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`IPR2017-00412
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`_______________
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`MONOSOL RX, LLC
`Petitioner
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`v.
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`ICOS CORPORATION,
`Patent Owner
`_______________
`
`Case: IPR2017-00412
`Patent 6,943,166
`_______________
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`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 6,943,166
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`IPR2017-00412
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`TABLE OF CONTENTS
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`REQUEST FOR INTER PARTES REVIEW OF CLAIMS 1-12 OF THE
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`
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`I.
`II.
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`PAYMENT OF FEES ................................................................................................. 1
`‘166 PATENT .................................................................................................... 1
`A. The Alleged Invention of the ‘166 Patent .......................................................... 2
`B. Brief Description of the Technology .................................................................. 3
`C. Critical Date ........................................................................................................... 4
`III. CLAIM CONSTRUCTION ....................................................................................... 4
`A. Standards For Claim Construction ...................................................................... 4
`B. Construction of Terms ......................................................................................... 5
`IV. GROUNDS FOR UNPATENTABILITY OF EACH CLAIM .......................... 6
`A. Ground 1: Claims 1-12 are Unpatentable Under 35 U.S.C. § 103(a) As
`Industry, Dose Response Information to Support Drug Registration .......... 7
`B. Ground 2: Claims 1-12 are Unpatentable Under 35 U.S.C. § 103(a) As
`Add Information About Sildenafil’s Danger’s To The Drug Label. ............ 23
`C. Ground 3: Claims 1-12 are Unpatentable Under 35 U.S.C. § 103(a)
`Over Daugan ‘675 ................................................................................................ 33
`V. MANDATORY NOTICES ...................................................................................... 44
`VI. CONCLUSION........................................................................................................... 47
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`Being Obvious Over Daugan ‘675 In View of the Guideline for
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`Being Obvious Over Daugan ‘675 Alone Or In View the Petition To
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`PETITIONERS’ EXHIBIT LIST
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`IPR2017-00412
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`Description
`U.S. Patent 6,943,166
`U.S. Patent 5,859,006
`U.S. Patent 6,140,329
`U.S. Patent 6,087,362
`WO 9703675
`VIAGRA® (sildenafil citrate) label
`CIALIS® (tadalafil) label
`D. Eros, et al., Structure-Activity Relationships of PDE5 Inhibitors, Current
`Medicinal Chemistry, 2008 (15), 1570-1585.
`Prosecution History for U.S. Patent No. 6,943,166
`Expert Declaration of Roger Williams, M.D. Regarding U.S. Patent No. 6,943,166
`Excerpt from Viagra Approval Pkg
`Filloon, Estimating the minimum therapeutically effective dose of a compound via
`regression modelling and percentile estimation, Stat Med. 1995 May 15-30;14(9-
`10):925-32
`Effects of sildenafil citrate on human hemodynamics, Am. J. of Cardiology, 83(5),
`Supp. 1, pp. 13-20 (March 4, 1999)
`The Guideline for Industry, Dose Response Information to Support Drug
`Registration (“Guideline for Industry”)
`Petition To Add Information About Sildenafil’s Danger’s To The Drug Label
`Cutler, et al., Defining the Maximum Tolerated Dose: Investigator, Academic,
`Industry and Regulatory Perspectives, J. Clin. Pharmacol. 1997; 37:767-783
`ICOS 10K FY 1998
`FDA Clinical Hold - 21-368 FDA Cialis Correspondence P5
`FDA Review – Pharmr Part 5
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`Exh #
`1001
`1002
`1003
`1004
`1005
`1006
`1007
`1008
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`1009
`1010
`1011
`1012
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`1013
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`1014
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`1015
`1016
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`1017
`1018
`1019
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`ii
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`IPR2017-00412
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`Pursuant to 35 U.S.C. § 311, MonoSol Rx, LLC (“Petitioner”) respectfully
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`petitions for Inter Partes Review, seeking cancellation of claims 1-12 of U.S.
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`Patent No. 6,943,166 (the ‘166 Patent). According to USPTO records, the '166
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`patent is assigned to ICOS CORP c/o Eli Lilly and Co. (“Patent Owner”). A copy
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`of the ‘166 Patent is attached as Exh. 1001. As demonstrated by the grounds
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`presented below, the alleged invention of the challenged claims are obvious and
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`should be canceled under 35 U.S.C. § 103.
