`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_______________
`
`
`AQUESTIVE THERAPEUTICS, INC.
`Petitioner
`
`v.
`
`ICOS CORPORATION,
`Patent Owner
`_______________
`
`Case: IPR2018-01183
`Patent 6,943,166
`_______________
`
`
`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 6,943,166
`
`

`

`IPR2018-01183
`
`TABLE OF CONTENTS
`I.
`PAYMENT OF FEES ..................................................................................... 1
`II.
`REQUEST FOR INTER PARTES REVIEW OF CLAIMS 1-12 OF THE
`‘166 PATENT ....................................................................................... 1
`A. Introduction ............................................................................................... 5
`B. Brief Description of the Scope and Content of the Prior Art .................. 13
`1. International Patent Publication No. WO 1997/03675 (“the ‘675
`PCT” or “Daugan ‘675”) (EX 1005). .................................................. 14
`2. Sildenafil Citrate (VIAGRA®) Approval Package for New Drug
`Application No. 020895 (“SNDA,” EX 1011). .................................. 15
`3. Dose-Response Information to Support Drug Registration (“FDA
`Guideline,” EX 1014) .......................................................................... 20
`4. Cutler Article (EX1016) .................................................................. 21
`5. Ruberg Article (EX1018) ................................................................ 22
`
`C. Level of Skill In the Art .......................................................................... 23
`D. Critical Date ............................................................................................ 24
`E. Knowledge of A Person of Ordinary Skill in the Art as of the
`Critical Date ............................................................................................ 25
`III. CLAIM CONSTRUCTION .......................................................................... 29
`A. Standards for Claim Construction ........................................................... 29
`B. Construction of Terms ............................................................................. 30
`IV. GROUNDS FOR UNPATENTABILITY OF EACH CLAIM ..................... 32
`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 SNDA and
`FDA Guideline for Industry .................................................................... 32
`B. Ground 2: Claims 1-12 are Unpatentable Under 35 U.S.C. § 103(a)
`Over Daugan ‘675, In View of the SNDA and FDA Guideline for
`Industry and Cutler .................................................................................. 48
`C. Ground 3: Claims 1-12 are Unpatentable Under 35 U.S.C. § 103(a)
`
`i
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`IPR2018-01183
`
`Over Daugan ‘675 In View of the SNDA and FDA Guideline for
`Industry and Ruberg ................................................................................ 50
`V. MANDATORY NOTICES ........................................................................... 58
`VI. CONCLUSION .............................................................................................. 61
`
`
`
`
`
`
`
`ii
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`IPR2018-01183
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`PETITIONERS’ EXHIBIT LIST
`
`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
`Sildenafil Citrate (VIAGRA®) Approval Package for New Drug
`Application No. 020895 (“SNDA”)
`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 (“Filloon”)
`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 (“FDA Guideline”)
`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 (“Cutler”)
`ICOS 10K FY 1998
`Ruberg, Stephen J. Ph.D., Dose response studies l. some design
`considerations, Journal of Biopharmaceutical Statistics, 5:1, 1-14 (1995)
`(“Ruberg”)
`Sildenafil NDA Access Data (indicating the files were created on March 27,
