`Lead counsel: Robert W. Hahl, Reg. No. 33,893
`Backup counsel: Robert Mihail, Reg. No. 66,021
`Backup counsel: John K. Pike, Reg. No. 41,253
`Neifeld IP Law, PC
`Backup counsel: James T. Carmichael, Reg. No. 45,306
`Carmichael IP, PLLC
`
`Paper No. __
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________________
`
`Coalition for Affordable Drugs V LLC,
`
`Petitioner,
`
`v.
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`BIOGEN MA, INC.,
`
`Patent Owner.
`
`________________________________________
`
`Case IPR2015-01993
`
`Patent 8,399,514
`
`________________________________________
`
`REPLY TO PATENT OWNER’S PRELIMINARY RESPONSE
`
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW
`
`OF U.S. PATENT 8,399,514 UNDER 35 U.S.C §§ 311-319
`
`
`
`
`
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`
`
`I.
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`INTRODUCTION
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`Case No. IPR2015-01993
`Patent 8,399,514
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`Pursuant to the Patent Trial and Appeal Board’s (PTAB’s) Order of 8
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`January 2016 (Paper 13), Petitioner respectfully submits this Reply to Patent
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`Owner’s Preliminary Response in IPR2015-01993 for U.S. Patent 8,399,514 (the
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`“’514 patent”). Petitioner respectfully submits institution is proper in light of the
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`new grounds of unpatentability set forth in the petition and the new arguments and
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`evidence introduced by the Patent Owner in its Preliminary Response (see e.g.,
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`Exs. 2005-2008 and 2013).
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`II. RESPONSE
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`On page 1 of the Preliminary Response, Patent Owner argues this petition
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`(hereafter “the second petition” or “Pet.”) “repackaged” the same arguments as
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`those in petition in IPR2015-01136 (hereafter “the first petition”) (Ex. 2002). The
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`response is the second petition did not repackage the same arguments as the first
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`petition. Critical differences include the second petition’s reliance on the PTAB’s
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`intervening decision in Interference No. 106,023, use of new and distinctive prior
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`art, and assertion of new and distinguishing arguments. The PTAB’s intervening
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`decision held the ‘514 patent was not entitled to the filing date of its provisional
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`application and was accorded an effective filing date of only February 7, 2008.
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`See Pet. at 14 and 19-21; Ex. 1010. As a result of this intervening decision,
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`Kappos 2006 became available under 35 U.S.C. § 102(b) for the first time,
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`1
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`
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`enabling the unpatentability arguments in the second petition to be presented for
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`the first time. The second petition includes fundamentally new arguments based,
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`inter alia, on actual results of a Phase II study shown in Kappos 2006, which was
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`neither relied upon in the first petition nor available as 102(b) art at the time the
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`first petition was filed.
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`On pages 2-3 and 6 of the Preliminary Response, Patent Owner argues the
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`interference decision concerning the priority date of the ‘514 patent is irrelevant
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`because Petitioner asserted the same alleged effective filing date in both petitions.
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`The response is a) the priority date is highly relevant since it determines under
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`which section of 35 U.S.C. 102 a prior art reference qualifies and b) that the
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`assertion the same effective filing date was relied upon in both petitions is
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`incorrect. First, to the extent an obviousness rejection relies on prior art qualifying
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`under 35 U.S.C. § 102(a) such prior art may be removed with a Rule 131
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`declaration, whereas prior art qualifying under §102(b) cannot. Second, the first
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`petition relied on printed publications published on dates repeatedly said to be
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`“more than one year prior to February 8, 2007, the earliest effective filing date of
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`the ’514 patent” (Ex. 2002 at 5) (underlining added). In contrast, the second
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`petition repeatedly identifies February 7, 2008 as “the earliest effective filing date
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`for the claims of the ‘514 patent,” based on the PTAB’s holding in the related
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`interference (Pet. at 5-6, 14, 19-21).