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`I.
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`PAYMENT OF FEES
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`Pursuant to 37 C.F.R. section 42.103, $23,000 is being paid at the time of
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`filing this petition, charged to Deposit Account 19-4293. Should any further fees
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`be required by the present Petition, the Patent Trial and Appeal Board (“PTAB”) is
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`hereby authorized to charge the above referenced Deposit Account.
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`II. REQUEST FOR INTER PARTES REVIEW OF CLAIMS 1-12 OF
`THE ‘166 PATENT
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`Pursuant to 37 C.F.R. §42.104(b), Petitioner requests that the PTAB find
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`unpatentable Claims 1-12 of the ‘166 patent. Such relief is justified as the alleged
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`invention of the ‘166 patent was described by others prior to the filing date of the
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`‘166 patent and obvious to one of skill in the art.
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`Petitioner is aware that the ‘166 patent was previously challenged by
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`IntelGenx Corp. in a request for Inter Partes Review, and that this Petition was
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`IPR2017-00412
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`denied institution on September 1, 2016. IPR2016-00678, Paper 13. That Petition
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`raised two grounds of unpatentability: (1) Daugan and (2) Daugan and SNDA (the
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`Viagra® Approval Package). However, in that case, the PTAB found that the
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`Petitioner “ignored the maximum-total dose requirement” in failing to “point to the
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`asserted prior art or otherwise explain why an ordinary artisan would limit the
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`tadalafil dose to 20 mg per day.” Id. at 7. The PTAB therefore concluded that the
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`Petitioner had “not established a reasonable likelihood it would prevail in showing
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`that claim 1 would have been obvious over Daugan, either alone or in combination
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`with SNDA.” Id.
`A. The Alleged Invention of the ‘166 Patent
`The ’166 patent relates generally to a method of treating sexual dysfunction
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`by orally administering tadalafil in a specific dose range that is encompassed by
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`the prior art. The ‘166 patent acknowledges that tadalafil was already known to be
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`administered in doses of 0.2-400 mg without apparent “significant side effects” Ex.
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`1001, col. 2, lines 12-21. The ‘166 patent therefore sought to claim a method of
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`administering a specific dose of tadalafil, namely “about 1 to about 20 mg, up to a
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`maximum total dose of 20 mg per day.” Id. at claim 1.
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`During prosecution, there was no dispute that the prior art taught methods of
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`treating sexual dysfunction by orally administering to a patient in need thereof one
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`or more unit dose of tadalafil, in 0.2 to 400 mg, once or several times per day and
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`2
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`IPR2017-00412
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`in fact, taught 50 mg of oral dosage forms and noted that “other strengths may be
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`prepared…” Daugan ‘675 at 5, 12-16. However, the applicants argued that there
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`were “unexpected results” for this claimed dose of “one or more unit dose
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`containing about 1 to about 20 mg, up to a maximum total dose of 20 mg per day.”
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`Ex. 1010, Decl. ¶¶ 64-76. The ‘166 patent was prosecuted and issued before 2007,
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`prior to development of the current applicable legal standard for obviousness under
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`KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007).
`B.
`Brief Description of the Technology
`Erectile dysfunction was a well-known condition prior to ‘166 patent.
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`Before ‘166 patent (or its alleged priority date of April 30, 1999), it was also well
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`known that sildenafil and tadalafil were highly selective phosphodiesterase (PDE)
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`enzyme inhibitors that were effective in treating sexual dysfunction. Ex. 1010,
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`Decl. ¶¶ 15-21. Sildenafil and tadalafil each share a common mechanism of action
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`and are only pharmacologically active when cGMP synthesis is activated. Ex.
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`1010, Decl. ¶¶ 20-21.
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`It was an accepted premise that PDE5 inhibitor such as sildenafil had certain
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`side effects that limited its use in certain individuals. Ex. 1001, col. 1, lines 58-
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`65. The ‘166 patent teaches that orally administered tetracyclic derivatives such as
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`tadalafil have been previously administered in doses of 0.2-400 mg, without
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`“significant side effects.” Id. (emphasis added). The ‘166 patent therefore attempts
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`to address a known problem with a known solution: orally administering tadalafil
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`in an optimal dose that maintains efficacy while minimizing its side effects.
