22,
`
`2010) (Exhibit M). A heightened anticipation for disease-modifying oral MS
`
`therapies has existed among health care professionals and patients alike since the first
`
`disease-modifying MS treatment entered the market (e.g., about 15 years p1ior to the
`
`Applicants' priority date). As indicated in Killestein, "[t]he need for oral drugs for
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`patients with MS is obvious .... Compliance is poor in many patients because of the
`
`low efficacy and frequent injections." (Killestein, page 1026).
`
`16.
`
`Recently, the first (and currently, the only) oral MS therapy, Gilenya®,
`
`was approved. See, e.g., Exhibit M. However, while providing the advantages of an
`
`oral tTeatment, Gilenya® can cause serious side effects such as "serious infections,
`
`transient reductions in heart rate, vision problems, and respiratory and liver
`
`complications." See, e.g., Sheridan C. Safety profiles come to fore as more drugs
`
`approach MS market. Nat BiotechnoL. 2012, 30(1 ): 6-8 ("Sheridan") (Exhibit N, page
`
`7). For these and other reasons, not every patient can take Gilenya®, leaving many
`
`patients having to rely on injectable drugs. (Exhibit K). Indeed, the US prescribing
`
`infonnation for Gilenya® was recently updated to include patient selection
`
`parameters as a result ofFDA's review of a reported death upon administTation of the
`
`drug. Thus, additional oral drugs that are safe, effective, appropriate for patients
`
`with comorbidities, and suitable for long-tenn treatment, are still needed.
`
`B.
`
`BG-12 (DMF) satisfies the long-felt but unsolved need
`
`17.
`
`BG-12 is an oral pharmaceutical formulation, which demonstrated
`
`significant efficacy for the treatment of MS coupled with favorable safety and
`
`tolerability in two pivotal Phase 3 clinical studies. See, e.g., Exhibit E and Exhibit
`
`F. "Results showed that 240 mg ofBG-12, administered either twice or three times a
`
`day, met the primary study endpoint, demonstrating a highly statistically significant
`
`reduction (p<O.OOOl) in the proportion of patients with RRMS who relapsed at two
`
`years compared with placebo." (Exhibit E) "BG-12 met the CONFIRM study's
`
`primary endpoint by sig11ificantly reducing annualized relapse rate (ARR) by 44
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`percent for BID (p< 0. 0001) and by 51 percent for TID (p< 0. 0001) versus placebo at
`
`two years." (Exhibit F).
`
`18.
`
`The results of the Phase 3 studies have created much excitement for
`
`me and other physicians in this field, as well as analysts of the pharmaceutical
`
`industry for this promising MS treatment. See, e.g., B loomberg article in response to
`
`CONFIRM data of Oct 26, 2011 ("Bloomberg article") (Exhibit 0 ).
`
`'confirm' BG-12's
`"These data generally
`efficacy . .. , "Mark Schoenebaum, an analyst
`with I!:Ji Group in New York, wrote in a note to
`clients today.
`"On a scale of l-10, with '10'
`being absolute best case, we would put these
`data at perhaps 8 or 9."
`
`/d. (emphasis added).
`
`19.
`
`Furthennore, tbe Food and Drug Administration (FDA) recently
`
`accepted Biogen Idee's New Drug Application (NDA) forBG-12 for the treatment of
`
`MS (see, e.g., B iogen Idee press release dated May 9, 2012, Exhibit P).
`
`20.
`
`There is no question in my mind that once BG-12 becomes available,
`
`it wiU make a significant clifference in the Lives of many MS patients. This v iew is
`
`shared by others in the field. For example, a Decision Resources article of June 25,
`
`2012 (Exhibit Q) discloses:
`
`percent of all
`fN} inety-five
`surveyed
`neurologists in Jhe EV 5 [France, Germany, Italy,
`Spain, United Kingdom] expect to prescribe
`BG-12 ....
`
`(emphasis added).
`
`21.
`
`As such, BG-12 at 480 mg/day of DMF will contribute significantly
`
`toward meeting the above discussed long-fell but uomet need for a safe and
`
`efficacious oral MS therapy.
`
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`22.