`1998)
`FDA Approval Letter, Sildenafil (Viagra®) NDA 020895, March 27, 1998
`(“Sildenafil Approval Letter)
`CNNMoney.com, March 27, 1998 (“CNN Article”)
`Dow Jones Online News, March 27, 1998 (“Dow Jones Article”)
`Boolell, M., et al., Sildenafil: an orally active type 5 cyclic GMP-specific
`
`Exh
`#
`1001
`1002
`1003
`1004
`1005
`1006
`1007
`1008
`
`1009
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`1018
`
`1019
`1020
`1021
`1022
`1023
`
`iii
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`IPR2018-01183
`
`phosphodiesterase inhibitor for the treatment of penile erectile dysfunction,
`8 Int. J. Impot. Res., (1996) 47-52 (“Boolell”)
`Terrett, N. K., et al., Sildenafil (ViagraTM), a Potent and Selective Inhibitor
`of Type 5 cGMP Phosphodiesterase with Utility for the Treatment of Male
`Erectile Dysfunction, 6 Bioorg. Med. Chem. Lett. (1996) 1819-1824
`("Terrett")
`Licht, M.R., Sildenafil (Viagra) for treating male erectile dysfunction, 65
`CLEVE. CLIN. J. MED., (1998) 301-304 (“Licht”)
`Gingell, C. J. C., et al., UK-92,480: A New Oral Treatment for Erectile
`Dysfunction: A Double-Blind, Placebo-Controlled, Once Daily Dose
`Response Study, 155 Suppl 5 J. UROL. (1996) Abstract No. 738
`("Gingell")
`Goldstein, I., et al., Oral Sildenafil in the Treatment of Erectile
`Dysfunction, 338 N. Engl. J. Med., (1998) 1397-1404 ("Goldstein")
`Morales, A., et al., Clinical safety of oral sildenafil citrate (VIAGRA TM)
`in the treatment of erectile dysfunction, 10 Int. J. Impot. Res., (1998) 69-74
`("Morales")
`de Mey, C., Opportunities for the Treatment of Erectile Dysfunction by
`Modulation of the NO Axis-Alternatives to Sildenafil Citrate, 14 Curr.
`Med. Res. Opin., (1998) 187-202 ("de Mey")
`Cheitlin, M.D., et al, Use of Sildenafil (Viagra) in Patients with
`Cardiovascular Disease, 33 J. Am. Coll. Cardiol. (1999) 273-282
`(“Cheitlin,”)
`Lilly and ICOS Establish a Joint Venture to Develop and Market PDE5
`Compounds to Treat Sexual Dysfunction Eli Lilly and Company PRESS
`RELEASE 1998 October 1 ("Lilly Press Release")
`Norman, P., IC-351 ICOS Corp, 1 Curr. Opin. Cpns Invest. Drugs (1999)
`268-271 (“Norman,”)
`Bourne, H. R., and Roberts, J. M., Drug Receptors & Pharmacodynamics,
`BASIC & CLINICAL PHARMACOLOGY (Katzung, B. G. ed., 6th Ed.
`1995) 9-32 (“Bourne”)
`Rowland and Tozer’s Clinical Pharmacokinetics (1995 Third Edition) at
`Section 5.20 ‘Pharmacologic Response’ page 340-341.
`
`1024
`
`1025
`1026
`
`1027
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`1033
`
`1034
`
`iv
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`IPR2018-01183
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`
`
`Pursuant to 35 U.S.C. § 311, Aquestive Therapeutics, Inc. (“Petitioner”),
`
`formerly MonoSol, respectfully petitions for Inter Partes Review, seeking
`
`cancellation of claims 1-12 of U.S. Patent No. 6,943,166 (the ‘166 Patent).
`
`According to USPTO records, the '166 patent is assigned to ICOS CORP c/o Eli
`
`Lilly and Co. (“Patent Owner”). A copy of the ‘166 Patent is attached as EX1001.
`
`As demonstrated by the grounds presented below, the alleged invention of the
`
`challenged claims are obvious and should be canceled under 35 U.S.C. § 103.
`
`I.
`
`PAYMENT OF FEES
`Pursuant to 37 C.F.R. Section 42.103, $23,000 is being paid at the time of
`
`filing this petition, charged to Deposit Account 19-4293. Should any further fees
`
`be required by the present Petition, the Patent Trial and Appeal Board (“PTAB”) is
`
`hereby authorized to charge the above referenced Deposit Account.
`
`II. REQUEST FOR INTER PARTES REVIEW OF CLAIMS 1-12 OF
`THE ‘166 PATENT
`Pursuant to 37 C.F.R. §42.104(b), Petitioner requests that the PTAB find
`
`unpatentable Claims 1-12 of the ‘166 patent. Such relief is justified as the alleged
`
`invention of the ‘166 patent was described by others prior to the filing date of the
`
`‘166 patent and obvious to one of skill in the art.