`C. Critical Date
`The ‘166 patent claims was filed as U.S. Patent Application No. 10/031,556.
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`This was a national stage application of
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`the PCT Application No.
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`PCT/US2000/011129 that claimed priority to a provisional patent application
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`number 60/132,036 filed on April 30, 1999. Ex. 1009, Prosecution History,
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`Transmittal Letter. However, the claimed feature of “maximum total dose” was
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`not present in the provision patent application. Rather, this feature first appears in
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`the file wrapper on October 19, 2001, the transmittal date of U.S. Patent
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`Application No. 10/031,556. Thus, Petitioner notes that the claimed subject matter
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`does not appear to be fully supported as of April 30, 1999. Regardless, as set forth
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`herein, Petitioner submits that the claims are obvious even if April 30, 1999 is
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`deemed the critical date.
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`III. CLAIM CONSTRUCTION
`A.
`Standards For Claim Construction
`37 C.F.R. § 42.100(b) provides that claims are construed according to the
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`“broadest reasonable interpretation” at the Patent Trial and Appeal Board (PTAB).
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`Under the broadest reasonable interpretation, claim terms are given their broadest
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`reasonable interpretation in view of the specification to one having ordinary skill in
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`the art at the time of the invention..
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`B. Construction of Terms
`Claim 1 of the ‘166 patent, shown below, is the only independent claim:
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`1. A method of treating sexual dysfunction in a patient in need thereof
`comprising orally administering one or more unit dose containing about 1 to
`about 20 mg, up to a maximum total dose of 20 mg per day, of a compound
`having the structure
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`The term “about 1 to about 20 mg” of tadalafil should be interpreted
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`according to its plain and ordinary meaning. In view of the intrinsic record, this
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`would be understood as the dose range purported to have unexpected results.
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`The term “up to a maximum total dose of 20 mg per day” of tadalafil
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`should be interpreted according to its plain and ordinary meaning. In view of the
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`intrinsic record, this would be understood as the maximum end of a daily dose
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`range.
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`The term “compound having the structure” is defined in the '166 patent,
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`which states that "[t]he present invention provides a pharmaceutical dosage form
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`for human pharmaceutical use, comprising about 1 to about 20 mg of (6R,12aR)-
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`2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-
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`methylenedioxyphenyl)pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione in a unit
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`dosage form suitable for oral administration, alternatively named (6R-trans)-6-
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`(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methylpyrazino-
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`[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione.” Id. at col. 2, lines 23-28. To a person of
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`ordinary skill in the art, the term would be interpreted as the common chemical
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`name for tadalafil.
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`Any other term not specifically discussed above should be interpreted
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`according to its plain and ordinary meaning to a person of ordinary skill in the art
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`(POSA) in view of the specification.
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`IV. GROUNDS FOR UNPATENTABILITY OF EACH CLAIM
`In light of the disclosures detailed below, the ‘166 patent is unpatentable for
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`at least the reasons summarized in the chart below and discussed in more detail
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`herein.
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`No. Ground
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`Prior art
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`Exhibit Nos.
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`Claims
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`1
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`103(a) Daugan ‘675 in View of
`Guideline for Industry, Dose
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`1005, 1014
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`1-12
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`6
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`2
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`Response Information to Support
`Drug Registration
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`103(a) Daugan ‘675 Alone or In View of
`the Petition To Add Information
`About Sildenafil’s Danger’s To
`The Drug Label
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`1005, 1015
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`1-12
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`3
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`103(a) Daugan ‘675
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`1005
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`1-12
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`A. Ground 1: Claims 1-12 are Unpatentable Under 35 U.S.C. §
`103(a) As Being Obvious Over Daugan ‘675 In View of the
`Guideline for Industry, Dose Response Information to Support
`Drug Registration
`Claims 1-12 are directed to a known method of treating sexual dysfunction
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`by orally administering a known drug (tadalafil) in a dose range that was taught in
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`the prior art. Claim 1 is independent. Daugan ‘675 alone or in view of The
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`Guideline for Industry, Dose Response Information to Support Drug Registration
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`(“Guideline for Industry”) teaches every element of claims 1-12 of the ‘166 patent
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`as set forth in more detail below, and therefore renders those claims unpatentable
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`under 35 U.S.C. §103(a). See Ex. 1010, Decl. ¶¶ 122-133.