`
`In addition to satisfying the unmet need, there are, in my view, two
`
`additional advantages of the 480 mg/day dose of DMF as compared with the 720
`
`mg/day DMF dose.
`
`(tl)
`
`Two times per tlav (BID) treatment regimen is superior to
`three times per tlay dosing regimen (TID)
`
`23.
`
`BG-12 at a dose of 480 mg/day DMF is administered using a twice a
`
`day dosing regimen - 240 mg DMF each administration (BID), whereas the other
`
`Phase 3 dose, the 720 mg/day dose, was administered in three doses o£240 mg each
`
`(TID).
`
`24.
`
`BID administration provides a significant advantage over TID
`
`administration because such dosing regimen significantly increases patient
`
`convenience and is expected to increase patient compliance with the treatment
`
`schedule. Increased patient compliance is crucial to achieving maximal benefit from
`
`the drug.
`
`(b)
`
`480 mg/tlay DMF mav pro vide a satety at/vantage (or long(cid:173)
`term treatment
`
`25.
`
`Safety concerns are on the forefront of the scientific discussion for
`
`additional long-term treatment options for MS. Oral dmgs that are not only
`
`efficacious, but are characterized by a favorable long-term safety profile have the best
`
`chances of providing long-term benefits to MS patients and are particularly desirable.
`
`See, e.g., Exhibit L and Exhibit N.
`
`26.
`
`In my opinion, the Phase 3 clinical studies demonstrate an
`
`extraordinary safety/adverse event profile for BG-12 (see, e.g. , slide 9 ofExhibit G).
`
`My opinion is shared by others in the field, including pharmaceutical analysts. For
`
`example, the Bloomberg article discloses
`
`Page 13 of 17
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`

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`LUKASHEV et al.
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`
`"[t} he most important thing is safety, and the
`safety profile looks exceptional, " Eric Schmidt,
`an analyst with Cowen & Co. in New York, said
`in a telephone interview today.
`"This will
`position BG-12 as a front-line drug. It's hard to
`imagine this won't be a blockbuster."
`
`ld. (emphasis added). Additionally, Sheridan indicates that "some highlight Biogeo
`
`Idee's oral small molecule BG-12 as the pipeline drug with the greatest potential to
`
`reconcile the twin goals of efficacy and safety." (Sheridan at page 6.)
`
`27.
`
`Furthermore, physicians (as well as the FDA and other regulatory
`
`agencies) will prefer the 480 mg/day dose of DMF given the similar safety/efficacy
`
`profile compared to the 720 mg/day dose. The lower 480 mg/day DMF dose is
`
`expected to offer fewer side effects/adverse events upon administration over a
`
`prolonged period of time (e.g., more than the 2-year period designated in each of the
`
`Phase 3 studies) than the similarly effective higher dose of 720 mg/day of DMF
`
`(although the BG-12 clinical studies di d not indicate a difference between the safety
`
`profi les of the 480 mg/day and the 720 mg/daydose over two years; see, e.g. , Exhibit
`
`E , Exhibit F, and slide 9 of Exhibit G). Io this sense, 480 mg/day Dl\1F satisfies the
`
`above discussed long-felt need for a safe and efficacious oral MS treatment
`
`particularly well.
`
`28.
`
`ln summary, at the time of the invention, there had been a long-felt
`
`need for oral therapies forMS, not met for several decades prior to the invention. A
`
`need for safe and efficacious oral MS therapies persists to this current day. 480
`
`mg/day ofDMF colllributes to meeting this long-felt but unmet need while providing
`
`additional advantages over the similarly effective, higher dose of 720 mg/day.
`
`Page 14 of 17
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`

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`Atty. Dkt. No. 2159.3210002
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`IV.
`
`Conclusion
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`- 15 -
`
`LUKAS HEY et al.
`Appl. No. 13/372,426
`
`29.
`
`ln view of the foregoing, I conclude that it would have been
`
`unexpected to a person of ordinary skill at the time of the invention that a 480 mg/day
`
`DMF dose is similarly effective in treating MS than a 720 mg/day DMF dose.