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`2
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`On pages 3-5 of the Preliminary Response, Patent Owner argues the Board,
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`relying on 35 U.S.C. § 325(d), should decline to institute an IPR based on the
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`second petition to the extent it raises the same or substantially the same prior art
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`and arguments as previously presented. The response is even if the second petition
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`raised the same or substantially the same arguments as previously presented (which
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`it did not), the Board is not required to reject such a petition. The statute includes
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`permissive language, e.g., “may,” rather than mandatory language, e.g., “must.” 35
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`U.S.C. § 325(d); see also Rackspace v. PersonalWeb Tech., IPR2014-00057, Paper
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`9 at 24-25 (PTAB Apr. 15, 2014). In the second petition, Petitioner relied on prior
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`art qualifying under § 102(b), to reject the ‘514 patent claims as obvious over the
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`appropriate known and available prior art. Indeed, once the Board held on August
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`19, 2015 that the ‘514 patent claims had an effective filing date of February 7,
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`2008 (not February 8, 2007) (Ex. 1010), Petitioner promptly filed its second
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`petition on September 28, 2015 in order to present its best challenges to the ‘514
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`patent. Further, none of the prior art used to challenge the ‘514 patent in the first
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`petition teaches “excipients,” an element in claims 1-10 and 15-19 of the ‘514
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`patent. In the second petition, Joshi teaches treating an oral preparation containing
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`DMF and excipients. (Pet. at 26 citing Ex. 1030, col. 4:39–42.) Joshi 2002 teaches
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`oral preparations containing MMF and excipients. (Pet. at 54 citing Ex. 1036, col.
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`11:21–25.) Even further, none of the prior art used to challenge the ‘514 patent in
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`3
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`the first petition teaches pharmaceutical compositions containing MMF.
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`Pharmaceutical compositions containing MMF are recited in claim 7 of the ‘514
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`patent. In the second petition, Joshi 2002 teaches pharmaceutical compositions
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`containing MMF. Petition at 54 citing Ex. 1036, col. 11:21–25. Further still, none
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`of the prior art used in the first petition teaches DMF or MMF as a “tablet, a
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`suspension or a capsule,” as recited in claim 2 of the ‘514 patent. In the second
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`petition, Kappos 2006 teaches capsules containing DMF (referred to as BG00012).
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`(Pet. at 30 citing Ex. 1003, at 27, col. 2:32–33.) On the other hand, Kappos 2005,
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`cited in the first petition, does not teach any particular form of pharmaceutical
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`composition. In the second petition Joshi teaches tablets. (Pet. at 30 citing Ex.
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`1030, col. 4:31–33.) Therefore, the Board should institute an IPR based on the
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`second petition because it does not raise the same or substantially the same prior
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`art and arguments as previously presented.
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`On pages 4-5 of the Preliminary Response, Patent Owner argues the
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`petitions abuse the system and unwarrantedly burden the Board because Petitioner
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`“markets no product and is not using IPRs as an alternative to litigation.” The
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`response is Article III standing is not a requirement to appear before the USPTO.
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`The America Invents Act (“AIA”) was designed to encourage the filing of
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`meritorious patentability challenges, by any person who is not the patent owner, in
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`order to further improve patent quality. The second petition is such a filing. See
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`
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`4
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`
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`Coalition for Affordable Drugs VI, LLC. v. Celgene Corp., IPR2015-01092, Paper
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`Case No. IPR2015-01993
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`19 (PTAB Sept. 25, 2015).
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`On page 7 of the Preliminary Response, Patent Owner argues Petitioner
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`discussed, but chose not to rely on, Kappos 2006 in the first petition. The response
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`is relying, for institution, on a reference qualifying as prior art under § 102(a), only
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`to have it removed by a possible Rule 131 declaration, would not be an efficient
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`use of resources—the PTAB’s resources, the Patent Owner’s resources, and the
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`Petitioner’s resources. As stated in the second petition, the PTAB’s intervening
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`Interference decision cut off the possibility of Patent Owner submitting such a
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`declaration after institution (and mooting all effort that would have been expended
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`up to and including institution). Importantly, the Preliminary Response does not
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`take issue with that statement. Now that Kappos 2006 cannot be sworn behind,
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`considering it on the merits for IPR institution will not waste those resources.
