`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`___________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________
`
`
`COALITION FOR AFFORDABLE DRUGS V LLC;
`HAYMAN CREDES MASTER FUND, L.P.;
`HAYMAN ORANGE FUND SPC – PORTFOLIO A;
`HAYMAN CAPITAL MASTER FUND, L.P.;
`HAYMAN CAPITAL MANAGEMENT, L.P.;
`HAYMAN OFFSHORE MANAGEMENT, INC.;
`HAYMAN INVESTMENTS, LLC;
`NXN PARTNERS, LLC;
`IP NAVIGATION GROUP, LLC;
`J KYLE BASS; and ERICH SPANGENBERG,
`Petitioner,
`
`v.
`
`BIOGEN MA INC.,
`Patent Owner.
`
`____________________________________________
`
`Case: IPR2015-01993
`U.S. Patent No. 8,399,514
`____________________________________________
`
`BIOGEN’S MOTION TO ANTEDATE
`
`
`
`
`
`
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`Page 1 of 30
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`Biogen Exhibit 2034
`Mylan v. Biogen
`IPR2018-01403
`
`
`
`TABLE OF CONTENTS
`
`Case: IPR2015-01993
`Patent No. 8,399,514
`
`
`
`Introduction ...................................................................................................... 1
`
`Precise Relief Requested ................................................................................. 1
`
`I.
`
`II.
`
`III. Biogen Is Entitled to Its February 8, 2007 Priority Date ................................. 1
`
`IV. Kappos 2006 Is Not Prior Art to Claims 1-16 and 20 ..................................... 2
`
`A. Dr. O’Neill Conceived of the Claimed Invention No Later Than
`February 2004 ........................................................................................ 2
`
`B.
`
`Biogen Was Diligent from Before Publication of Kappos 2006
`Until the Claimed Invention Was Constructively Reduced to
`Practice on February 8, 2007 ................................................................. 6
`
`1.
`
`2.
`
`The BG-12 Program Involved Many People and Teams ........... 9
`
`Biogen Worked Every Day During the Relevant Time
`Period on Activities Toward Reduction to Practice ................. 12
`
`i.
`
`ii.
`
`Category 1: Nonclinical Animal Studies (October
`2004 - June 2007) ........................................................... 13
`
`Category 2: Advancing Clinical Development
`Toward Phase 3 Clinical Trials (May 2006 –
`February 2007) ................................................................ 15
`
`(a) Activities Related to MS IND No. 73,061 ........... 15
`
`(b) European Regulatory Activities ........................... 16
`
`(c) Activities Related to Drafting Phase 3
`Clinical Trial Protocols ........................................ 17
`
`(d)
`
`Phase 3 Start-Up Activities .................................. 22
`
`V.
`
`Conclusion ..................................................................................................... 25
`
`
`
`
`
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`i
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`Page 2 of 30
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`
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`TABLE OF AUTHORITIES
`
`Case: IPR2015-01993
`Patent No. 8,399,514
`
`
` Page(s)
`
`Federal Cases
`Bey v. Kollonitsch,
`806 F.2d 1024 (Fed. Cir. 1986) ............................................................................ 6
`
`Broadcom Corp. v. Qualcomm Inc.,
`543 F.3d 683 (Fed. Cir. 2008) .............................................................................. 2
`
`Brown v. Barbacid,
`436 F.3d 1376 (Fed. Cir. 2006) ............................................................................ 7
`
`Burroughs Wellcome Co. v. Barr Labs., Inc.,
`40 F.3d 1223 (Fed. Cir. 1994) .............................................................................. 2
`
`De Solms v. Schoenwald,
`15 U.S.P.Q.2d 1507 (B.P.A.I. 1990) .................................................................... 7
`
`In re Jolley,
`308 F.3d 1317 (Fed. Cir. 2002) ............................................................................ 7
`
`Jones v. Evans,
`46 F.2d 197 (C.C.P.A. 1931) ................................................................................ 8
`
`Keizer v. Bradley,
`270 F.2d 396 (C.C.P.A. 1959) ............................................................................ 24
`
`Louis v. Okada,
`Intf. No. 104,311, Paper 293, 2002 WL 31358222 (B.P.A.I. Oct.
