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`Paper No. 2
`Filed: July 10, 2017
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_________________________
`
`
`DR. REDDY’S LABORATORIES, INC.
`Petitioner,
`
`v.
`
`ICOS CORPORATION
`Patent Owner.
`
`_________________________
`
`Case No. IPR2017-01757
`U.S. Patent No. 6,943,166
`_________________________
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 6,943,166
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`Table of Contents
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`Page
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`INTRODUCTION .......................................................................................... 1
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`I.
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`A.
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`B.
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`C.
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`D.
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`E.
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`Brief Overview of the ’166 Patent ........................................................ 3
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`Brief Overview of the Prosecution History .......................................... 5
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`Brief Overview of the Scope and Content of the Prior Art .................. 7
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`Brief Overview of the Level of Skill in the Art .................................. 15
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`Background Knowledge in the Art Prior to April 30, 1999 ............... 18
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`II. GROUNDS FOR STANDING ..................................................................... 24
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`III. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8 ................................ 25
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`IV. STATEMENT OF THE PRECISE RELIEF REQUESTED FOR EACH
`CLAIM CHALLENGED .............................................................................. 27
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`V.
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`CLAIM CONSTRUCTION .......................................................................... 27
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`A.
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`B.
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`C.
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`“up to a maximum total dose” ............................................................ 28
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`“female arousal disorder” ................................................................... 29
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`“free drug” .......................................................................................... 29
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`VI. DETAILED EXPLANATION OF GROUNDS FOR
`UNPATENTABILITY ................................................................................. 30
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`A.
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`[Ground 1] Claims 1-12 are Obvious under 35 U.S.C. §
`103 over the ’675 PCT (EX1007) in view of the
`Sildenafil NDA (EX1008) and FDA Guideline (EX1009) ................ 30
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`VII. NO OBJECTIVE INDICIA OF NON-OBVIOUSNESS ............................. 46
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`A.
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`B.
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`Legal Standard .................................................................................... 46
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`The Claimed Dosing Method Does Not Produce Unexpected
`Results ................................................................................................ 47
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`
`
`i
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`C. No Long-Felt Need for the claimed Dosing Regimen ....................... 60
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`VIII. CONCLUSION ............................................................................................. 62
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`IX. CERTIFICATE OF COMPLIANCE ............................................................ 63
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`X.
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`PAYMENT OF FEES UNDER 37 C.F.R. §§ 42.15(A) AND 42.103 ......... 64
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`XI. APPENDIX – LIST OF EXHIBITS ............................................................. 65
`
`ii
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`I.
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`INTRODUCTION
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`Pursuant to the provisions of 35 U.S.C. § 311 and § 6 of the Leahy-Smith
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`America Invents Act (“AIA”), and to 37 C.F.R. Part 42, Dr. Reddy’s Laboratories,
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`Inc., (“Petitioner”) hereby requests inter partes review of United States Patent No.
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`6,943,166 to Pullman (“the ’166 patent,” EX1001), which issued on September 13,
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`2005, and is currently assigned to ICOS Corp., which is owned by Eli Lilly and
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`Co. (collectively “Patent Owner”).
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`The ’166 patent is directed to a dosing regimen for treating sexual
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`dysfunction using a prior art compound now known as tadalafil, a
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`phosphodiesterase type 5 (PDE5) inhibitor with previously reported and previously
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`claimed utility for treating sexual dysfunction. The dosing regimen claimed in the
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`’166 is the administration of about 1 to about 20 mg of tadalafil, where the total
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`maximum daily dose is no larger than 20 mg. The art taught not only the
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`compound tadalafil itself, but that (i) orally administered tadalafil was useful in
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`treating sexual dysfunction at daily dosages as low as 0.5 mg (EX1007); and (ii)
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`tadalafil was nearly twice as potent as sildenafil citrate (Viagra®), another inhibitor
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`of the same PDE5 enzyme that gained FDA approval in March 1998. EX1008.
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`Sildenafil (25 mg, 50 mg, and 100mg) was approved, as a once-daily
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`treatment for male erectile dysfunction, and it was known to produce only minor
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`adverse events at the approved once-daily doses of 25 and 50 mg. As tadalafil was
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`1
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`
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`nearly twice as potent as sildenafil for the same PDE5 enzyme, the person of
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`ordinary skill in the art would have been motivated to adjust the dosing of tadalafil
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`proportionately based on known data regarding the approved doses of sildenafil.