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`On page 7 of the Preliminary Response, Patent Owner argues the first and
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`second petitions rely principally on similar arguments, i.e., the first petition relied
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`on the “clinical trial design” of the Phase II study disclosed in Kappos 2005 and
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`ClinicalTrials NCT00168701, including proposed BG00012 (DMF) doses of 120,
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`360 and 720 mg/day; and, the second petition relies on the same Phase II “clinical
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`trial design” disclosed in Kappos 2006 and ClinicalTrials NC00168701 with the
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`same three doses. The response is the disclosures of Kappos 2005 and Kappos
`
`
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`5
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`
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`2006 are different. As acknowledged by Patent Owner, Kappos 2006, unlike
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`Kappos 2005, discloses the results of the Phase II study (Preliminary Response at
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`7). Further, the unpatentability grounds of the second petition are different from
`
`the first. The first petition contained only a single ground that was interpreted by
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`the Board as Challenges 1-3 (First Petition, Paper 23 at page 5):
`
`Ground 1: Claims 1-20 are unpatentable under 35 U.S.C.
`§103 as obvious over any one of Kappos 2005 (Ex.
`1003A) or ClinicalTrials NCT00168701 (Ex. 1022A) or
`‘514 Patent admission of prior art (“Fumaric acid esters,
`such as DMF, have been proposed for treatment of MS”)
`in view of ICH Guideline E4 (Ex. 1004A). (First petition,
`page 6).
`
`By contrast, the second petition includes the following grounds, all of which are
`
`different from the unpatentability grounds of the first petition:
`
`Ground 1: Claims 1-6, 8-16 and 20 are unpatentable
`under 35 U.S.C. §103 as obvious over Kappos 2006 (Ex.
`1003), ClinicalTrials NCT00168701 (Ex. 1022), Joshi
`(Ex. 1030), and ICH Guideline E4 (Ex. 1004).
`
`Ground 2: Claim 7 is unpatentable under 35 U.S.C. §103
`as obvious over Kappos 2006 (Ex. 1003), ClinicalTrials
`NCT00168701 (Ex. 1022), Joshi (Ex. 1030), ICH
`Guideline E4 (Ex. 1004) and Joshi 2002 (Ex. 1036).
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`6
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`Ground 3: Claims 17-19 are unpatentable under 35
`U.S.C. §103 as obvious over Kappos 2006 (Ex. 1003),
`ClinicalTrials NCT00168701 (Ex. 1022), Joshi (Ex.
`1030), ICH Guideline E4 (Ex. 1004), and Begleiter (Ex.
`1027). (Second petition, pages 7–8.)
`
`On pages 7-11 of the Preliminary Response, Patent Owner argues the second
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`petition never attempts to tie the claimed dose of about 480 mg/day of dimethyl
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`fumarate (“DMF” or “BG00012”) and/or monomethyl fumarate (“MMF”) to the
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`results of the Kappos2006 Phase II study results, but instead, relies on combining
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`the disclosure of Kappos 2006 with that of ICH Guideline E4 and ClinicalTrials
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`NCT00168701 to advance the proposed obviousness conclusion that one of
`
`ordinary skill in the art (“POSITA”) would have been motivated to administer
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`DMF at 480 mg/day (as well as at 600 mg/day) as a standard process of drug
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`development. The response is POSITA would have been motivated to treat a
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`subject with MS with the claimed dose of about 480 mg/day DMF and/or MMF
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`with a reasonable expectation of success given the combined disclosures of the
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`phase II study and results of Kappos 2006, ClinicalTrials NCT00168701, Joshi and
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`ICH Guideline E4 (Pet. at 24-30 and 42-54). In the second petition, the claimed
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`dose of 480 mg/day DMF and/or MMF is tied directly to the results of the Kappos
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`2006 study by way of reducing a proven efficacious dose, i.e., 720 mg/day of DMF
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`7
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`(Pet. at 27, 45 and 51). Working from those results, the second petition provides a
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`strong motivation to step down from the 720 mg/day dose proven in Kappos 2006:
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`to alleviate known side effects of DMF, e.g., gastrointestinal irritation as described
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`by ClinicalTrials NCT00168701 and Joshi (Pet. 27-29, 45, 47 and 51-52; see also
`
`Ex. 1022; Ex. 1030 at 5:29-33). Stepping down from a proven efficacious dose is
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`different than the argument in the first petition, which purportedly did not disclose
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`a proven efficacious dose.