`16, 2002) ............................................................................................................... 7
`
`Monsanto Co. v. Mycogen Plant Sci., Inc.,
`261 F.3d 1356 (Fed. Cir. 2001) ...................................................................... 6, 12
`
`Price v. Symsek,
`988 F.2d 1187 (Fed. Cir. 1993) ............................................................................ 3
`
`Rey-Bellet v. Engelhardt,
`493 F.2d 1380 (C.C.P.A. 1974) ............................................................................ 7
`
`ii
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`Page 3 of 30
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`
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`Scott v. Koyama,
`281 F.3d 1243 (Fed. Cir. 2002) ...................................................................... 7, 13
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`Case: IPR2015-01993
`Patent No. 8,399,514
`
`
`Slip Track Sys., Inc. v. Metal-Lite, Inc.,
`304 F.3d 1256 (Fed. Cir. 2002) ........................................................................ 2, 6
`
`Tyco Healthcare Grp. LP v. Ethicon Endo–Surgery, Inc.,
`774 F.3d 968 (Fed. Cir. 2014) .................................................................... 2, 7, 12
`
`Vogt v. Neuschotz,
`154 U.S.P.Q. 376 (B.P.A.I. 1966) ........................................................................ 7
`
`Federal Statutes
`
`U.S.C. § 119(e)(1) ...................................................................................................... 1
`
`U.S.C. § 120 ............................................................................................................... 1
`
`35 U.S.C. § 102(a) ................................................................................................. 1, 2
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`
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`iii
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`Page 4 of 30
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`Case No. IPR2015-01993
`Patent 8,399,514
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`I.
`
`Introduction
`Petitioner relies on Kappos 2006 (Ex. 1003A) for each alleged ground of
`
`unpatentability. But Kappos 2006 is not prior art to at least claims 1-16 and 20 of
`
`U.S. Patent No. 8,399,514 (“the ’514 patent,” Ex. 1001). In particular, Biogen is
`
`entitled to its February 8, 2007 priority date. As such, Kappos 2006 is prior art
`
`only under 35 U.S.C. § 102(a) because it was published less than one year before
`
`this date. Because Dr. Gilmore O’Neill conceived of the invention of claims 1-16
`
`and 20 before Kappos 2006 was published, and he and others at Biogen worked
`
`diligently to reduce his invention to practice, Kappos 2006 is not prior art as to
`
`those claims. Petitioner’s first two grounds of unpatentability therefore must fail.
`
`II.
`
`Precise Relief Requested
`
`Biogen respectfully requests that the Board find (1) that Biogen is entitled to
`
`its February 8, 2007 priority date, and (2) that Kappos 2006 (Ex. 1003A) and Dr.
`
`Kappos’ slide presentation (Ex. 1007 at 56-77) are not prior art to at least claims 1-
`
`16 and 20 of the ’514 patent based on Dr. O’Neill’s prior conception and his and
`
`Biogen’s reasonable diligence to reduce his invention to practice.
`
`III. Biogen Is Entitled to Its February 8, 2007 Priority Date
`As established in Biogen’s Opposition, the chain of applications leading to
`
`the ’514 patent meets the requirements of §§ 119(e)(1) and 120, and the ’514
`
`patent claims are therefore entitled to the February 8, 2007 filing date of U.S.
`
`1
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`Case No. IPR2015-01993
`Patent 8,399,514
`Provisional Appl. No. 60/888,921 (“the provisional application”). (Opp’n at 5-17.)
`
`IV. Kappos 2006 Is Not Prior Art to Claims 1-16 and 20
`A patent owner may disqualify § 102(a) prior art by showing prior invention.
`
`Broadcom Corp. v. Qualcomm Inc., 543 F.3d 683, 693-94 (Fed. Cir. 2008). Here,
`
`Dr. O’Neill conceived of the claimed invention no later than February 19, 2004.
`
`He and others then worked diligently to reduce his invention to practice, including
`
`from before May 2006 until February 2007 when Biogen constructively reduced
`
`the invention to practice by filing the provisional application. Tyco Healthcare
`
`Grp. LP v. Ethicon Endo–Surgery, Inc., 774 F.3d 968, 974-75 (Fed. Cir. 2014).
`
`A. Dr. O’Neill Conceived of the Claimed Invention No Later Than
`February 2004
`Conception concerns the mental part of an invention. Burroughs Wellcome
`
`Co. v. Barr Labs., Inc., 40 F.3d 1223, 1227-28 (Fed. Cir. 1994). It requires a
`
`“definite and permanent” idea such that one of ordinary skill would understand and
`
`be able to reduce the invention to practice without extensive research or
`
`experimentation. Id. at 1228. Conception requires only that the inventor had an
`
`idea, not that he knew it would work. Id. An inventor’s testimony about his
`
`conception must be corroborated by documents or testimony of other witnesses.
`
`Slip Track Sys., Inc. v. Metal-Lite, Inc., 304 F.3d 1256, 1263 (Fed. Cir. 2002)
`
`(inventor testimony, but not physical exhibits, require corroboration). Conception,
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`2
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`reduction to practice, and diligence are legal questions based on underlying facts.
`
`See Price v. Symsek, 988 F.2d 1187, 1190 (Fed. Cir. 1993).
`
`When Dr. O’Neill joined Biogen in 2003, the only U.S. Food and Drug
`
`Administration (FDA) approved multiple sclerosis (MS)
`
`treatments were
`
`administered by injection. (Ex. 2076 ¶ 10; Ex. 2078 ¶ 11.) Recognizing a need,
`
`Biogen sought to develop an oral MS treatment. (Ex. 2076 ¶ 10; Ex. 2078 ¶ 11.)