`
`Petitioner is aware that the ‘166 patent was previously challenged by
`
`IntelGenx Corp. in a request for Inter Partes Review, and that this Petition was
`
`1
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`IPR2018-01183
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`denied institution on September 1, 2016. IPR2016-00678, Paper 13. That Petition
`
`raised two grounds of unpatentability: (1) Daugan and (2) Daugan and SNDA (the
`
`Viagra® Approval Package). However, in that case, the PTAB found that the
`
`Petitioner “ignored the maximum-total dose requirement” in failing to “point to the
`
`asserted prior art or otherwise explain why an ordinary artisan would limit the
`
`tadalafil dose to 20 mg per day.” Id. at 7. The PTAB therefore concluded that the
`
`Petitioner had “not established a reasonable likelihood it would prevail in showing
`
`that claim 1 would have been obvious over Daugan, either alone or in combination
`
`with SNDA.” Id.
`
`The ’166 patent was previously challenged by MonoSol Rx, LLC
`
`(“MonoSol”) in a request for Inter Partes Review, and this Petition (“2017
`
`Petition) was denied institution on July 3, 2017. IPR2017-00412, Paper 11.
`
`Petitioner is also aware that the ’166 patent was previously challenged by
`
`Mylan Pharmaceuticals Inc. (“Mylan”) in a request for Inter Partes Review.
`
`IPR2017-00323, Paper 12. This Petition was granted on June 12, 2017. The
`
`PTAB concluded that Petitioner has “offered sufficient evidence to institute an
`
`inter partes review” and that the “information presented in the Petition and
`
`accompanying evidence establishes a reasonable likelihood that Petitioner would
`
`prevail in showing the unpatentability of claim 1of the ’166 patent.” Id. at 17.
`
`2
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`IPR2018-01183
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`Petitioner had considered a joinder with Mylan’s granted Petition, however,
`
`Mylan settled out of proceedings on July 7, 2017, making joinder legally
`
`impossible. Thus, Petitioner submits this Petition separately. In the interest of
`
`efficiency, Petitioner adopts the arguments and evidence of Mylan’s petition
`
`herein, with the addition of new prior art which was not previously known to
`
`Petitioner until a few weeks ago.
`
`In reviewing petitions, the Board considers seven factors: (1) whether the
`
`same petitioner previously filed a petition directed to the same claims of the same
`
`patent; (2) whether at the time of filing the first petition, the petitioner knew of the
`
`prior art asserted in the second petition or should have known of it; (3) whether at
`
`the time of filing of the second petition, the petitioner already received the patent
`
`owner’s preliminary response to the first petition or received the Board’s decision
`
`on whether to institute review in the first petition; (4) the length of time that
`
`elapsed between the time the petitioner learned of the prior art asserted in the
`
`second petition and the filing of the second petition; (5) whether the petitioner
`
`provides adequate explanation of the time elapsed between the filings of multiple
`
`petitions directed to the same claims of the same patent: (6) the finite resources of
`
`the Board; and (7) the requirement under 35 U.S.C. 316(a)(11) to issue a final
`
`determination not later than 1 year after the date on which the Director notices
`
`3
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`IPR2018-01183
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`institution of review. Gen. Plastic Indus. Co., Ltd. v. Canon Kabushiki Kaisha,
`
`IPR2016-01357, (Paper No. 19) (PTAB Sept. 6, 2017).
`
`Notwithstanding the above factors, the Board recognizes that, “there may be
`
`circumstances where multiple petitions by the same petitioner against the same
`
`claims of a patent should be permitted, and that such a determination is dependent
`
`on the facts at issue in the case” and “additional factors may arise in other cases for
`
`consideration, where appropriate.” Panduit Corp. v. CCS Technology Inc.,
`
`IPR2017-01375 (Paper No. 8) (PTAB Nov. 8, 2017) (instituting inter partes
`
`review).