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`On page 12 of the Preliminary Response, Patent Owner argues new prior art
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`reference Joshi is repetitive and cumulative to ClinicalTrials NCT00168701 and
`
`Kappos 2006 in disclosing DMF’s potential gastrointestinal side effects. The
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`response is insofar as Joshi additionally discloses pharmaceutical compositions
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`containing DMF in combination one or more pharmaceutically acceptable
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`excipients as well as tablets, micro-tablets, pellets, granulates, or sachets, Joshi is
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`not merely repetitive and cumulative (Pet. at 26, 30, 34 and 44-45; Ex. 1030 at
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`4:31-33 and 6:8-28).
`
`On page 12 of the Preliminary Response, Patent Owner parenthetically
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`argues Joshi is repetitive and cumulative to Kappos 2005. The response is Patent
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`Owner has not explained how Joshi is repetitive and cumulative to Kappos 2005
`
`because, in fact, Kappos 2005 does not address gastrointestinal side effects as does
`
`Joshi. See Ex. 1030, col. 5:29–33 cited in Pet. at 19, 40, 47, 52. Additionally,
`
`
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`8
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`Kappos 2005 does not teach tablets containing DMF whereas Joshi does. See Ex.
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`Case No. IPR2015-01993
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`1030, col. 4:31–33 cited in Pet. at 30. Furthermore, Kappos 2005 does not teach
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`administering an oral preparation containing DMF and excipients. Joshi does. See
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`Ex. 1030, col. 4:39–42 cited in Pet. at 26, 34, 45.
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`
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`On page 12 of the Preliminary Response, Patent Owner argues Joshi’s
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`disclosure of combining DMF with excipients in the second petition merely
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`substitutes for Nieboer’s disclosure in the first petition. The response is Nieboer
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`was relied upon in the first petition for its disclosure of DMF’s adverse effects, not
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`for teaching excipients (Ex. 2002 at 19, 24, 27, 28 and 41).
`
`
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`On page 12 of the Preliminary Response, Patent Owner argues Joshi’s
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`disclosure that MMF is a metabolite of DMF in the second petition merely
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`substitutes for the disclosure of Werdenberg in the first petition. The response is
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`both references disclose MMF as a metabolite of DMF, but Joshi further discloses
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`one or more pharmaceutically acceptable excipient combinations and formulation
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`forms not disclosed by Werdenberg.
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`
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`On page 13 of the Preliminary Response, Patent Owner argues Joshi 2002
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`discloses that MMF is a metabolite of DMF and adds nothing to the first petition’s
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`obviousness arguments, including providing new arguments as to “Ground 2.” The
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`response is Joshi 2002 is relied upon in Ground 2 as disclosing that the metabolite
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`9
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`MMF is itself useful to treat multiple sclerosis (Pet. at 54; Ex. 1036 at 4:27-30 and
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`11:21-25).
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`
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`On page 13 of the Preliminary Response, Patent Owner argues every prior
`
`art reference and argument in the second petition was fully available to Petitioner
`
`at the time it filed the first petition (citing to Unilever, Inc. v. Procter & Gamble
`
`Co., IPR2014-00506, Paper 17 at 6 (PTAB July 7, 2014)). The response is every
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`prior art reference and argument in the second petition was not fully available to
`
`Petitioner at the time it filed its first petition. Kappos 2006 was not available as
`
`§102(b) prior art at the time the first petition was filed.