`
`Not long after Dr. O’Neill joined Biogen in the second quarter of 2003, and subject
`
`to a confidentiality agreement, he learned of a proprietary drug candidate program
`
`called “FAG-201” being pursued by a company called Fumapharm AG. (Ex. 2076
`
`¶ 8.) Under its program, Fumapharm AG had studied a DMF-only drug product in
`
`psoriasis patients. (Id.)
`
`In September 2003, Biogen
`
`licensed certain exclusive rights from
`
`Fumapharm AG to develop and market treatments for MS and psoriasis using a
`
`DMF-only drug product. (Ex. 2076 ¶ 11; Ex. 2078 ¶ 12; Ex. 2079 ¶ 11.) Biogen
`
`called this development program “BG-12.” (Ex. 2076 ¶ 11; Ex. 2078 ¶ 12; Ex.
`
`2079 ¶ 11.) Biogen initiated projects for MS (MS BG-12 program) and psoriasis
`
`(psoriasis BG-12 program). (Ex. 2076 ¶ 11; Ex. 2078 ¶ 12; Ex. 2079 ¶¶ 7, 11.)
`
`Dr. O’Neill was the Medical Director for the MS BG-12 program when the
`
`project started. (Ex. 2076 ¶¶ 5, 12, 18; Ex. 2078 ¶ 13; Ex. 2079 ¶¶ 7, 16.) He was
`
`responsible for designing an ongoing Clinical Development Plan for the MS
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`3
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`indication, which included designing a Phase 2 proof-of-concept clinical trial of
`
`BG-12 (DMF) in MS patients. (Ex. 2076 ¶¶ 12, 24; Ex. 2078 ¶¶ 13, 16; Ex. 2079
`
`¶ 16.) A key component of his trial design was dosing BG-12. (Ex. 2076 ¶ 18; Ex.
`
`2078 ¶ 13.)
`
`By February 19, 2004, Dr. O’Neill conceived of orally administering BG-12
`
`at a therapeutically effective amount of 480 mg/day in two equal doses to treat MS
`
`patients. (Ex. 2076 ¶¶ 4, 18; Ex. 2078 ¶ 14; Ex. 2079 ¶¶ 23, 53; Ex. 2309 at 6, 14,
`
`16, 21.) He presented his ideas in a slide presentation (Ex. 2309) to Biogen’s
`
`Clinical Trial Review Board (CTRB) as part of his overall Phase 2 clinical trial
`
`design. (Ex. 2076 ¶¶ 19-20; Ex. 2078 ¶ 14; Ex. 2079 ¶ 24.) The CTRB was a
`
`committee charged with reviewing protocol concepts and providing company
`
`approval for Biogen-sponsored clinical studies. (Ex. 2076 ¶ 19; Ex. 2078 ¶ 14.) Dr.
`
`Carmen Bozic chaired the CTRB. (Ex. 2076 ¶ 19; Ex. 2078 ¶ 14.)
`
`Although Dr. O’Neill believed that orally administering 720 mg/day of DMF
`
`could be more efficacious for treating MS patients, he also strongly believed that a
`
`dose of 480 mg/day could be efficacious and should be tested in Biogen’s clinical
`
`trials for BG-12. (Ex. 2076 ¶¶ 18, 21-23; Ex. 2078 ¶¶ 14, 18; Ex. 2079 ¶ 24.)
`
`Consistent with these beliefs, his lead protocol concept (Option 1) and his first
`
`proposed alternative (Option 2) included orally administering 480 mg/day of DMF
`
`in two equal doses. (Ex. 2076 ¶ 19; Ex. 2078 ¶ 14; Ex. 2079 ¶ 24; Ex. 2309 at 14;
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`Ex. 2310 at 2.) For Options 1 and 2, Dr. O’Neill also contemplated an initial
`
`treatment period of 24 weeks, followed by a 24-week extension phase. (Ex. 2076
`
`¶ 19; Ex. 2078 ¶ 15; Ex. 2079 ¶ 25; Ex. 2309 at 16, 21.) BG-12 was to be
`
`administered orally using Biogen’s BG-12 capsules. (Ex. 2076 ¶ 19; Ex. 2078
`
`¶ 15; Ex. 2079 ¶ 25; Ex. 2309 at 15.) Moreover, as evidenced by each of the
`
`protocol concepts, Dr. O’Neill contemplated administering DMF for certain dosing
`
`arms in three equal doses. (Ex. 2078 ¶ 14; Ex. 2079 ¶ 24; Ex. 2309 at 14.) And
`
`although Dr. O’Neill’s presentation does not expressly describe orally
`
`administering 480 mg/day of monomethyl fumarate (MMF), Petitioner asserts that
`
`DMF and MMF have essentially the same biological activity and that the effective
`
`amounts of DMF and MMF are the same. (Pet. at 14-15.)