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`Daugan ‘675 discloses and teaches tadalafil as one of the two preferred
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`tetracyclic derivatives for treating erectile dysfunction. Ex. 1010, Decl. ¶¶ 103-
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`112, 131-157. It teaches that tadalafil can be orally administered daily. Ex. 1005,
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`Daugan ‘675, 5:4-7 (for a typical adult patient, tadalafil can be orally administered
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`in “a range of from 0.5-800 mg daily for an average adult patient,” including “0.2-
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`400 mg of active compound, . . for administration in single or multiple doses, once
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`or several times per day.”) Id. at 5:4-7 (emphasis added). Thus, at the very least,
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`Daugan ‘675 teaches a dosage range from 0.2-400 mg per day.
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`Moreover, in several examples, Daugan ‘675 discloses 50 mg of tadalafil in
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`oral dosage form. Daugan ‘675, p. 5, line 5. Daugan ‘675 also noted that “other
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`strengths may be prepared…” Id. at 12-16. Daugan ‘675 also teaches that in
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`practice, the physician will determine the actual dosing regimen most suitable for
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`an individual patient. Id. at 5, lines 9-14. Thus, Daugan ‘675 teaches that an
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`actual dosing regimen can be narrower within the described range.
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`In view of the foregoing, Daugan ‘675 teaches a method of treating sexual
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`dysfunction in a patient in need thereof comprising orally administering one or
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`more unit dose containing about 1 to about 20 mg, up to a maximum total dose of
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`20 mg per day, of a compound having the structure
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`
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`Since Daugan ‘675 teaches that for a typical adult patient, individual tablets
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`can be provided in single or multiple doses of 0.2-400 mg for oral administration
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`“once or several times per day,” a POSA would only need routine optimization to
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`IPR2017-00412
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`find that 1 to about 20 mg, up to a maximum total dose of 20 mg per day would be
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`obvious even in view of Daugan ‘675 alone. Daugan ‘675, 5:5-7, Ex. 1010, Decl.
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`¶¶ 105, 131-155.
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`Under post-KSR law, the specific dose range need not be expressly found in
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`Daugan ‘675. Rather, a POSA can apply common sense, particularly when there is
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`a “design need or market pressure to solve a problem and there are a finite
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`number of identified, predictable solutions.” KSR Int'l Co. v. Teleflex Inc., 550
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`U.S. 398, 420 (2007). In such a situation, a person of ordinary skill has good
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`reason to pursue the known options within his or her technical grasp. In view of
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`these principles, a POSA would have found the claimed range of “about 1 to about
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`20 mg, up to a maximum total dose of 20 mg per day” to be obvious in view of the
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`prior art including known optimization methods.
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`To the extent it was not obvious based on Daugan ‘675 alone, it would have
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`been obvious to a POSA to optimize the dose range to minimize adverse side
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`effects while maintaining pharmaceutical efficacy, as was typical for the
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`pharmaceutical industry. Ex. 1010, Decl. ¶¶ 158-188. Specifically, a POSA would
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`be motivated to administer tadalafil in the claimed dose range, “up to a maximum
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`total dose of 20 mg per day” in order to maintain efficacy, minimize side effects,
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`and comply with the accepted guidance in the field of drug design. A POSA would
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`also have been motivated to optimize the dose of tadalafil to arrive at “about 1 to
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`about 20 mg, up to a maximum total dose of 20 mg per day” in view of market
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`pressure to compete with Viagra® and the design need to avoid side effects of the
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`claimed drug. See ‘166 patent at col. 1, line 58-col. 2, line 21 (acknowledging that
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`certain side effects limited sildenafil’s use in certain individuals). Ex. 1010, Decl.
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`¶¶ 22-26, 168-188, 191.
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`The Guideline for Industry, Dose Response Information to Support Drug
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`Registration (“Guideline for Industry”) was published in the Federal Register on
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`November 9, 1994 (59 FR 55972), and was viewed by POSA’s prior to the critical
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`date. Ex. 1010, Decl.¶ 122. It is therefore prior art to the’166 patent.