`
`
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`On pages 15-16 of the Preliminary Response, Patent Owner argues the
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`second petition should be denied if it used the PTAB’s prior decision to remedy
`
`flaws in the first petition and thereby unreasonably burdened the Patent Owner and
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`the Office after the petitioner already had a chance to present its best case. The
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`response is the Preliminary Response does not contend Petitioner actually used the
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`PTAB’s prior decision in this manner. In fact, Petitioner did not already have a
`
`chance to present its best case at the time of the first petition. The PTAB’s
`
`subsequent interference decision allowed Petitioner to present its best case for the
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`first time in the second petition, since Kappos 2006 now cannot be disqualified
`
`with a Rule 131 declaration. None of the PTAB cases cited in the Preliminary
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`10
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`Response had this type of change in circumstances between the first petition and
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`the second petition.
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`
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`On page 16 of the Preliminary Response, Patent Owner again incorrectly
`
`argues the first petition asserted February 7, 2008 as the effective filing date of the
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`‘514 patent claims. The response is the first petition relied on printed publications
`
`published on dates repeatedly said to be “more than one year prior to February 8,
`
`2007, the earliest effective filing date of the ’514 patent” (Ex. 2002 at 5)
`
`(underlining added). In contrast, the second petition repeatedly identifies February
`
`7, 2008 as “the earliest effective filing date for the claims of the ‘514 patent,”
`
`based on the PTAB’s holding in the related interference (Pet. at 5-6, 14, 19-21).
`
`Moreover, to the extent the first petition argued the ’514 patent might not be
`
`entitled to the 2007 effective filing date, (See Ex. 2002 at 10, 11) the basis was an
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`inventorship issue that turned out to have been already corrected during pendency
`
`of the affected application (the ‘921 provisional). The PTAB’s intervening
`
`Interference decision held the ’514 patent was not entitled to the 2007 effective
`
`filing date for a completely different reason, one that was not corrected during
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`pendency of the affected application (the ‘296 application). See Second Petition
`
`Ex. 1010 at 2. Given that decision, for the first time it is now settled the ’514
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`patent is not entitled to the 2007 effective filing date.
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`11
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`
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`On page 16-17 of the Preliminary Response, Patent Owner argues even if a
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`different effective filing date applied, Kappos 2006 was still available as § 102(a)
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`prior art at the time of the first petition. The response is availability under § 102(a)
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`is very different than under § 102(b), at least because a Patent Owner can file a
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`Rule 131 declaration to swear behind a reference if it is treated under § 102(a).
`
`Compare In re Stepan Co., 660 F.3d 1341, 1344-46 (Fed. Cir. 2011) (remand for
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`further consideration of Rule 131 declaration where Board changed statutory basis
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`of prior art reference from 35 U.S.C. § 102(b) to § 102(a)). Petitioner was not
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`required to rely on a reference when it might be disqualified by a Rule 131
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`declaration after institution. As explained above, that would waste PTAB
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`resources, Patent Owner resources, and Petitioner resources. Petitioner put its
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`strongest patent challenges forward in both petitions based on the available
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`information at the time of filing each petition. The available information changed
`
`due to the PTAB’s intervening Interference decision.
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`
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`On pages 17-18 and 30-38 of the Preliminary Response, the Patent Owner
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`argues the second petition presents no evidence, let alone new evidence, rebutting
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`the unexpected results alleged to have been established during prosecution through
`
`the declarations of Drs. Dawson and Rudick. The response is the alleged
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`unexpected results are discussed at length in the second petition (Pet. at 10-14). In
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`particular, Petition cited a report from the European Medicines Agency (“Agency
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`12
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`
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`report”) (Ex. 1006) concerning assessment of DMF for marketing authorization.