`
`Dr. O’Neill’s conception is further corroborated by Biogen employees who
`
`attended the February 19, 2004 CTRB meeting. Dr. Bozic (then Senior Director,
`
`Medical Research and CTRB chair) and Ms. Cara Lansden (then Manager, Clinical
`
`Development) attended that meeting, and both confirm that Dr. O’Neill prepared
`
`and presented the slides (Ex. 2309) at the CTRB meeting. (Ex. 2078 ¶¶ 14-15; Ex.
`
`2079 ¶¶ 24-27.) They also recall his conviction that orally administering 480
`
`mg/day of DMF could be therapeutically effective to treat MS patients and should
`
`be tested in clinical trials. (Ex. 2076 ¶ 18; Ex. 2078 ¶¶ 14, 18; Ex. 2079 ¶¶ 24, 27.)
`
`Moreover, Dr. Katherine Dawson, who has known Dr. O’Neill since 1992 and
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`worked in the office next to his in 2004, recalls through their many conversations
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`around that time that he felt very strongly about the 480 mg/day dose and its
`
`potential to be therapeutically effective in MS patients. (Ex. 2077 ¶ 8.)
`
`Thus, as independently corroborated by the testimony of Dr. Dawson, Dr.
`
`Bozic, and Ms. Lansden and contemporaneous documents, Dr. O’Neill conceived
`
`of the invention by no later than February 19, 2004. Slip Track, 304 F.3d at 1263
`
`(inventor testimony, but not physical exhibits, require corroboration).
`
`B.
`
`Biogen Was Diligent from Before Publication of Kappos 2006
`Until the Claimed Invention Was Constructively Reduced to
`Practice on February 8, 2007
`
`Reasonable diligence toward reducing an invention to practice is required
`
`throughout the relevant time period. Monsanto Co. v. Mycogen Plant Sci., Inc., 261
`
`F.3d 1356, 1369 (Fed. Cir. 2001). Petitioner has asserted that Kappos 2006 would
`
`have been publicly available no later than July 1, 2006. (Ex. 1020 at 3.)
`
`Nevertheless, Biogen was diligent from before the Kappos slide presentation (Ex.
`
`1007 at 56-77) on May 30, 2006, until Biogen constructively reduced the invention
`
`to practice on February 8, 2007, by filing a provisional application. See Bey v.
`
`Kollonitsch, 806 F.2d 1024, 1026 (Fed. Cir. 1986) (awarding priority based on
`
`prior conception coupled with diligence to constructive reduction to practice).
`
`Diligence is determined by the facts and circumstance of each case.
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`Monsanto, 261 F.3d at 1369. Activities demonstrating diligence may take a
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`“diversity of forms.” Scott v. Koyama, 281 F.3d 1243, 1248 (Fed. Cir. 2002). The
`
`length of time needed to reduce an invention to practice is not material. De Solms
`
`v. Schoenwald, 15 U.S.P.Q.2d 1507, 1511 (B.P.A.I. 1990) (that the inventor did
`
`not take the most expeditious course was immaterial); Louis v. Okada, Intf. No.
`
`104,311, Paper 293, at 12, 2002 WL 31358222, at *6 (B.P.A.I. Oct. 16, 2002)
`
`(diligence requires continuous effort, but not necessarily a quick result). A patent
`
`owner may rely on others’ activities in establishing diligence. De Solms, 15
`
`U.S.P.Q.2d at 1511.
`
`Activities that are part of an overall scheme of inventive activity directed to
`
`reducing the invention to practice may be relied on to prove diligence. In re Jolley,
`
`308 F.3d 1317, 1326-28 (Fed. Cir. 2002) (screening research outside the count was
`
`diligent activity because it represented a first step toward practicing the invention).
`
`Similarly, activities geared to a government sponsor’s needs may be credited as
`
`diligence. Vogt v. Neuschotz, 154 U.S.P.Q. 376, 378 (B.P.A.I. 1966).
`
`Reasonable diligence must account for the natural course of a project. See
`
`Tyco, 774 F.3d at 975 (reasoning that periodic reports showing lab results, due
`
`dates, milestones, and similar evidence of ongoing activity evidenced reasonable
`
`diligence despite an apparent five-month gap in weekly records during a sixteen-
`
`month period); Brown v. Barbacid, 436 F.3d 1376, 1381 (Fed. Cir. 2006) (finding
`
`diligence despite many short periods of inactivity); Rey-Bellet v. Engelhardt, 493
`
`7
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`F.2d 1380, 1388-89 (C.C.P.A. 1974) (finding diligence despite a three-month delay
`
`due to shortage of available test subjects); Jones v. Evans, 46 F.2d 197, 202-03
`
`(C.C.P.A. 1931) (reasoning that evidence of ongoing activity showed reasonable
`
`diligence despite lack of affirmative evidence that steps were taken).