`
`In Panduit, the Board granted a second petition. The first petition was
`
`denied because one of the references relied upon by Petitioner was not shown to be
`
`publicly accessible. However, the Board decided that Petitioner’s reliance on that
`
`reference was not unreasonable, especially in light of the proffered declaration to
`
`support its argument of public accessibility. In the second petition, the Board was
`
`persuaded by the contentions that the teachings of the asserted prior art and the
`
`reasons to combine them. The same principle applies here.
`
`
`
`Two of the references relied upon by Petitioner in the 2017 Petition (the
`
`“FDA Clinical Hold” and “FDA Review”) were not shown to be publicly
`
`accessible. However, Petitioner had relied on a proffered declaration supporting
`
`public accessibility, which is not unreasonable.
`
`4
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`IPR2018-01183
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`In addition, at least one reference relied upon in this present Petition, the
`
`Ruberg reference, was not previously known to Aquestive (or MonoSol) until a
`
`few weeks ago. Petitioner filed the current petition soon after learning of and
`
`reviewing the additional reference.
`
`Finally, because Mylan settled out of proceedings on July 7, 2017, joinder
`
`became legally impossible for Petitioner. Since the current Petition adopts the
`
`arguments and evidence of Mylan’s petition herein, which the Board already
`
`reviewed and granted institution, there is little additional review that needs to be
`
`undertaken which weighs in favor of efficiency for the Board’s time and
`
`resources. Applicant therefore respectfully requests inter partes review for at least
`
`the same reasons that Mylan’s petition was granted
`A.
`Introduction
`The ’166 patent is generally directed to a method of treating sexual
`
`dysfunction using a prior art compound now known as tadalafil, a
`
`phosphodiesterase type 5 (PDE5) inhibitor with previously known utility for
`
`treating sexual dysfunction. The dosing regimen claimed is the oral administration
`
`of about 1 to about 20 mg of tadalafil, where the total maximum daily dose is no
`
`greater than 20 mg.
`
`The prior art taught not only the compound tadalafil itself, but also that: (i)
`
`orally administered tadalafil was useful in treating sexual dysfunction at daily
`
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`IPR2018-01183
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`dosages as low as 0.5 mg (Daugan, EX1005); and (ii) tadalafil was nearly twice as
`
`potent as sildenafil citrate (Viagra®), another inhibitor of the same PDE5 enzyme
`
`that gained FDA approval in March 1998 for male erectile dysfunction. (Center for
`
`Drug Evaluation and Research, Approval Package for VIAGRA, Approval Date
`
`March 27, 1998, EX1011). Sildenafil (Viagra®) (25 mg, 50 mg, and 100mg) was
`
`previously approved as a once-daily treatment and it was known to produce only
`
`minor adverse events at the approved once-daily doses of 25 and 50 mg. Id.;
`
`EX1010 ¶¶15-29, 48-53.
`
`As explained by Dr. Roger Williams, to determine an appropriate daily dose
`
`of tadalafil, a person of ordinary skill would have compared its potency data with
`
`that of sildenafil by comparing the IC50 values for the PDE5 enzyme reported in
`
`the prior art. A person of ordinary skill in the art would understand that an IC50
`
`value (the concentration of an inhibitor where the response or binding is reduced
`
`by half) is often used to measure a drug’s potency. A lower IC50 value means that
`
`lower doses of a drug would achieve similar efficacy as another drug having a
`
`higher IC50 value. Tadalafil has an IC50 value of 2.0nM; sildenafil has an IC50
`
`value of 3.5-3.9 nM. Accordingly, those in the art would have been aware that
`
`tadalafil is a more potent inhibitor of PDE5 than sildenafil. Put another way, lower
`
`doses of tadalafil would achieve similar efficacy as comparatively higher doses of
`
`6
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`IPR2018-01183
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`sildenafil in the treatment of sexual dysfunction. EX1010 ¶17, 24, 101, 138, 141,
`
`165-166, 174, 188.
`
`Based on this IC50 value comparison of 3.5-3.9 nM (for sildenafil) to 2.0
`
`nM (for tadalafil), tadalafil would have been expected to be about 1.75 times or
`
`nearly twice as potent as sildenafil. In short, the dose response for tadalafil would
`
`have been expected to be analogous to sildenafil except similar efficacies would be
`
`obtained at lower doses of tadalafil. Thus, the efficacy and adverse events reported
`
`for a once-daily dose of 25 mg sildenafil would have been expected to be
`
`approximately equivalent to roughly 15 mg of tadalafil in a once-daily dose.