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`On page 37-38, the Patent Owner further argues that the Agency report is not prior
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`art and that the Petition does not rely on it for any proposed ground of
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`unpatentability. The response is that the Agency report is not being used as a prior
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`art document to support unpatentability, but rather to rebut Patent Owner’s
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`supposed unexpected results. (Cf. Genetics Institute, LLC v. Novartis Vaccines &
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`Diagnostics, Inc., 655 F.3d 1291, 1307 (Fed. Cir. 2011) holding that “evidence of
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`unexpected results may be used to rebut a case of prima facie obviousness even if
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`that evidence was obtained after the patent's filing or issue date”.) The Agency
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`report noted “considerable imbalances” in the baseline for the 360 mg/day dosing
`
`group studied in Kappos 2006. The Agency report requested that the data for the
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`360 mg dosing group be reanalyzed. In so doing, the Agency report found that
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`“when correcting for baseline number of Gd-enhancing lesions in the statistical
`
`models as a covariate, the effect of the 120 mg TID [i.e., 360 mg/day] dosing
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`regimen [of DMF] also reached statistical significance for the various MRI
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`endpoints, at least in one of the requested models” (Pet. at 12; Ex. 1006 at 34 and
`
`79.) (emphasis added). It is small wonder that Drs. Rudick and Dawson pointed
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`out that the dose-response behaviors of DMF in subjects with RRMS were clearly
`
`not dose-proportional (Pet. at 10-13; see also Ex. 2011 at ¶9). Thus, not only were
`
`the results of the 360 mg/day dosage test group suspect, but also any results
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`13
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`between 360 mg/day and the next tested dosage group, i.e., 720 mg/day, vis-à-vis
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`placebo. As stated in the second petition at page 13, “determining the dose-
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`response behavior of a compound that is already known to be therapeutically
`
`effective is ‘the product not of innovation but of ordinary skill and common sense.’
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`KSR, 550 U.S. at 421.” Contrary to Patent Owner’s assertions, Petitioner not only
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`provided new evidence, e.g., the Agency report (Ex. 1006), but also explained the
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`relevancy of the new evidence (see e.g., Pet. at 12-13). Thus, there is no lack of
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`“specific reasoning” in the second petition as Patent Owner asserts. The supposed
`
`evidence of unexpected results has been thoroughly rebutted, and cannot overcome
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`the strong prima facie case of obviousness in any event.
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`
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`At pages 19-30 of the Preliminary Response, Patent Owner argues the
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`second petition lacks factual support and is based on improper hindsight reasoning
`
`because (1) ICH Guideline E4 does not provide a reason to select a dose of about
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`480 mg/day, (2) gastrointestinal side effects do not provide a sufficient reason to
`
`select a dose of about 480 mg/day, (3) there is no reasonable expectation that a
`
`dose of about 480 mg/day would be therapeutically effective or useful, and (4) the
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`cited cases are distinguishable. The response is each of these four reasons is
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`without merit and the obviousness challenges set forth in the second petition are
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`legally sound, relying on articulated reasoning supported by established facts and
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`testimonial evidence for the reasons set forth below.
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`14
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`At pages 21-22 of the Preliminary Response, Patent Owner argues ICH
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`Guideline E4 does not provide a reason to select a dose of about 480 mg/day. The
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`response is it is well established that one cannot show nonobviousness by attacking
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`references individually where the rejections are based on combinations of
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`references. In re Keller, 642 F.2d 413 (CCPA 1981); In re Merck & Co., Inc., 800
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`F.2d 1091 (Fed. Cir. 1986). The ICH Guideline E4 is just that – a guideline to help
`
`identify “an appropriate starting dose, the best way to adjust dosage to the needs of
`
`a particular patient, and a dose beyond which increases would be unlikely to
`
`provide added benefit or would produce unacceptable side effects” (Pet. at 29, Ex.
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`1004 at 5:7-10; Ex. 1005 at ¶¶33, 47, 61 and 70). Kappos 2006 provides three
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`putative negative result dosages – placebo, 120 mg/day DMF and 360 mg/day
`
`DMF – and one putative positive result dosage – 720 mg/day DMF. As recognized
`
`by Patent Owner (Preliminary Response at 21), ICH Guideline E4, recommends a
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`study “with three or more dosage levels” (Ex. 1004 at 13, emphasis added).