`
`Throughout the Phase 2b clinical trial and in preparing for the Phase 3
`
`clinical trials, Dr. O’Neill remained a strong proponent of evaluating the 480
`
`mg/day dose, and he and many others worked diligently to reduce his invention to
`
`practice. After his conception, Biogen worked diligently every day on the BG-12
`
`program from before May 30 2006, through Biogen’s constructive reduction to
`
`practice on February 8, 2007. (See, e.g., Ex. 2051 (Daily Activity Chart); Ex. 2076
`
`¶¶ 4-64; Ex. 2078 ¶¶ 4-29; Ex. 2079 ¶¶ 4-54; Ex. 2080 ¶¶ 12-71; Ex. 2077 ¶¶ 4-
`
`75, 81.) While analyzing the results of the Phase 2b clinical trial, which established
`
`the safety of a dose of 720 mg/day or less, including the 480 mg/day dose, Biogen
`
`was eager to move forward with Phase 3 clinical trials. (Ex. 2076 ¶¶ 22, 37; Ex.
`
`2078 ¶¶ 17, 24; see Ex. 2080 ¶¶ 41-43, 58; Ex. 2077 ¶ 24.) Different overlapping
`
`activities occurred every day, each a required step toward actual reduction to
`
`practice of the invention. (Ex. 2076 ¶¶ 4-64; Ex. 2078 ¶¶ 4-29; Ex. 2079 ¶¶ 4-54;
`
`Ex. 2080 ¶¶ 12-71; Ex. 2077 ¶¶ 4-75, 81.) These daily activities can be grouped
`
`into two categories:
`
`(1) nonclinical animal studies (Oct. 2004 – June 2007); and
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`(2) advancing clinical development toward Phase 3 clinical trials (May 2006
`
`– Feb. 2007).
`
`(Ex. 2076 ¶¶ 4-64; Ex. 2078 ¶¶ 4-29; Ex. 2079 ¶¶ 4-54; Ex. 2080 ¶¶ 12-71; Ex.
`
`2077 ¶¶ 4-75, 81.) Biogen conducted several nonclinical animal studies in which
`
`BG-12 was administered to animals on each day of the critical time period while
`
`Biogen prepared regulatory submissions and planned for Phase 3 trials. (See Ex.
`
`2033 (showing overlapping daily-dosing periods of nonclinical studies); Ex. 2076
`
`¶¶ 4-64; Ex. 2078 ¶¶ 4-29; Ex. 2079 ¶¶ 4-54; Ex. 2080 ¶¶ 12-71; Ex. 2077 ¶¶ 4-
`
`75, 81.)
`
`1.
`The BG-12 Program Involved Many People and Teams
`The development of BG-12 (approved as Tecfidera®), an embodiment of the
`
`claimed invention, was a high priority at Biogen, involving many people and
`
`departments. (Ex. 2076 ¶¶ 7, 13; Ex. 2078 ¶¶ 5-6; Ex. 2079 ¶¶ 13, 52; Ex. 2080
`
`¶ 18; Ex. 2077 ¶ 9.) To manage this effort, Biogen established teams to support the
`
`BG-12 program. (See Ex. 2052; Ex. 2076 ¶ 13; Ex. 2079 ¶ 13; Ex. 2077 ¶ 9.) As
`
`Medical Director for developing BG-12 for MS, Dr. O’Neill played a key role on
`
`several of these teams. (Ex. 2076 ¶ 13; Ex. 2079 ¶¶ 13, 17.) At the program level,
`
`Dr. O’Neill was part of the BG-12 Program Team, which typically met weekly and
`
`included individuals who supervised and directed the overall BG-12 program. (See
`
`Ex. 2052; Ex. 2076 ¶ 13; Ex. 2079 ¶¶ 13, 17; Ex. 2077 ¶ 9.) It also included key
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`members from the MS and psoriasis BG-12 teams. (Ex. 2076 ¶ 13; Ex. 2079 ¶ 13.)
`
`The BG-12 Program Team created and managed an integrated development plan
`
`for
`
`the BG-12 program,
`
`including nonclinical and clinical development,
`
`operations, manufacturing, financing, and commercialization. (Ex. 2076 ¶ 13; Ex.
`
`2079 ¶ 13; Ex. 2077 ¶ 9.)
`
`Biogen established two Clinical Development Teams (CDTs)—an MS CDT
`
`and a psoriasis CDT. (Ex. 2076 ¶ 14; Ex. 2079 ¶ 14; Ex. 2077 ¶ 11.) Dr. O’Neill
`
`led the MS CDT, which usually met weekly. (Ex. 2076 ¶ 14; Ex. 2079 ¶ 17; Ex.
`
`2077 ¶ 11.) The MS CDT developed and managed an ongoing Clinical
`
`Development Plan for the MS indication and ensured that the program met
`
`company deadlines and goals. (Ex. 2076 ¶ 14; see Ex. 2079 ¶ 14.) The MS CDT
`
`included a Manager, Clinical Development and a Program Statistician. (See Ex.