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`Dose response analyses of sildenafil for treatment of sexual dysfunction
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`were documented in the prior art. See, e.g., EX1008 at 0070. Skilled artisans
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`routinely produced these dose-response curves to inform dosage decisions and,
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`following FDA Guidelines (e.g., EX1009), routinely selected doses below a dose-
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`response plateau as a preferred daily dosage. In accordance with this, and as
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`discussed in detail below, a 25 mg daily dose of sildenafil falls near the top of the
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`dose-response curve but below its plateau. EX1008 at 0070. In other words, the
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`dose response curve generated for sildenafil identified that daily dose as within the
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`optimal dose range with respect to efficacy and adverse events.
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`As explained by Dr. Fatemeh Akhlaghi, a professor and pharmacokineticist
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`with over 18 years of experience in clinical pharmacology research and an
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`extensive history of collaboration with academia and the pharmaceutical industry,
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`to determine an appropriate daily dose of tadalafil a person of ordinary skill would
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`have compared the potency data for tadalafil and sildenafil (consisting of IC50
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`values for the PDE5 enzyme) that were reported in the prior art. Based on this
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`comparison (3.5 nM to 2.0 nM), tadalafil would have been expected to be nearly
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`twice as potent as sildenafil, and the dose response for tadalafil would have been
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`2
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`
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`expected to be analogous to that reported for sildenafil except similar efficacies
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`would be obtained at lower doses of tadalafil. Thus, the efficacy and adverse events
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`reported for a once-daily dose of 25 mg sildenafil would have been expected by the
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`skilled artisan to be approximately equivalent to those occurring with a once-daily
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`dose of roughly 15 mg of tadalafil. Id. From the Patent Owner’s own press
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`releases, it was already known in the art that tadalafil had been used for treating
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`sexual dysfunction in a variety of clinical trials in Europe and the U.S., that the
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`drug was safe and well tolerated, and that patients showed significant
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`improvement.
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`Administering a once-daily dose of 15 mg of tadalafil to a patient with
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`sexual dysfunction satisfies each element of claim 1 of the ’166 patent, including
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`that that the unit dose contains about 1 to about 20 mg of tadalafil, and that the
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`daily dose is no larger than 20 mg. Moreover, each of claims 1-12 of the ʼ166
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`patent merely recite doses that would have been expected to be efficacious and
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`cause only minimal adverse events based on comparison to sildenafil’s known
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`potency and approved dosing. EX1008.
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`A. Brief Overview of the ’166 Patent
`Generally, the ’166 patent is directed to a dosing regimen used in methods to
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`treat sexual dysfunction with tadalafil, a highly-selective PDE5 inhibitor. See, e.g.,
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`EX1001, abstract. The ’166 patent has only one independent claim, claim 1, which
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`3
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`recites:
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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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`Dependent claims 4, 5, 8, and 12 recite specific dosage values within the 1-
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`20 mg range, and dependent claims 6, 9, and 10 additionally recite specific dosage
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`values that are to be administered once per day. Dependent claims 2 and 3 recite
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`that the sexual dysfunction is male erectile dysfunction and female arousal
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`disorder, respectively. Dependent claims 7 and 11 recite dosage forms in which the
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`unit dose is to be given (i.e., formulated as a liquid, tablet, capsule or gelcap, or as
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`a free drug).
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`The ’166 patent admits that the prior art had previously identified “certain
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`tetracyclic derivatives” including tadalafil and that such compounds are potent
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`PDE5 inhibitors, have an “oral dosage” of “0.58 mg daily for an average adult
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`patient (70 kg),” and have unit doses between “0.2 to 400 mg of active compound.”
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`Id. at 2:12-22 (citing disclosures that include tadalafil). The ’166 patent also
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`4
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`acknowledges that no significant adverse side effects are disclosed for these prior
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`art tetracyclic derivatives. Id.
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`The ’166 patent then states: “Applicants have discovered that one such
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`tetracyclic derivative, [tadalafil], can be administered in a unit dose that provides
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`an effective treatment without the side effects associated with the presently
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`marketed PDE5 inhibitor, sildenafil.” Id. at 2:23-32. The ’166 patent
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`subsequently states: “The present invention is based on detailed experiments and
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`clinical trials, and the unexpected observations that side effects previously believed
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`to be indicative of PDE5 inhibition can be reduced to clinically insignificant levels
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`by the selection of a compound and unit dose.” Id. at 5:15-19.
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`As discussed in this Petition and in the accompanying declaration of Dr.