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`As shown in the Guideline for Industry, a POSA would recognize that every
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`drug has a maximum daily dose insofar as after a certain dose, additional dosing
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`fails to confer additional clinical benefit and the beneficial effects of a drug are
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`outweighed by risks of adverse effects. Ex. 1010, Decl. ¶¶ 122-127. POSAs often
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`refer to this concept as the maximum tolerated dose (MTD). Ex. 1010, Decl. ¶¶
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`128-129. A POSA would understand that a MTD, which is typically determined in
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`a Phase 1 safely/tolerance study in a target population, defines the “upper limit of
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`the therapeutic dose range to be investigated in a Phase II efficacy study.” Id. An
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`example of such a MTD is shown below. The figure notes the MTD as “the upper
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`limit of a therapeutic dose range for efficacy”:
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`See, e.g., Ex. 1016, Cutler, et al., Defining the Maximum Tolerated Dose:
`Investigator, Academic, Industry and Regulatory Perspectives at Fig. 2.
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` POSA would have known prior to the critical date that “An acceptable
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` A
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`balance of observed undesired effects and beneficial effects” is required to “make
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`marketing at one of those doses reasonable.” See Ex. 1014, The Guideline for
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`Industry, p. 6. A POSA would be motivated to find a maximum dose that would
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`maintain efficacy and lower side effects.
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`Conclusive proof of efficacy is not necessary to show obviousness. All that
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`is required is a reasonable expectation of success. See PharmaStem Therapeutics,
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`Inc. v. ViaCell, Inc., 491 F.3d 1342, 1363-64 (Fed. Cir. 2007); Pfizer, Inc. v.
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`Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir.2007). Such is the case here. The
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`Guideline for Industry states that a drug sponsor should “Identify a reasonable
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`starting dose, ideally with specific adjustments…” Id. at 13. Then, the sponsor
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`should “identify reasonable, response-guided titration steps, and the interval at
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`which they should be taken, again with appropriate adjustments for patient
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`characteristics.” Id. at 14. Then, the sponsor should “identify a dose, or a response
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`(desirable of undesirable), beyond which titration should not ordinarily be
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`attempted because of a lack of further benefit or an unacceptable increase in
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`undesirable effects. This guidance applies here, as is typical for pharmaceutical
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`testing.
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`In this case, the drug sponsor already had a reasonable starting dose: a range
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`of from “0.5-800 mg daily for an average adult patient,” including a range of “0.2-
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`400 mg of active compound. . . for administration in single or multiple doses, once
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`or several times per day,” and a further exemplary dose of 50 mg as taught in
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`Daugan ‘675 at 5:4-7. In short, Daugan ‘675 taught “per day” dosing in a range
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`that included the claimed dose range.
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`In view of Daugan ‘675’s teachings, the drug sponsor could then identify
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`reasonable, response-guided titration steps and the intervals at which they should
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`be taken, with appropriate adjustments. Then, the sponsor can identify a dose
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`beyond which titration should not ordinarily be attempted because of a lack of
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`further benefit or an unacceptable increase in undesirable effects. This is routine
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`and conventional testing, as shown in the Guideline for Industry. Routine titration
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`or optimization would have shown that in doses higher than 20 mg per day, there
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`were increased side effects without any significant added benefit. Ex. 1010, Decl.
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`¶¶ 122-130.
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`This is confirmed by the prosecution history of the patent, in which the
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`patent applicant submitted a Declaration that stated:
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`“Phase 3 studies were conducted using 20 mg or lower doses because higher
`doses above 20 mg of Compound (I) had a sufficient number of adverse events
`such that the dose would have reduced tolerability to the general public.”
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`See Ex. 1009, Pros. History, Sides Affidavit dated 1-15-2004.
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`A POSA would recognize that beyond a certain maximum dose, the
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`beneficial effects of a drug are outweighed by risks of adverse effects. Indeed, a
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`POSA would recognize that a “balance of observed undesired effects and
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`beneficial effects” is accepted to “make marketing at one of those doses
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`reasonable.” See The Guideline for Industry, p. 6. In view of this industry
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`guidance, a POSA would be motivated to find a maximum daily dose, in this case,
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`20 mg, that would maintain efficacy and lower side effects.