`
`2052; Ex. 2076 ¶ 14; Ex. 2077 ¶ 11.) During Dr. O’Neill’s time as Medical
`
`Director, Ms. Lansden served as Manager, Clinical Development, and she and Dr.
`
`O’Neill communicated regularly regarding BG-12. (Ex. 2076 ¶ 14; Ex. 2079 ¶¶ 16,
`
`19, 22, 51.) They often attended the same meetings and received or were copied on
`
`the same communications. (Ex. 2076 ¶ 14; Ex. 2079 ¶¶ 19, 22.) For meetings that
`
`Dr. O’Neill could not attend, Ms. Lansden updated him concerning discussions and
`
`developments, and vice versa. (Ex. 2076 ¶ 14; Ex. 2079 ¶¶ 19, 22.) The MS CDT
`
`also included lead representatives from Regulatory Affairs, Drug Safety and Risk
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`
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`Management, Planning
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`and Operations, Data Management, Clinical
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`Communications, Drug Logistics, and other groups as needed. (See Ex. 2052; Ex.
`
`2076 ¶ 14; Ex. 2079 ¶ 14; Ex. 2077 ¶ 11.) These representatives coordinated the
`
`group’s efforts toward reducing to practice Dr. O’Neill’s invention and obtaining
`
`approval of Tecfidera®. (Ex. 2076 ¶ 14; Ex. 2079 ¶¶ 14, 20.)
`
`The MS and psoriasis BG-12 teams communicated regularly, including
`
`during BG-12 Program Team meetings in which key members from the MS and
`
`psoriasis teams regularly participated. (Ex. 2076 ¶ 16.) Thus, as Medical Director
`
`and a core member of and regular participant in BG-12 Program Team meetings,
`
`Dr. O’Neill participated in discussions of issues and decisions relevant to the MS
`
`and psoriasis indications, such as the safety and tolerability of BG-12 dosing. (Id.)
`
`In addition to Biogen employees who directly supported the MS BG-12
`
`program, external parties were contracted to carry out Biogen’s protocols for
`
`nonclinical and clinical trials. (Id. ¶ 17; Ex. 2077 ¶ 13.) These groups included
`
`Contract Research Organizations (CROs) and other vendors, manufacturers,
`
`laboratories, investigators, medical researchers, and technicians. (Ex. 2076 ¶ 17.)
`
`Thus, in the context of preparing for and carrying out nonclinical and clinical trials,
`
`“Biogen” also includes those entities and individuals contracted to perform trial-
`
`related services on Biogen’s behalf. (Id.)
`
`In July 2006, Dr. O’Neill transferred his BG-12 Medical Director
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`responsibilities to Dr. Dawson. (Ex. 2076 ¶¶ 38, 63; Ex. 2079 ¶¶ 21, 48; Ex. 2077
`
`¶¶ 4, 9, 12; Ex. 2316 at 5.) Moving forward, Dr. Dawson attended BG-12 Program
`
`Team meetings and MS CDT meetings, usually on a weekly basis. (Ex. 2077 ¶ 9.)
`
`Dr. Dawson was also a key member of the MS Study Management Teams (SMTs)
`
`for carrying out Biogen’s Phase 3 studies. (Id. ¶ 10.)
`
`Through these three teams—the BG-12 Program Team, the MS CDT, and
`
`the MS SMT—Biogen worked every day from before May 30, 2006, until
`
`February 8, 2007, to reduce Dr. O’Neill’s invention to practice. During the relevant
`
`time period, Biogen’s BG-12 teams collectively met at least three times a week.
`
`(Ex. 2076 ¶¶ 13-15; Ex. 2079 ¶¶ 17-20; Ex. 2077 ¶¶ 9-11.) Meeting minutes were
`
`generated and circulated showing current and future tasks. (Ex. 2076 ¶¶ 13-15.)
`
`The minutes also charted each team’s progress. (See id.) This constant activity,
`
`which supported Phase 3 clinical trials to actually reduce Dr. O’Neill’s invention to
`
`practice, constitutes reasonable diligence. Tyco, 774 F.3d at 975 (lab results and
`
`reports showing due dates and milestones and similar evidence established
`
`reasonable diligence); Monsanto, 261 F.3d at 1370 (evidence of continuous work
`
`demonstrated diligence despite lack of daily notebook entries).
`
`2.
`
`Biogen Worked Every Day During the Relevant Time
`Period on Activities Toward Reduction to Practice
`
`On each day of the relevant time period, Biogen worked to reduce Dr.