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`Akhlaghi (EX1002), however, the compound and claimed dosing regimens were
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`both disclosed and suggested in the art. At most, the unit dose containing about 1
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`to about 20 mg, up to a maximum total dose of 20 mg per day as claimed in the
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`’166 patent is simply the result of routine optimization. EX1002, ¶¶22-28.
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`Brief Overview of the Prosecution History
`B.
`U.S. Patent Application No. 10/031,556 (“the ’556 application”) was filed
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`on April 26, 2000 and issued on September 13, 2005 as U.S. Patent No. 6,943,166.
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`The ’556 application was a national stage entry of PCT/US00/11129, which claims
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`priority to Provisional Application No. 60/132,036, filed on April 30, 1999. The
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`5
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`earliest claimed priority date of the ’166 patent is April 30, 1999.
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`During prosecution, the examiner rejected claims under 35 U.S.C. § 103(a)
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`over U.S. Patent No. 6,140,329, which discloses “oral administration and a dosage
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`within the recited range” of the “the instant compound and a method of using it to
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`treat sexual dysfunction.” EX1006 at 0385. In response, applicants argued that the
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`range of about 1-20 mg “is critical because this dose range exhibits the surprising
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`and unexpected results of low adverse events and still being unexpectedly
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`efficacious in treating sexual dysfunction.” EX1006 at 0053.
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`As purported evidence of alleged unexpected results, Applicants submitted
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`two declarations of Dr. Gregory Sides, an employee of Patent Owner. EX1006 at
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`0058-62, 0296-0301; EX1002, ¶18-21. Dr. Sides compared the efficacy and
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`adverse events associated with 20 mg to 50 mg of tadalafil, but he did not submit
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`data sufficient to permit any conclusion of statistical significance, nor did he
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`provide a statistical analysis of the data. EX1002, ¶21. A Notice of Allowability
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`followed thereafter. Id. at 0034-36. In the “Reasons for Allowance,” the examiner
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`stated that there was no statistical difference between the two doses with respect to
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`efficacy (id. at 0035) despite the fact that the Sides declarations did not provide a
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`statistical analysis. The examiner also stated that “the adverse side effects at 20 mg
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`are dramatically reduced when compared to 50 mg” and concluded that the data
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`was sufficient to show unexpected results. Id.; EX1002, ¶21.
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`6
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`As shown in this Petition and by the supporting evidence, the data presented
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`during prosecution and in the specification of the ’166 patent do not establish
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`unexpected results. In fact, they merely confirm the predictable results of routine
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`dose optimization studies. Moreover, the data comparison used in the Sides
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`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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`C. Brief Overview of the Scope and Content of the Prior Art
`In obviousness cases, Graham v. John Deere Co. of Kansas City, requires an
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`evaluation of any differences between the claimed subject matter and the asserted
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`prior art. 383 U.S. 1, 17-18 (1966). As noted in KSR Int’l Co. v. Teleflex Inc., the
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`obviousness inquiry may account for inferences that would be employed by a
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`person of ordinary skill in the art. 550 U.S. 398, 418 (2007).
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`1.
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`International Patent Publication No. WO 1997/03675
`(“the ’675 PCT”) (EX1007).
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`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-dione)(
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`7
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`
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`EX1007 at 3, lines 24-25), now known, and referred to herein as tadalafil (see,
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`“Cialis® label,” EX1010), as one of two “highly selective” PDE5 inhibitors that are
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`useful in the treatment of male sexual dysfunction disorders, including erectile
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`dysfunction, as well as female sexual dysfunction disorders. EX1007 at 3-4;
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`EX1002, ¶¶57-60; EX1004, ¶37, 39.
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`The ’675 PCT teaches tadalafil has an IC50 of 2 nM for PDE5 and “hence [has]
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`
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`utility in the treatment of erectile dysfunction substantially as hereinbefore
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`described.” EX1007 at 17; EX1002, ¶59; EX1004, ¶38.
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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 pharmaceutically acceptable vehicle or carrier, for administration
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`in single or multiple doses, once or several times per day.” EX1007 at 5; EX1002,
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`¶¶57, 60. The ’675 PCT also notes that “[f]or human use, compounds of formula
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`(I), and in particular compounds A [(tadalafil)] and B [(3-methyl-tadalafil)] can be
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`8
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`administered alone, but will generally be administered in admixture with a
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`pharmaceutical carrier[.]” EX1007 at 5; EX1002, ¶60.
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`2.
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`Sildenafil Citrate (VIAGRA®) Approval Package for New Drug
`Application No. 020895 (“Sildenafil NDA,” EX1008).