`
`A person of ordinary skill in the art (POSA) would be motivated to adjust
`
`the dosing of tadalafil proportionately based on known data regarding the approved
`
`doses of sildenafil, and to have a reasonable expectation of success in doing so.
`
`EX1010 ¶174. POSAs routinely produced dose-response curves to inform dosage
`
`decisions and, following FDA Guidelines (e.g., EX1014), routinely selected doses
`
`below a dose response plateau as a preferred daily dosage. Dose response analyses
`
`of sildenafil for treatment of sexual dysfunction were well documented in the prior
`
`art. See, e.g., EX1011 at 0070; EX1010 ¶175. In accordance with this data, and as
`
`discussed in detail below, a 25 mg daily dose of sildenafil “is already fairly high”
`
`on the dose-response curve. EX1011 at 0070. This means that it is approaching the
`
`point at which no further clinical benefits are realized from increasing dosage.
`
`7
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`IPR2018-01183
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`EX1010 ¶¶ 188-189. In short, the dose response curve generated for sildenafil
`
`identified that daily dose (25 mg daily) as within the optimal dose range with
`
`respect to efficacy and adverse events. EX1010 ¶¶174-185, 190-204.
`
`Given that tadalafil is about 1.75 times more potent than sildenafil, a person
`
`of ordinary skill in the art would find it expected that a 25 mg sildenafil dose
`
`would produce the same result as about 14-15 mg tadalafil dose with no more than
`
`routine optimization (since 25 ÷1.75 = 14.3). EX1010 ¶164. Administering a
`
`once-daily dose of 15 mg of tadalafil to a patient with sexual dysfunction satisfies
`
`each element of claim 1 of the ’166 patent, including that the unit dose contains
`
`about 1 to about 20 mg of tadalafil, and that the daily dose is no greater than 20
`
`mg.
`
`Moreover, each of claims 1-12 of the ʼ166 patent merely recite doses that
`
`would have been expected to be efficacious and cause minimal adverse events
`
`based on comparison to sildenafil’s known potency and approved dosing.
`
`EX1011; EX1010 ¶¶138-164; 165-167;168-173.
`
`Brief Overview of the ’166 Patent
`
`The ’166 patent is generally directed to a dosing regimen used in methods to
`
`treat sexual dysfunction with tadalafil, a highly-selective PDE5 inhibitor. See, e.g.,
`
`EX1001, abstract.; EX1010, ¶47-52. The ‘166 patent acknowledges that tadalafil
`
`was already known to be administered in doses of 0.2-400 mg without apparent
`
`8
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`IPR2018-01183
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`“significant side effects” EX1001, col. 2, lines 12-21. The ‘166 patent therefore
`
`sought to claim a method of administering a specific dose of tadalafil, namely
`
`“about 1 to about 20 mg, up to a maximum total dose of 20 mg per day.” Id. at
`
`claim 1.
`
`The ’166 patent has only one independent claim, claim 1, which recites
`
`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
`
`
`
`Dependent claims 4, 5, 8, and 12 recite specific dosage values within the 1-
`
`20 mg range. Dependent claims 6, 9, and 10 additionally recite specific dosage
`
`values that are to be administered once per day. Dependent claims 2 and 3 recite
`
`that the sexual dysfunction is male erectile dysfunction and female arousal
`
`disorder, respectively. Dependent claims 7 and 11 recite dosage forms in which the
`
`unit dose is to be given (i.e., formulated as a liquid, tablet, capsule or gelcap, or as
`
`a free drug).
`
`The ’166 patent admits that the prior art had previously identified “certain
`
`tetracyclic derivatives” including tadalafil and (2) that such compounds are potent
`
`9
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`IPR2018-01183
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`PDE5 inhibitors, (3) have an “oral dosage” of “0.58 mg daily for an average adult
`
`patient (70 kg),” and have unit doses between “0.2 to 400 mg of active compound.”