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`Case No. IPR2015-01993
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`O’Neill’s invention to practice. In four nonclinical animal studies, BG-12 was
`
`administered to animals on each day. (See Ex. 2033 (showing the overlapping
`
`daily-dosing periods of Biogen’s nonclinical studies); Ex. 2076 ¶¶ 25-26, 44-45;
`
`Ex. 2078 ¶ 7; Ex. 2080 ¶¶ 23-35; Ex. 2077 ¶¶ 15-20, 34, 36, 43, 48, 54, 58, 63, 67,
`
`71.) These studies were required to plan for and execute Biogen’s Phase 3 clinical
`
`trials, where a daily dose of 480 mg/day was tested and reduced to practice. (Ex.
`
`2076 ¶¶ 25, 45; Ex. 2080 ¶¶ 21, 70.) And, after assimilating the data from its Phase
`
`2 study where the safety of a dose of 480 mg/day was established, Biogen
`
`concurrently prepared regulatory submissions and planned for Phase 3 trials,
`
`including accounting for a 480 mg/day dosing arm. (See Ex. 2079 ¶ 38; Ex. 2080
`
`¶ 41; Ex. 2289 at 12; Ex. 2316 at 6.) These overlapping activities were required for
`
`actual reduction to practice of the invention. Scott, 281 F.3d at 1248 (crediting
`
`activities focused on selecting a company to construct a plant to practice the
`
`claimed method).
`
`i.
`
`Category 1: Nonclinical Animal Studies (October
`2004 - June 2007)
`
`From October 2004 to June 2007, Biogen worked every day to conduct four
`
`overlapping, nonclinical animal studies. (Ex. 2076 ¶¶ 25-26, 44-45; Ex. 2078 ¶ 7;
`
`Ex. 2080 ¶¶ 21-35, 37-38; Ex. 2077 ¶¶ 15-20, 34, 36, 43, 48, 54, 58, 63, 67, 71.)
`
`These FDA-required studies were needed to establish the safety and efficacy of
`
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`BG-12 as a treatment for MS in humans. (Ex. 2076 ¶¶ 25, 45; Ex. 2080 ¶¶ 21, 70;
`
`Ex. 2077 ¶ 15.) Each study is described below and summarized in Ex. 2033.
`
`Biogen conducted a two-year rat carcinogenicity study (Study No. P00012-
`
`04-11) in which rats were administered BG-12 daily and checked daily and weekly
`
`for health observations. These activities began on October 26, 2004, and continued
`
`every day (except December 23, 2004, and January 6, 2005, due to inclement
`
`weather) until October 23, 2006. (Ex. 2076 ¶¶ 52, 57, 61; Ex. 2078 ¶ 7; Ex. 2080
`
`¶¶ 25-26; Ex. 2077 ¶ 18; Ex. 2274 at 20-21; Ex. 2375 at 18.)
`
`Biogen also conducted a two-year mouse carcinogenicity study (Study No.
`
`P00012-05-03) in which mice were administered BG-12 daily and checked daily
`
`and weekly for health observations. These activities began on June 28, 2005, and
`
`continued every day until June 25, 2007. (Ex. 2076 ¶¶ 52, 57, 61; Ex. 2078 ¶ 7;
`
`Ex. 2080 ¶¶ 27-29; Ex. 2077 ¶ 17; Ex. 2375 at 26; Ex. 2377 at 19.)
`
`Biogen also conducted an eleven-month dog toxicity study (Study No.
`
`P00012-05-05) in which dogs were administered BG-12 daily and checked daily
`
`and weekly for health observations. These activities began on October 18, 2005,
`
`and continued every day until September 13, 2006. (Ex. 2076 ¶¶ 52, 57, 61; Ex.
`
`2078 ¶ 7; Ex. 2080 ¶¶ 30-32; Ex. 2077 ¶ 16; Ex. 2275 at 9, 14, 15.)
`
`In addition, Biogen conducted a one-year monkey toxicity study (Study No.
`
`P00012-05-08). Beginning on January 17, 2006, monkeys were administered BG-
`
`14
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`Case No. IPR2015-01993
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`12 daily until January 15, 2007. Beginning on day seven, monkeys were checked
`
`twice daily for clinical observations until the end of the dosing period. (Ex. 2076
`
`¶¶ 53, 58, 62; Ex. 2078 ¶ 7; Ex. 2080 ¶¶ 33-35; Ex. 2077 ¶ 19; Ex. 2276 at 9-11.)
`
`Biogen communicated the results of these four studies, which were required
`
`to actually reduce the invention to practice in Phase 3 clinical trials, to the FDA.
`
`(Ex. 2080 ¶¶ 21-22, 70; Ex. 2077 ¶ 15; Ex. 2087 at 1.)
`
`ii.
`
`Category 2: Advancing Clinical Development Toward
`Phase 3 Clinical Trials (May 2006 – February 2007)
`
`From May 2006 until February 2007, Biogen worked every day to further
`
`advance clinical development toward Phase 3 clinical trials. (Ex. 2076 ¶¶ 47-48;
`
`Ex. 2079 ¶¶ 38-39, 54; Ex. 2077 ¶ 33.) These efforts were essential to reducing Dr.
`
`O’Neill’s invention to practice.