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`a)
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`Brief Description of the Sildenafil NDA
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`The Sildenafil NDA is the Center for Drug Evaluation and Research
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`Approval Package for the use of sildenafil citrate (Viagra®) in the treatment of
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`erectile dysfunction. The Sildenafil NDA includes a joint clinical review, which
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`outlines clinical trial data available for sildenafil citrate, as well as
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`pharmacokinetic, pharmacological, toxicological, safety and efficacy data
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`compiled for review by FDA for formal drug approval. EX1002, ¶63; EX1004,
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`¶41, 42.
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`The Sildenafil NDA identifies sildenafil’s mechanism of action,
`teaching: Sildenafil is a selective inhibitor of phosphodiesterase, an
`enzyme that catalyzes cleavage of cAMP or cGMP. Different tissues
`have different forms of this enzyme, and these different forms have
`different affinities for sildenafil. Sildenafil has the lowest IC50 for
`PDE5 . . . PDE5 is found in the corpus cavernosum, platelets, skeletal
`muscle, and vascular and visceral smooth muscle.
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`EX1008 at 0088.
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`The Sildenafil NDA also teaches that sildenafil’s PDE6 IC50 is only 10-fold
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`higher (less potent) than its PDE5 IC50. Id. PDE6 is present in ocular tissues,
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`providing the probable cause of the visual adverse events that sometimes occur
`9
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`following administration of sildenafil. Id.; EX1002, ¶48. As phosphodiesterase
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`enzymes are found in a variety of tissues throughout the body, the on-target effects
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`of PDE inhibition are predictable adverse events:
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`On the basis of the proposed mechanism of action, relative affinities
`of sildenafil for different forms of phosphodiesterase, and the
`distribution of phosphodiesterase in different tissues, there are effects
`of sildenafil that can be predicted. These effects include (a) penile
`erection resulting from relaxation of smooth muscle controlling inflow
`of blood to the corpus cavernosum, (b) systemic vasodilation and,
`possibly hypotension, (c) inhibition of platelet aggregation and
`increased risk of hemorrhage, (d) skeletal muscle weakness, (e)
`reduced activity of the gastrointestinal tract, and (f) interference with
`vision.
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`EX1008 at 0088-89. Accordingly, the Sildenafil NDA concludes that “common
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`treatment-related adverse events—notably headache, vasodilation, dyspepsia, and
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`vision disturbance—were clearly dose-related.” EX1008 at 0095.
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`The Sildenafil NDA states that sildenafil has an IC50 of 3.5 nM for PDE5
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`(id. at 0037), that the therapeutic effectiveness of sildenafil is dose-dependent, and
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`that sildenafil is therapeutically effective for the treatment of erectile dysfunction
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`at doses as low as 5 mg. EX1008 at 0126-28, 0215-16; EX1002, ¶63; EX1004,
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`¶44. The Sildenafil NDA also teaches that maximum recommended dosing
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`schedule is once per day. EX1008 at 0126, 0132, 0139, 0146, 0155, 0217, 0223,
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`0238, 0245, 0251; EX1002, ¶63.The Sildenafil NDA also notes where the tested
`10
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`dosages fall along a dose-response curve, noting, “[t]he 25 mg-placebo difference
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`is more than half of the 100 mg-placebo difference; this suggests that the 25-mg
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`dose is already fairly high on the dose-response curve.” EX1008 at 0070.
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`b)
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`The Sildenafil NDA was publically available at least as
`early as March 27, 1998.
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`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) (quoting In re Hall, 781 F.2d
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`897, 898-899 (Fed. Cir. 1986) (internal quotes omitted). Public accessibility is
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`proven “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 diligence, can locate it.” Id.
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`(quoting SRI Int'l, Inc. v. Internet Sec. Sys. Inc., 511 F.3d 1186, 1194 (Fed. Cir.
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`2008)).
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`Public accessibility of a printed publication is evaluated on a “case-by-case
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`basis.” Id. (citing In re Cronyn, 890 F. 2d 1158, 1161 (Fed. Cir 1989)). Notably,
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`public availability does not require a “show[ing] that particular members of the
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`11
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`public actually received the information.” Constant v. Advanced Micro-Devices,
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`Inc., 848 F.2d 1560, 1569 (Fed. Cir. 1988) (Finding “[e]vidence of routine business
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`practice” sufficient for proving public accessibility.); see also In re Wyer, 655 F.