`
`Id. at 2:12-22 (citing disclosures that include tadalafil). The ’166 patent also
`
`acknowledges that no significant adverse side effects are disclosed for these prior
`
`art tetracyclic derivatives. Id.
`
`The ’166 patent then states: “Applicants have discovered that one such
`
`tetracyclic derivative, [tadalafil], can be administered in a unit dose that provides
`
`an effective treatment without the side effects associated with the presently
`
`marketed PDE5 inhibitor, sildenafil.” Id. at 2:23-32. The ’166 patent subsequently
`
`states: “The present invention is based on detailed experiments and clinical trials,
`
`and the unexpected observations that side effects previously believed to be
`
`indicative of PDE5 inhibition can be reduced to clinically insignificant levels by
`
`the selection of a compound and unit dose.” Id. at 5:15-19.
`
`As discussed in this Petition and in the accompanying declaration of Dr.
`
`Williams (EX1010), however, the compound and claimed dosing regimens were
`
`both disclosed and suggested in the art. EX1010 ¶¶52-53. At most, the unit dose
`
`containing about 1 to about 20 mg, up to a maximum total dose of 20 mg per day
`
`as claimed in the ’166 patent is simply the result of routine optimization. EX1010,
`
`e.g., ¶¶48-53, 136, 174.
`
`Brief Overview of the Prosecution History of the ’166 Patent
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`10
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`IPR2018-01183
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`U.S. Patent Application No. 10/031,556 (“the ’556 application”) was filed
`
`on April 26, 2000 and issued on September 13, 2005 as U.S. Patent No. 6,943,166.
`
`The ’556 application was a national stage entry of PCT/US00/11129, which claims
`
`priority to Provisional Application No. 60/132,036, filed on April 30, 1999. The
`
`earliest claimed priority date of the ’166 patent is April 30, 1999.
`
`During prosecution, there was no dispute that the prior art taught methods of
`
`treating sexual dysfunction by orally administering to a patient in need thereof one
`
`or more unit doses of tadalafil, in 0.2 to 400 mg, once or several times per day and
`
`in fact, taught 50 mg of oral dosage forms and noted that “other strengths may be
`
`prepared…” Daugan ‘675 at 5, 12-16; EX1010¶57.
`
`Indeed, the examiner rejected claims under 35 U.S.C. § 103(a) over U.S.
`
`Patent No. 6,140,329, which discloses “oral administration and a dosage within the
`
`recited range” of the “the instant compound and a method of using it to treat sexual
`
`dysfunction.” EX1009 at 527. In response, applicants argued that the range of
`
`about 1-20 mg is critical because this dose range exhibits the surprising and
`
`unexpected results of low adverse events and still being unexpectedly efficacious
`
`in treating sexual dysfunction. EX1009 at 612.
`
`In response the applicants submitted two declarations of Dr. Gregory Sides,
`
`an employee of Patent Owner, and argued that there were “unexpected results” for
`
`11
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`

`IPR2018-01183
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`this claimed dose of “one or more unit dose containing about 1 to about 20 mg, up
`
`to a maximum total dose of 20 mg per day.” EX1009 at 615-620 .
`
`Dr. Sides compared the efficacy and adverse events associated with 20 mg to
`
`50 mg of tadalafil, but he did not submit data sufficient to permit any conclusion of
`
`statistical significance, nor did he provide a statistical analysis of the data. EX1010
`
`¶¶ 63-76.
`
`The U.S. Patent Office then issued a Notice of Allowability. Id. at 0034-36.
`
`In the “Reasons for Allowance,” the examiner stated that there was no statistical
`
`difference between the two doses with respect to efficacy (id. at 0035) despite the
`
`fact that the Sides declarations did not provide a statistical analysis. The examiner
`
`concluded that “the adverse side effects at 20 mg are dramatically reduced when
`
`compared to 50 mg” and concluded that the data was sufficient to show unexpected
`
`results. EX1010 ¶¶ 78-80.