`
`(a) Activities Related to MS IND No. 73,061
`Before human clinical trials can begin in the United States, a drug sponsor
`
`must submit an Investigational New Drug Application (IND) to the FDA. (Ex.
`
`2080 ¶ 39; Ex. 2077 ¶ 14.) An IND provides information about a drug’s chemical
`
`composition, summarizes nonclinical animal and clinical studies involving the
`
`drug, explains the drug’s intended use, and describes the protocols for proposed
`
`clinical studies. (Ex. 2080 ¶ 39.)
`
`On February 22, 2006, the MS BG-12 team submitted IND No. 73,061 for
`
`15
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`the use of BG-12 to treat MS (MS IND). (Ex. 2078 ¶ 20; Ex. 2080 ¶¶ 12, 44-48;
`
`Ex. 2077 ¶ 14; Ex. 2118.) On March 24, 2006, the FDA notified Biogen that it had
`
`placed the MS IND on clinical hold in view of additional required safety
`
`information, requiring Biogen to suspend any further clinical investigation until the
`
`information could be obtained. (Ex. 2078 ¶ 21; Ex. 2080 ¶¶ 49-51; Ex. 2250 at 2.)
`
`From May 1 to 12, 2006, Biogen prepared and submitted a response to the MS
`
`IND clinical hold. (Ex. 2076 ¶ 49; Ex. 2078 ¶ 21; Ex. 2079 ¶ 40; Ex. 2080 ¶¶ 51-
`
`52; Ex. 2343.) On June 14, 2006, the FDA lifted the clinical hold, allowing Biogen
`
`to begin planning an FDA-required study to evaluate the QTc interval prolongation
`
`potential of BG-12 when administered to healthy volunteers (Study No.
`
`109HV101).1 (Ex. 2076 ¶ 54; Ex. 2078 ¶ 21; Ex. 2079 ¶ 47; Ex. 2080 ¶¶ 53, 56;
`
`Ex. 2308 at 1; Ex. 2321.) This planning continued throughout June and into July,
`
`and on July 5, 2006, Dr. Bozic approved the study protocol. (See Ex. 2080 ¶ 56;
`
`Ex. 2077 ¶¶ 22, 40; Ex. 2308 at 1.) The first patient in the study was treated on
`
`September 10, 2006, and treatment continued daily until November 16, 2006. (Ex.
`
`2077 ¶ 27, 59; Ex. 2090 at 1.)
`
`(b) European Regulatory Activities
`
`1 A study of drug’s QTc interval prolongation potential evaluates its effect on
`
`cardiac repolarization.
`
`16
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`Case No. IPR2015-01993
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`From May to June 2006, Biogen prepared for and conducted several
`
`meetings with European regulatory agencies, including preparing a detailed agency
`
`briefing document for its Phase 3 clinical trials. In particular, in May 2006, Biogen,
`
`anticipating June 2006 meetings with European regulatory agencies, prepared an
`
`agency briefing document concerning a Phase 3 clinical trial development plan.
`
`(Ex. 2076 ¶ 50; Ex. 2122 at 2; Ex. 2350 at 1.) This document was circulated within
`
`Biogen for comments on May 8, 2006, and submitted to a regulatory authority in
`
`Sweden on May 26, 2006. (Ex. 2076 ¶ 50; Ex. 2122 at 2.) After the document was
`
`submitted, Biogen prepared throughout June 2006 for the meetings, and Dr.
`
`O’Neill and other members of the MS BG-12 team met with the regulatory
`
`agencies of Sweden, the Netherlands, the U.K., and Spain in June 2006. (Ex. 2076
`
`¶ 55; Ex. 2251 at 1; Ex. 2346; Ex. 2351.) These meetings were imperative for
`
`Biogen to begin its Phase 3 trials in Europe.
`
`(c) Activities Related to Drafting Phase 3 Clinical
`Trial Protocols
`
`Dosing for Biogen’s Phase 2b clinical trial began on November 24, 2004,
`
`after which patients took their study doses daily until approximately March 1,
`
`2006. (See Ex. 2076 ¶¶ 27-35, 46; see Ex. 2078 ¶¶ 8, 16, 19; Ex. 2079 ¶¶ 28-36;
`
`Ex. 2080 ¶ 36; Ex. 2077 ¶ 14; Ex. 2092 at 1.) After the Phase 2b clinical trial
`
`ended, Biogen prepared for and participated in an End-of-Phase-2 (EOP2) meeting
`
`17
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`Case No. IPR2015-01993
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`with the FDA. The EOP2 meeting was intended to present the data from the
`
`completed Phase 2b clinical trial and to provide the Phase 3 clinical trial protocols
`
`for the FDA to evaluate. (Ex. 2080 ¶ 54; Ex. 2077 ¶ 14.) Before the EOP2 meeting
`
`on August 30, 2006, Biogen prepared a comprehensive EOP2 mee
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