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`2d 221, 226-227 (C.C.P.A. 1981) (Finding “actual viewing or dissemination of any
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`copy of the application” unnecessary to prove public accessibility “given that there
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`[was] also no genuine issue as to whether the application was properly classified,
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`indexed, or abstracted.”); In re Hall, 781 F. 2d at 899 (Dissertation was publicly
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`accessible based on a showing of “routine business practice” of “cataloging and
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`shelving before the critical date.”).
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`The Sildenafil NDA became publicly available on March 27, 1998, a date
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`more than one year before the April 30, 1999 priority date. Under FDA rules, NDA
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`application documents are accessible to the public immediately upon approval. 21
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`C.F.R. § 314.430(e) (“After FDA sends an approval letter to the applicant” certain
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`data and information associated with that application become “immediately
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`available for public disclosure.”). These data and information available to the
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`public include a “summary or summaries of the safety and effectiveness data and
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`information submitted with or incorporated by reference in the [new drug]
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`application” and a “Summary Basis of Approval (SBA) document that contains a
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`summary of the safety and effectiveness data and information evaluated by FDA
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`during the drug approval process.” See 21 C.F.R. § 314.430(e)(2)(ii); see also, 21
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`12
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`
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`C.F.R. § 312.130 (Availability for public disclosure of data and information in an
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`Investigation New Drug (IND) application). In the case of sildenafil, the data and
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`information accessible to the public includes over 500 pages of information
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`relevant to the “FDA's Clinical, Statistical and Biopharmacological Review of
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`Viagra Clinical Development.” EX1008; Viagra (Sildenafil) NDA 020895
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`Approval Package Access Data,
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`http://www.accessdata.fda.gov/drugsatfda_docs/NDA/98/viagra/viagra_toc.cfm
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`(Sildenafil NDA Access Data, “EX1031”) (indicating the files were created on
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`March 27, 1998).
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`FDA approved sildenafil (Viagra®) on March 27, 1998. EX1008 at 1; FDA
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`Approval Letter, Sildenafil (Viagra®) NDA 020895, March 27, 1998 (“Sildenafil
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`Approval Letter,” EX1032). FDA approval of the sildenafil NDA was publicized
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`broadly that same day. See, e.g., Drug company’s shares rise on FDA approval of
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`pill to treat impotence, CNNMoney.com, March 27, 1998 (“CNN Article,”
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`EX1033) reporting: “Shares of pharmaceutical giant Pfizer Inc. were pushed higher
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`Friday on news that the U.S. Food and Drug Administration has approved its
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`treatment for impotence.”); Pfizer’s Eagerly Anticipated Impotence Drug Viagra
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`Wins FDA Approval, Dow Jones Online News, March 27, 1998 (“Dow Jones
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`Article,” EX1034) reporting: “The Food and Drug Administration Friday
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`announced approval of a long-awaited impotence drug, Pfizer Inc.’s Viagra, which
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`13
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`
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`is the first pill for the disorder.” (original formatting removed)). Thus, as of March
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`27, 1998, the general public and skilled artisans alike would have been aware that
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`FDA had approved the sildenafil NDA.
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`FDA sent Pfizer the approval letter on March 27, 1998, and this event
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`resulted in “immediate” public availability of the Sildenafil NDA documents.
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`EX1032; 21 C.F.R. § 314.430(e). A skilled artisan would have been aware of
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`sildenafil’s approval because of the intense publicity the event garnered and could
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`have requested and obtained the documents containing the safety and effectiveness
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`information contained within the NDA (i.e. the Sildenafil NDA, EX1008) on
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`March 27, 1998. Id. Thus, the Sildenafil NDA is prior art under 35 U.S.C. § 102(b)
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`because it was publically available more than one year before April 30, 1999.
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`3.
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`Dose-Response Information to Support Drug Registration
`(“FDA Guideline,” EX1009)
`FDA Guideline, which was originally authored by the International
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`Conference on Harmonisation (ICH) and was then adopted and published by FDA
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`in the Federal Register on November 9, 1994 (EX1009 at 55972), is prior art to the
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`claims of the ’166 patent under 35 U.S.C. § 102(b). FDA Guideline discloses that
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`dose-response information “help[s] identify an appropriate starting dose, the best
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`way to adjust dosage to the needs of a particular patient, and a dose beyond which
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`increases would be unlikely to provide added benefit or would produce
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`unacceptable side effects.” EX1009 at 55972; EX1002, ¶65; EX1004, ¶43. FDA
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`14
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`
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`Guideline advocates use of dose-ranging studies to identify doses that are sufficient
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`for clinical effect without subjecting patients to unnecessary or excessive dosing.