`
`As shown in this Petition and by the supporting evidence, the data presented
`
`during prosecution and in the specification of the ’166 patent do not establish
`
`unexpected results. Rather, they merely confirm the predictable results of routine
`
`dose optimization studies. In addition, the data comparisons in the Sides
`
`Declarations suffer from various defects that undermine any legitimate conclusion
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`of unexpected results. As such, Petitioner respectfully submits that the examiner’s
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`acquiescence to Patent Owner’s one-sided attorney argument and accompanying
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`declarations regarding unexpected results should receive little, if any, deference by
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`the Board.
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`B.
`Brief Description of the Scope and Content of the Prior Art
`In an obviousness analysis, Graham v. John Deere Co. of Kansas City,
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`requires an evaluation of any differences between the claimed subject matter and
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`the asserted prior art. 383 U.S. 1, 17-18 (1966). The Supreme Court ruled in KSR
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`Int’l Co. v. Teleflex Inc., that the obviousness inquiry may account for inferences
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`that would be employed by a person of ordinary skill in the art. 550 U.S. 398, 418
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`(2007).
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`The ‘166 patent was prosecuted and issued before KSR Int’l Co. was decided
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`in 2007, which may explain why the examiner did not account for inferences
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`that would be employed by a person of ordinary skill in the art .
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`Erectile dysfunction was a well-known condition prior to ‘166 patent.
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`EX1010¶16-20. Before ‘166 patent (or its alleged priority date of April 30, 1999),
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`it was also well known that sildenafil and tadalafil were highly selective
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`phosphodiesterase (PDE) enzyme inhibitors that were effective in treating sexual
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`dysfunction. EX1010, Decl. ¶¶ 15-21. Sildenafil and tadalafil each share a
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`common mechanism of action and are only pharmacologically active when cGMP
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`synthesis is activated. EX1010, 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. EX1001, 1:58- 65;
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`EX1010¶¶124-129. The ‘166 patent teaches that orally administered tetracyclic
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`derivatives such as tadalafil have been previously administered in doses of 0.2-400
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`mg, without “significant side effects.” Id. (emphasis added). The ‘166 patent
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`therefore attempts to address a known problem with a known solution: orally
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`administering tadalafil in an optimal dose that maintains efficacy while minimizing
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`its side effects. EX1010, Decl. ¶¶130-137.
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`1.
`International Patent Publication No. WO 1997/03675 (“the
`‘675 PCT” or “Daugan ‘675”) (EX 1005).
`The ‘675 PCT published on February 6, 1997, and is prior art to the claims
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`of the ‘166 patent under 35 U.S.C. § 102(b). The ‘675 PCT prominently discloses
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`Compound A ((6R,12aR)-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-
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`dione)(EX1007 at 3, lines 24-25), now known, and referred to herein as tadalafil
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`(see, “Cialis® label,” EX1007), as one of two “highly selective” PDE5 inhibitors
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`that are useful in the treatment of male sexual dysfunction disorders, including
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`erectile dysfunction, as well as female sexual dysfunction disorders. EX1005 at 3-
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`4.
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`The ‘675 PCT teaches tadalafil has an IC50 of 2 nM for PDE5 and “hence [has]
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`utility in the treatment of erectile dysfunction substantially as hereinbefore
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`described.” EX1005 at 17.
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`The ‘675 PCT teaches that tadalafil may be administered orally, for example
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`using “individual tablets or capsules [which] contain from 0.2-400mg of active
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`compound, in a suitable pharmaceutically acceptable vehicle or carrier, for
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`administration in single or multiple doses, once or several times per day.” EX1007
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`at 5. The ‘675 PCT also notes that “[f]or human use, compounds of formula (I),
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`and in particular compounds A [(tadalafil)] and B [(3-methyl-tadalafil)] can be
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`administered alone, but will generally be administered in admixture with a
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`pharmaceutical carrier[.]” EX1005 at 5; EX1010¶¶98-102.
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`2.