`
`Consistent with ICH Guideline E4, POSITA would not have been limited to only
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`three or four dosage levels (which may include a placebo), but rather would have
`
`been motivated in view of Kappos 2006 to determine an appropriate starting
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`dosage between about 360 mg/day and 720 mg/day which provides therapeutic
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`efficacy with an acceptable level of side effects. “[B]ecause doses in multiples of
`
`120 mg were readily available, a POSITA would have been motivated to develop a
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`15
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`method of treating a subject in need of treatment for multiple sclerosis by
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`administering dimethyl fumarate at about 480 mg per day (as well as 600 mg per
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`day) in order to identify an appropriate dose of DMF that minimized side effects”
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`(Pet. at 29). Thus, the combined disclosures of Kappos 2006, ClinicalTrials
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`NNCT00168701, Joshi and ICH Guideline E4 would have provided ample
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`reasoning/motivation to have selected a dose of about 480 mg/day as claimed.
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`At pages 22-25 of the Preliminary Response, Patent Owner argues
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`gastrointestinal side effects do not provide a sufficient reason to select a dose of
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`about 480 mg/day because (1) Joshi ties DMF-related gastrointestinal irritation to a
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`high DMF concentration, not to frequency of administration or any build-up of
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`DMF in the system, (2) the petition’s dose-reduction theory is based on an
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`incorrect factual assertion that DMF was available in 240 mg/day capsules, and (3)
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`dose reduction in the 720 mg/day group was accomplished by cutting the daily
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`dose in half from two 120 mg capsules TID to one 120 mg capsule TID, i.e., to 360
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`mg/day. The response is Patent Owner not only relies on a different passage in
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`Joshi to raise a new argument, but also introduces new evidence (Ex. 2005–2008,
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`2013) not of record in either petition said to correct a “fundamentally incorrect
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`understanding of the study design.” It is respectfully submitted that Petitioner be
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`allowed to submit rebuttal evidence to these newly raised arguments and evidence.
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`Petitioner reasonably cannot anticipate in advance everything that may be
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`presented with the Preliminary Response. Liberty Mutual Ins. Co. v. Progressive
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`Casualty Ins. Co., CBM2012-00002, Paper 38 at 2-3 (PTAB Sept. 3, 2013).
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`Nonetheless, the newly cited disclosure from the Patent Owner in Joshi (on page
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`23 of the Preliminary response citing to Ex. 1030 at 5:33-36) states administration
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`of conventional tablets results in a release of a fumarate concentration which is
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`presumably too high, thereby causing intestinal irritation and then goes on to state,
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`in the same paragraph, that very low local fumarate concentrations are achievable
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`by using enteric-coated micro-tablets in capsules (Ex. 1030 5:36-45). The second
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`petition reasonably could not have anticipated addressing modified release drug
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`formulations as a means of reducing side effects when none of the ‘514 patent
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`claims is limited to enteric-coated micro-tablets in capsules or other such modified
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`release drug formulations. Second, the poster submitted by Patent Owner as Ex.
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`2005 discussing a BG00012 (DMF) Phase II clinical trial is NOT the Kappos 2005
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`meeting abstract relied on in the first petition. Granted the poster indicates that the
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`DMF was administered in various combinations of 120 mg capsules, but no such
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`disclosure was present in Kappos 2005 of the first petition. A fair reading of
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`Kappos 2006 (and Kappos 2005) and ClinicalTrials NNCT00168701 is that since
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`subjects received DMF capsules 120 mg orally daily or three times daily, then
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`receiving “240 mg three times daily” reasonably implied 240 mg DMF capsules
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`could have been used (See Ex. 1003 at 27, abstract O108, and Ex. 1022 at 2).
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`Finally, for reasons stated above, Petitioner could not have put forward a “flawed
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`dose-reduction theory” based on the disclosure of a reference, i.e., Ex. 2005, that
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`Petitioner did not have. Moreover, POSITA would not have been motivated to cut
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`the daily dose in half from 720 mg/day to 360 mg/day because 360 mg/day was
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`disclosed as not being effective in Kappos 2006. Regardless, as discussed above,
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`Petitioner explicitly argued that “because doses in multiples of 120 mg were
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`readily available, a POSITA would have been motivated to develop a method of
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`treating a subject in need of treatment for multiple sclerosis by administering
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`dimethyl fumarate at about 480 mg per day (as well as 600 mg per day) in order to
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`identify an appropriate dose of DMF that minimized side effects” (Pet. at 29).
