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`FORWARD PHARMA EXHIBIT 1018
`Biogen MA Inc. v. Forward Pharma A/S
`Contested Case 106,023
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`1
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 1
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`Atty. Dkt.No.2159.3210001
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`LUKASHEV
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`Appl. No. 12/526,296
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`2.
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`I have personal knowledge of the matters in this declaration — knowledge which is
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`either first—hand, or derived from my experience in this field and from interacting with others on
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`the BG-12 development team at Biogen Idec.
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`II.
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`Long Felt Need for Oral Treatment of Multiple Sclerosis
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`3.
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`Multiple sclerosis ("'MS") is an autoimmune disease characterized by inflammation,
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`myelin destruction, axonal damage and neuronal loss in the central nervous'system and affects
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`about 2.5 million people worldwide.
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`4.
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`Patients with MS are typically treated with injectable medications. Despite the
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`recent approval of one oral MS therapy, a substantial challenge remains to develop efficacious yet
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`safe oral therapies to treat MS patients. As such, there is a high, unmet, long-felt need for oral
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`therapies that are effective in treating MS.
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`5.
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`In an attempt to address this high, unmet, long-felt need, Biogen Idec has completed
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`Phase 2 and Phase 3 clinical trials to investigate BG-12 as an oral treatment for MS. The only
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`active ingredient of BG-l 2 is dimethyl fumarate ("DMF").
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`III.
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`The 480 mg DMF Per Day Dose is Unexpectedly Efficacious
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`A.
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`6.
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`Phase 2 Clinical Trial
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`In 2004, Biogen Idec initiated a Phase 2 six-month placebo controlled clinical trial
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`of BG-12 in 10 countries and enrolled 257 patients with relapsing remitting MS (RRMS). The
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`clinical trial included an additional six-month safety extension. Overall, ninety-one percent ofthe
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`patients completed the placebo-controlled part of the Phase 2 clinical trial.
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`2
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 2
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`2
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 2
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`Atty. Dkt.No.2159.3210001
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`- 3 —
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`LUKASHEV
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`Appl. No. 12/526,296
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`Men and women 18 to 55 years of age were eligible for the study if they had a
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`diagnosis of RRMS and an Expanded Disability Status Scale ("EDSS") score (a
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`well-known measure of the disabilities suffered by MS patients) between 0.0 and
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`5.0. Additionally, the patients had to have had at least 1 relapse within 12 months
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`prior to randomization or gadolinium-enhancing (Gd+) lesions (Gd+ lesions in the
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`brain are a well-known marker of MS) on brain MRI within six weeks of
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`randomization.
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`The patients were randomly assigned to one of four treatment groups for 24 weeks:
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`(a) 120 mg BG-12 once daily (120 mg/day); (b) 120 mg BG—12 three times daily
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`(360 mg/day); (c) 240 mg BG-l2 three times daily (720 mg/day); and (d) placebo.
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`The primary end point of the Phase 2 clinical trial was the sum of all new Gd+
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`lesions from four brain MRI scans obtained at Weeks l2, 16, 20, and 24. The
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`number of Gd+ lesions is considered a surrogate end point for clinical efficacy and
`as such is accepted as a primary end point for a proof of concept study.
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`I
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`The secondary end points of the Phase 2 clinical trial included the cumulative
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`number of new Gd+ lesions on scans from Weeks 4 and 24, the number of new or
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`newly enlargingTZ-hyperintense lesions at Week 24, and the number of new T1
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`hypointense lesions at week 24.
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`Additional end points included annualized relapse rate ("ARR") and disability
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`progression as measured by EDSS.
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`7,
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`The results of the Phase 2 clinical trial are reported in the peer-reviewed publication
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`of Kappos, L., et al., "Efficacy and safety of oral fumarate in patients with relapsing-remitting
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`multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study,"
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`3
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 3
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`3
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 3
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`Atty. Dkt.No. 2159.321000]
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`- 4 -
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`LUKASHEV
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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
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`single—agent fumarate, BG00012, in patients with relapsing-remitting multiple sclerosis: results of
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`a phase 2 study," 16th Meeting of the EurOpean Neurological Society (presentation given on May
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`30, 2006) (Exhibit C); Kappos, L., et al., "Efficacy of a novel oral single-agent Fumarate,
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`BG00012, in patients with relapsing—remitting multiple sclerosis: results of a phase II study," 16th
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`Meeting of the European Neurological Society (abstract to presentation given on May 30, 2006)
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`(cid:9) (cid:9)
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`(Exhibit D); and "Oral Compound BG-12 Achieves Primary Endpoint in Phase 11 Study of
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`Relapsing-Remitting MS with BG-12 Led to Statistically Significant Reductions in MRI
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`Measures," Biogen Idec News Release (May 30, 2006) (Exhibit E).
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`V
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`Only the patients who were administered 720 mg/day DMF exhibited a statistically
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`I significant effect on the primary endpoint vs. placebo. Patients in this dose group
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`showed a 69% decrease (P<0.001) in the mean number of new Gd+ lesions over
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`MRI scans Weeks 12 to 24 as shown in Figure 1 below.
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 4
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 4
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`Atty. Dkt. No.2159.32l000[
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`- 21 -
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`LUKASHEV
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`Appl. No. 12/526,296
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`l7 .
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`I hereby declare that all statements made herein of my own knowledge are true and
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`that all statements made on information and belief are believed to be true; and further that these
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`statements were made with the knowledge that willful false statements and the like so made are
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`punishable by fine or imprisonment, or both, under Section 1001 of Title 18 of the United States
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`Code and that such willful false statements may jeopardize the validity of the present patent
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`application or any patent issued thereon.
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`Respectfully submitted,
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` atherine T. Dawson
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`WWII
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`l43l835_l.DOC
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 5
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 5
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`Atty. Dkt. No. 2159.3210001
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`Appendix A
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`Exhibit A
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`Curriculum Vitae for Katherine T. Dawson
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`Exhibit B
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`Exhibit C
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`Exhibit D
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`Kappos, L., et al., "Efficacy and safety of oral fumarate in patients with
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`relapsing-remitting multiple sclerosis: a multicenter, randomised, double-blind,
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`placebo-controlled phase IIIb study," Lancet 3 72: 1463-72 (2008)
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`Kappos, L., et al., "Efficacy of a novel oral single-agent fumarate, BG00012, in
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`patients with relapsing-remitting multiple sclerosis: results of a phase 2 study,"
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`16th Meeting of the European Neurological Society (May 30, 2006) (Slide
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`Presentation)
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`Kappos, L., et al., "Efficacy of a novel oral single-agent Fumarate, BG00012, in
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`patients with relapsing-remitting multiple sclerosis: results of a phase II study,"
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`16th Meeting of the European Neurological Society (May 30, 2006) (Abstract to
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`Exhibit E
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`"Oral Compound BG-12 Achieves Primary Endpoint in Phase II Study of
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`Relapsing-Remitting MS with BG-12 Led to Statistically Significant Reductions
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`in MRI Measures," Biogen Idec News Release (May 30, 2006)
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 6
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`Exhibit C
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`to Exhibit 1
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 7
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 7
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`3.93m=$93m”.03:52
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 9
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`25
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 9
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 10
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`26
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 10
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 11
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 12
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 13
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 14
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`30
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 14
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 15
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 16
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 16
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 17
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 17
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 18
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 19
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 20
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 21
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 22
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 23
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 24
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 25
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 26
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 26
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 27
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 28
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 28
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`MYLAN PHARMS. INC. EXHIBIT 1046 PAGE 29
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