`Sildenafil Citrate (VIAGRA®) Approval Package for New
`Drug Application No. 020895 (“SNDA,” EX 1011).
`a.
`Brief Description of the SNDA
`The SNDA is the Center for Drug Evaluation and Research Approval
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`Package for the use of sildenafil citrate (Viagra®) in the treatment of erectile
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`dysfunction. The SNDA includes a joint clinical review, which outlines clinical
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`trial data available for sildenafil citrate, as well as pharmacokinetic,
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`pharmacological, toxicological, safety and efficacy data compiled for review by
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`FDA for formal drug approval. EX1010, ¶ 108.
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`The SNDA identifies sildenafil’s mechanism of action as a selective
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`inhibitor of phosphodiesterase, an enzyme that catalyzes cleavage of cAMP or
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`cGMP. Different tissues have different forms of this enzyme, each having
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`different affinities for sildenafil. Sildenafil has the lowest IC50 for PDE5, which is
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`found in the corpus cavernosum, platelets, skeletal muscle, and vascular and
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`visceral smooth muscle. EX1011 at 0088. The SNDA also teaches that sildenafil’s
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`PDE6 IC50 is only 10-fold higher (less potent) than its PDE5 IC50. Id. PDE6 is
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`present in ocular tissues, providing the probable cause of the visual adverse events
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`that sometimes occur following administration of sildenafil. Id. As
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`phosphodiesterase enzymes are found in a variety of tissues throughout the body,
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`the on-target effects of PDE inhibition are predictable adverse events.
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`On the basis of the proposed mechanism of action, relative affinities of
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`sildenafil for different forms of phosphodiesterase, and the distribution of
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`phosphodiesterase in different tissues, there are effects of sildenafil that can be
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`predicted. These effects include (a) penile erection resulting from relaxation of
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`smooth muscle controlling inflow of blood to the corpus cavernosum, (b) systemic
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`vasodilation and, possibly hypotension, (c) inhibition of platelet aggregation and
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`increased risk of hemorrhage, (d) skeletal muscle weakness, (e) reduced activity of
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`the gastrointestinal tract, and (f) interference with vision. EX1011 at 0088-89.
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`Accordingly, the SNDA concludes that “common treatment-related adverse
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`events—notably headache, vasodilation, dyspepsia, and vision disturbance—were
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`clearly dose-related.” EX1011 at 0095; EX1010¶114.
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`The SNDA states that sildenafil has an IC50 of 3.5 nM for PDE5 (id. at
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`0037), that the therapeutic effectiveness of sildenafil is dose-dependent, and that
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`sildenafil is therapeutically effective for the treatment of erectile dysfunction at
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`doses as low as 5 and 25 mg. EX1011 at 0126-28, 0215-16; E X1010, ¶ 115. The
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`SNDA also teaches that maximum recommended dosing schedule is once per day.
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`EX 1011 at 0126, 0132, 0139, 0146, 0155, 0217, 0223, 0238, 0245, 0251; EX
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`1010, ¶ 115 .The SNDA also notes where the tested dosages fall along a dose-
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`response curve, noting, “[t]he 25 mg-placebo difference is more than half of the
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`100 mg-placebo difference; this suggests that the 25-mg dose is already fairly high
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`on the dose-response curve.” EX1011 at 0070; EX1010 at 116.
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`b.
`The SNDA was publicly available at least as early as
`March 27, 1998.
`Under 35 U.S.C. § 102(b), “a person shall be entitled to a patent unless …
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`the invention was patented or described in a printed publication … more than one
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`year prior to the date of the application for patent in the United States.” Because of
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`the variety of ways in which a publication may be disseminated, “public
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`accessibility has been called the touchstone in determining whether a reference
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`constitutes a printed publication bar under 35 U.S.C. § 102(b).” Kyocera Wireless
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`Corp. v. ITC, 545 F.3d 1340, 1350 (Fed. Cir. 2008). Public accessibility is proven
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`“upon a satisfactory showing that such document has been disseminated or
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`otherwise made available to the extent that persons interested and ordinarily skilled
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`in the subject matter or art exercising reasonable