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`At pages 25-27 of the Preliminary Response, Patent Owner argues there is
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`no reasonable expectation that a dose of about 480 mg/day would be
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`therapeutically effective or useful since Kappos 2006 did not find doses lower than
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`720 mg/day DMF to be effective. The response is Kappos 2006 discloses that
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`efficacy occurs at a dosage above about 360 mg/day and at least about 720 mg/day
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`and that ICH Guideline E4 discloses reducing dosage in subjects experiencing
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`DMF-related side effects. Thus, POSITA would have had a reasonable expectation
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`that a dosage between about 360 mg/day and about 720 mg/day would have
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`provided an acceptable balance of safety and efficacy by reducing the 720 mg/day
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`dose in available dosing increments of 120 or 240 mg. Obviousness over the prior
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`art relied on requires a reasonable expectation of success, not absolute certainty. In
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`re O’Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988).
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`At pages 28-30 of the Preliminary Response, Patent Owner argues the cited
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`cases are distinguishable because its arguments are not premised on an incorrect
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`claim construction and the prior art does not disclose all the claim elements. The
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`response is Patent Owner has not shown how the claim construction issue renders
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`the cases inapposite, and, as described above and in the second petition, the prior
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`art in this case, in fact, discloses all the claim elements.
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`At pages 30-38 of the Preliminary Response, Patent Owner argues the
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`second petition fails to rebut purported evidence of unexpected results. The
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`response is the second petition, as discussed above, rebuts the purported evidence
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`of unexpected results. The Petition provides new evidence (e.g. the Agency report)
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`and argument rebutting the purportedly unexpected results. (See, e.g. Pet. at 10-
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`14). Furthermore, on pages 30-38 of the Preliminary Response, Patent Owner
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`offers in evidence ex parte declarations made by Drs. Dawson and Rudick to prove
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`the truth of the matter asserted in said declarations. Until these witnesses are
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`deposed, it would be fundamentally unfair to give weight to their statements. The
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`Board should not consider these declarations until after Petitioner has had an
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`opportunity to cross-examine Drs. Dawson and Rudick. Petitioner will request the
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`right to depose Drs. Dawson and Rudick.
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`At page 36 of the Preliminary Response, Patent Owner argues unrebutted
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`unexpected results must be considered in evaluating obviousness. The response is
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`even if the purported evidence of unexpected results were unrebutted, which it is
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`not, consideration of it does not overcome the strong showing of obviousness
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`established in the second petition. See e.g., Allergan Inc. v. Sandoz Inc.,
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`726 F.3d 1286, 1293 (Fed. Cir. 2013) (“We agree with the court’s finding that this
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`result was unexpected. However, we do not find that these unexpected results are
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`sufficient to outweigh the other evidence of obviousness.”). Pfizer, Inc. v. Apotex,
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`Inc., 480 F.3d 1348, 1372 (Fed. Cir. 2007); Leapfrog Enterprises Inc. v. Fisher-
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`Price Inc., 485 F.3d 1157, 1162 (Fed. Cir. 2007); and, Newell Cos., Inc. v. Kenney
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`Mfg. Co., 864 F.2d 757, 768 (Fed. Cir. 1988).
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`/RobertHahl#33,893/
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`Robert Hahl, Reg. No. 33,893
`Lead Counsel for the Petitioner
`Email: rhahl@neifeld.com
`Neifeld IP Law, PC
`4813-B Eisenhower Avenue
`Alexandria, VA 22304
`Tel: 1-703-415-0012 Ext. 107
`Fax: 1-703-415-0013
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`42.6(e) CERTIFICATE OF SERVICE
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`42.6(e)(1) Agreements on Service: “Under 37 C.F.R. § 42.6(e), Patent Owner