`
`Furthermore, it is my opinion that 480 mg/day (240 mg BID) DMF satisfies a long-
`
`felt, but unmet need for an oral MS therapy.
`
`30.
`
`I hereby declare that all statements made herein of my own knowledge
`
`are true and that all statements made on information and belief are believed to be true;
`
`and further that these statements were made with the knowledge that willful false
`
`statements and the like so made are punishable by tine or imprisonment, or both,
`
`under Section tOOl ofTitle 18 of the United States Code and that such willful false
`
`statements may jeopardize the validity of the present patent application or any patent
`
`issued thereon.
`
`Richard A. Rudick, M.D.
`
`Date:
`
`1562474vl
`
`Page 15 of 17
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`

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`Atty. Dkt. No. 2159.3210002
`
`A ppendix A
`
`- 16-
`
`LUKASHEV et al.
`Appl. No. 13/372,426
`
`Exhibit A
`
`Curriculum Vitae for Richard A. Rudick, M.D.
`
`Exhibit B
`
`ExbibitC
`
`Exhibit D
`
`Kappos, L., eta!., "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) (Abstract)
`
`Kappos, L., et al., "Efficacy of a novel oral single-agent Fumarate,
`BG00012, in patients with relapsing-remitting multiple sclerosis:
`results of a phase ll study," 16th Meeting of the European
`Neurological Society (May 30, 2006) (Slide Presentation)
`
`"Oral Compound BG-12 Achieves Primary Endpoint in Phase 11
`Study ofRelapsing-Remitting MS with BG-12 Led to Statistically
`Significant Reductions in MRI Measures," Biogen Idee News
`Release (May 30, 2006)
`
`Exhibit E
`
`Biogen Idee Press Release (April ll , 20 I I)
`
`Exhibit F
`
`Biogen Idee Press Release (October 26, 2011)
`
`ExhibitG
`
`Biogen Idee Slide Presentation "BG-12 for RRMS -Registration
`Submitted"
`
`Exhibit H
`
`Exhibit I
`
`Exhibit J
`
`E xhibitK
`
`Exhibit L
`
`Killestein, J., eta/., "Oral treatment for multiple sclerosis." Lancet
`Neurology 20 l l, 10: 1 026-34
`
`Klauer, T. and Zettl, U.K., "Compliance, adherence, and the
`treatment of multiple sclerosis," J. Neurol. 2008, 255 Suppl 6: 87-
`92
`
`Devonshire, V., eta!. , "The Global Adherence Pr~ject (GAP): a
`multicenter observational study on adherence to disease-modifying
`therapies in patients with relapsing-remitting multiple sclerosis,"
`Eur. J. Neurol. 2011, L8(1): 69
`
`Miller, A.E. and Rhoades, R.W., "Treatment ofrelapsing-remitting
`multiple sclerosis: current approaches and unmet needs," Curr.
`Opin. Neural. 2012, 25 (suppl l ):S4-SIO
`
`Gold R. Oral therapies for multiple sclerosis: a review of agents in
`phase ill development or recently approved. CNS Drugs 2011 ,
`25(1): 37-52
`
`Exhibit M
`
`"FDA approves first oral drug to reduce MS relapses," Food and
`Drug Administration News Release (September 22, 20 10)
`
`Page 16 of 17
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`

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`
`LUKASHEV et al.
`Appl. No. 13/372,426
`
`Exhibit N
`
`Sheridan, C., "Safety profi les come to fore as more drugs approach
`MS market," Nat Btotechnol. 2012, 30(1): 6-8
`
`Exhibit 0
`
`"Biogen MS Pill With $3 Billion Potential Hits Study Goals,"
`Bloomberg.com (October 26, 2011)
`
`Exhibit P
`
`Biogen Idee Press Release (May 9, 2012)
`
`Exhibit Q
`
`"For the treatment of Multiple Sclerosis, More than 85 Percent of
`Slll'Veyed Neurologists in the EU5 Expect to Prescribe Biogen
`Idee's BG-12, Sanofi/Genzyme's Aubagio and
`Sanofi!Genzyme/Bayer HealthCare's Lemtrada" (Decision
`Resources, June 25, 2012)
`
`Page 17 of 17