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`The claim chart below provides more detail regarding the obviousness of
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`claims 1-12 over Daugan ‘675 in view of Guideline for Industry.
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`Claim 1 of ‘166 Patent
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`Daugan ‘675, FDA Review and FDA
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`1. (A) A method of treating sexual
`dysfunction in a patient in need thereof
`comprising
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`(B) orally administering
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`Clinical Hold
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`"Although the compounds of the
`invention are envisaged
`primarily for the treatment of erectile
`dysfunction or male
`sexual dysfunction, they may also be
`useful for the
`treatment of female sexual dysfunction
`. . . ." Daugan ‘675,
`4:25-27
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`"[T]he invention includes the use of a
`compound of
`formula (I), . . . for the manufacture of a
`medicament for
`the curative or prophylactic treatment
`of erectile
`dysfunction in a male animal,
`including man." Daugan ‘675,
`6:13-15 (emphasis added).
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`"[T]he compounds may be
`administered orally, thereby
`obviating the disadvantages associated
`with i.c. administration." Daugan ‘675,
`3:32 to 4:1 (emphasis added).
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`"Generally, in man, oral administration
`of the compounds
`of the invention is the preferred route,
`being the most
`convenient and avoiding the
`disadvantages associate with
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`(C) one or more unit dose containing
`about 1 to about 20 mg,
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`(D) up to a maximum total dose of 20
`mg per day,
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`i.c. administration." Daugan ‘675, 4:29-
`31 (emphasis added).
`"[F]or a typical adult patient, individual
`tablets or capsules
`contain from 0.2-400mg of active
`compound, . . . for
`administration in single or multiple
`doses, once or several
`times per day." Daugan ‘675, 5:4-7.
`
`"In practice the physician will determine
`the actual dosing
`regimen which will be most suitable for
`an individual
`patient and it will vary with the age,
`weight and response
`of the particular patient. The above
`dosages are
`exemplary of the average case but there
`can be individual
`instances in which higher or lower
`dosage ranges may be
`merited, and such are within scope of
`this invention"
`Up to a maximum total dose of 20 mg
`Prior art taught tadalafil in “0.5-800 mg
`daily for an average adult patient,”
`including “0.2-400 mg of active
`compound, . . . for
`administration in single or multiple
`doses, once or several
`times per day." Daugan ‘675, 5:4-7.
`Prior art also disclosed examples of
`orally administered tadalafil in 50 mg
`doses. Id. at 12-16 (noting that “other
`strengths may be prepared…”) Id. at 12-
`16.
`
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`Per Day
`Prior art taught tadalafil in “0.5-800 mg
`daily for an average adult patient,”
`including “0.2-400mg of active
`compound, . . . for
`administration in single or multiple
`doses, once or several
`times per day." Daugan ‘675, 5:4-7.
`
`20 mg as a maximum total dose would
`be obvious to try in view of the known
`clinical data and routine optimization.
`Ex. 1010, Decl. at ¶¶ 122-130, 158-185
`15
`
`
`
`
`
`
`(E) of a compound having the structure
`
`
`
`
`IPR2017-00412
`
`(noting that Viagra® was known to be
`effective and administered in 25, 50 and
`100 mg doses). Given the known higher
`efficacy of tadalafil, a POSA would be
`motivated to use lower doses of tadalafil
`to achieve the same effects. Id.
`
`
`See The Guideline for Industry, which
`states that a drug sponsor should
`“Identify a reasonable starting dose,
`ideally with specific adjustments…” Id.
`at 13. Then, the sponsor should
`“identify reasonable, response-guided
`titration steps, and the interval at which
`they should be taken, again with
`appropriate adjustments for patient
`characteristics.” Id. at 14. Then, the
`sponsor should “identify a dose, or a
`response (desirable of undesirable),
`beyond which titration should not
`ordinarily be attempted because of a
`lack of further benefit or an
`unacceptable increase in undesirable
`effects. This is the case for the 20 mg
`maximum total dose per day.
`The compounds may be represented by
`the following
`general formula (I):
`
`
`
`and salts and solvates (e.g. hydrates)
`thereof, in which:
`
`RO represents hydrogen, halogen or C1-
`6 alkyl;
`
`R1 represents hydrogen, C1-6alkyl, C2-
`6alkenyl, C2-6 alkynyl,
`haloC1-6alkyl, C3-8cycloalkyl, C3-
`8cycloalkylC1-3alkyl,
`arylC1-3alkyl or heteroarylC1-3alkyl;
`
`R2 represents an optionally substituted
`monocyclic
`aromatic ring selected from benzene,
`thiophene, furan and
`
`16
`
`
`
`
`
`
`Claim 2
`2. The method of claim 1 wherein the
`sexual dysfunction is male erectile
`dysfunction.
`
`IPR2017-00412
`
`pyridine or an optionally substituted
`
`bicyclic ring
`
`
`attached to the rest of the molecule via
`one of the benzene
`ring carbon atoms and wherein the fused
`ring A is a 5- or 6-
`membered ring which may be saturated
`or partially or
`fully unsaturated and comprises carbon
`atoms and
`optionally one or two heteroatoms
`selected from oxygen,
`sulphur and nitrogen; and
`
`R3 represents hydrogen or C1-3 alkyl, or
`R1 and R3 together
`represent a 3- or 4- membered alkyl or
`alkenyl chain."
`Id. at, 2:3-20 (emphasis added).
`
`The specific compounds of the
`invention are: (6R,12aR)-
`2,3,6,7,12,12a-hexahydro-2-methyl-6-
`(3,4-methylenedioxyphenyl)-
`pyrazino[2',1':6,1]pyrido[3,4-
`b]indole-1,4- dione (Compound A);
`and (3S,6R,12aR)-
`2,3,6,7,12,12ahexahydro-
`2,3-dimethyl-6-(3,4-methylene-
`dioxyphenyl)-
`pyrazino[2',1':6,1]pyrido[3,4-b]indole-
`1,4-dione
`(Compound B); and physiologically
`acceptable salts and solvates
`(e.g.
`hydrates) thereof." Daugan ‘675, 3:23-
`29 (emphasis added).
`The “present invention concerns the use
`of compounds of formula (I)…for the
`curative or prophylactic treatment of
`erectile dysfunction in a male animal,
`including man” Daugan ‘675, 4:2-6.
`
`17
`
`
`
`
`IPR2017-00412
`
`The [compounds] “may also be used for
`the treatment of female sexual
`dysfunction including orgasmic
`dysfunction related to clitoral
`disturbances.” Daugan ‘675, 4:26-28.
`Daugan ‘675, 5:4-7.
` POSA would therefore be motivated
`to optimize within the known dose
`range of 0.2-400 mg, to arrive at the
`claimed dose range of 2-20 mg to lower
`adverse effects, maintain efficacy,
`compete with Viagra®, and obtain FDA
`approval, as discussed for claim 1
`herein. See Daugan ‘675 and the
`Guideline for Industry, discussed above.
`
` A
`
`Daugan ‘675, 5:4-7.
` POSA would therefore be motivated
`to optimize within the known dose
`range of 0.2-400 mg, to arrive at the
`claimed dose of 5 mg to lower adverse
`effects, maintain efficacy, compete with
`Viagra®, and obtain FDA approval, as
`discussed for claim 1 herein. See
`Daugan ‘675, and the Guideline for
`Industry, discussed above.
`"[F]or a typical adult patient, individual
`tablets or capsules
`contain from 0.2-400mg of active
`compound, . . . for
`administration in single or multiple
`doses, once or several
`times per day." Daugan ‘675, 5:4-7.
`
`
` A
`
`See also routine optimization, design
`need, market pressure, no unexpected
`results as discussed for claim 1.
`
`The motivation to arrive at a narrower
`dose of about 10 mg is found in the need
`to arrive at an effective dose that also
`minimizes adverse side effects.
`
`18
`
`
`
`Claim 3
`3. The method of claim 1 wherein the
`sexual dysfunction is female arousal
`disorder.
`
`Claim 4
`4. The method of claim 1 wherein the
`unit dose contains about 2 to about 20
`mg of the compound.
`
`Claim 5
`5. The method of claim 1 wherein the
`unit dose contains about 5 mg of the
`compound.
`
`Claim 6
`6. The method of claim 1 wherein the
`unit dose contains about 10 mg of the
`compound and
`
`
`
`
`
`is administered once per day.
`
`Claim 7
`7. The method of claim 1 wherein the
`unit dose is in a form selected from the
`group consisting of a liquid, a tablet, a
`capsule, and a gelcap.
`Claim 8
`8. The method of claim 1 wherein the
`unit dose contains about 2.5 mg of the
`compound.
`
`Claim 9
`9. The method of claim 8 wherein the
`unit dose is administered once per day.
`
`Claim 10
`
`IPR2017-00412
`
`
`“Thus for a typical adult patient,
`individual tablets … for administration
`in single or multiple doses, once or
`several times per day.” Daugan ‘675,
`5:5-7.
`
`“The compounds of formula (I)…may
`be administered orally, buccally or
`sublingually, in the form of tablets…or
`in capsules.” Daugan ‘675 5:15-21.
`"[F]or a typical adult patient, individual
`tablets or capsules
`contain from 0.2-400mg of active
`compound, . . . for
`administration in single or multiple
`doses, once or several
`times per day." Daugan ‘675, 5:4-7.
`
`
`See also routine optimization, design
`need, market pressure, no unexpected
`results as discussed for claim 1.
`
`The motivation to arrive at a narrower
`dose of about 2.5 mg is found in the
`need to arrive at an effective dose that
`also minimizes adverse side effects.
`A POSA would therefore be motivated
`to optimize within the known dose
`range of 0.2-400 mg, to arrive at the
`claimed dose of 2.5 mg to lower
`adverse effects, maintain efficacy,
`compete with Viagra®, and obtain FDA
`approval, as discussed for claim 1
`herein. See Daugan ‘675, and the
`Guideline for Industry, discussed above.
`“Thus
`for a
`typical adult patient,
`individual tablets … for administration
`in single or multiple doses, once or
`several times per day.” Daugan ‘675,
`5:5-7.
`
`19
`
`
`
`
`IPR2017-00412
`
`typical adult patient,
`for a
`“Thus
`individual tablets … for administration
`in single or multiple doses, once or
`several times per day.” Daugan ‘675,
`5:5-7.
`"For human use, compounds of formula
`(I), . . . can be
`administered alone, but will generally
`be administered in
`admixture with
`a pharmaceutical
`carrier selected with regard
`to the intended route of administration
`and standard
`pharmaceutical practice." Daugan ‘675
`at 5:15-18.
`Daugan ‘675, 5:4-7.
`
`"[F]or a typical adult patient, individual
`tablets or capsules
`contain from 0.2-400mg of active
`compound, . . . for
`administration in single or multiple
`doses, once or several
`times per day." Daugan ‘675, 5:4-7.
`
`See also routine optimization, design
`need, market pressure, no unexpected
`results as discussed for claim 1.
`
`The motivation to arrive at a narrower
`dose of about 20 mg is found in the need
`to arrive at an effective dose that also
`minimizes adverse side effects.
`
` POSA would therefore be motivated
`to optimize within the known dose
`range of 0.2-400 mg, to arrive at the
`claimed dose range of 2-20 mg to lower
`adverse effects, maintain efficacy,
`compete with Viagra®, and obtain FDA
`approval, as discussed for claim 1
`herein.
` See Daugan ‘675 and the
`Guideline for Industry, discussed above.
`
` A
`
`
`10. The method of claim 5 wherein the
`unit dose is administered once per day.
`
`Claim 11
`11. The method of claim 1 wherein the
`compound is administered as a free
`drug.
`
`Claim 12
`12. The method of claim 1 wherein the
`unit dose contains about 20 mg of the
`compound.
`
`
`
`20
`
`
`
`
`
`
`IPR2017-00412
`
`The prosecution history of the ‘166 patent shows that the patent was allowed
`
`due to perceived “unexpected results” in the claimed dose range. Ex. 1009, Pros.
`
`History, Reasons for Allowance. However, since the ‘166 patent was allowed, the
`
`Federal Circuit has since established that evidence supporting superior efficacy at a
`
`specific claimed dose “does nothing to undercut the showing that there was a
`
`reasonable expectation of success even if the level of success
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