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`EX1009 at 55973.
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`FDA Guideline provides examples of dose-ranging study procedures that
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`may be used to obtain dose-response data and further recommends “choos[ing] as
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`wide a range of doses as is compatible with practicality and patient safety to
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`discern clinically meaningful differences.” Id. at 55974. FDA Guideline cautions
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`against using excessive doses, described as being “well onto the plateau of the
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`dose-response curve[.]” Id. at 55973. FDA Guideline notes that using a dosage
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`well onto the plateau in the past has resulted in adverse patient effects that were
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`only realized post-marketing. Id.; EX1002, ¶65.
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`D. Brief Overview of the Level of Skill in the Art
`A person of ordinary skill in the relevant field as of April 30, 1999, would
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`likely have some combination of (a) experience with the research or development
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`of pharmaceuticals; (b) the ability to gather and interpret pharmacokinetic and
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`pharmacodynamics data including dose-response curves; and (c) the ability to
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`understand results and findings presented or published by others in the field,
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`including the references discussed in this Petition. EX1002, ¶¶38-39; EX1004,
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`¶¶24-25. Typically this person would have, or would be a member of a team with
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`individuals having, a Pharm.D. or Ph.D. with experience in clinical pharmacology,
`
`
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`15
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`
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`medicinal chemistry, or in a related field, or less education but considerable
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`professional experience in one or more of these fields. Id. at ¶38. The skilled
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`artisan may also have, or have access as part of a team to a person having, an M.D.
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`with experience in the field of urology, with specific experience in sexual
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`dysfunction.
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`This Petition is supported by the declaration of Dr. Fatemeh Akhlaghi. Dr.
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`Akhlaghi received a Pharm. D. from the University of Mashhad, Iran, in 1990, and
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`a Ph.D. in Pharmaceutical Sciences from the University of Sydney, Australia, in
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`1997. EX1002, ¶2; EX1003 (CV). Dr. Akhlaghi completed a post-doctoral
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`fellowship at the University of Sydney in 1998, and another post-doctoral
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`fellowship at the University of Cambridge in 2001 before joining the University of
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`Rhode Island as an Assistant Professor. Id. at ¶3; EX1003. By 2011, Dr. Akhlaghi
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`was promoted to Full Professor at the University of Rhode Island, and she was also
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`promoted to Adjunct Professor at the Brown University Medical School. Id. at ¶4;
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`EX1003. Dr. Akhlaghi’s research interests include the general area of
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`pharmaceutical sciences with a focus on pharmacokinetic/pharmacodynamics
`
`modeling, clinical pharmacology, translational sciences, drug metabolism, and
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`pharmacogenomics, and she has authored more than 70 full-length peer-reviewed
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`articles and 100 abstracts in these areas. Id. at ¶5; EX1003.
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`In addition, she has given more than 30 invited presentations and have
`
`
`
`16
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`
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`consulted with multiple pharmaceutical companies involving clinical research,
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`design of pharmacokinetic studies and pharmacokinetic/pharmacodynamics
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`modeling. Id. Currently, Dr. Akhlaghi is Professor of Pharmacokinetics and Ernest
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`Mario Distinguished Chair of Pharmaceutics in the College of Pharmacy,
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`University of Rhode Island. EX1002, ¶1. Dr. Akhlaghi is well qualified as an
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`expert, possessing the necessary scientific, technical, and other specialized
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`knowledge and training to assist in an understanding of the evidence presented
`
`herein, as well as possessing the expertise necessary to determine and explain the
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`level of ordinary skill in the art as of April 30, 1999. See EX1003.
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`This Petition is also supported by the declaration of Dr. Anthony Sliwinski.
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`EX1004. Dr. Sliwinski is a board certified M.D. with over 26-years of experience
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`as a practicing urologist. EX1004, ¶¶ 1, 5. Dr. Sliwinski received his M.D. from
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`Georgetown University in 1986, after which he became Chief Resident in Urology
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`at the Medical College of Virginia. EX1004, ¶2; EX1005 (CV).
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`Dr. Sliwinski has given numerous presentations in the field of urology,
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`including multiple presentations regarding sexual/erectile dysfunction. EX1004,
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`¶3; EX1005. Dr. Sliwinski also has extensive experience as a principal investigator
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`involving research in the urological field, which include multiple studies
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`concerning sexual/erectile dysfunction. EX1004, ¶4; EX1005. Dr. Sliwinski has
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`treated over 4000 patients with sexual/erectile dysfunction, and has broad
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`
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`17
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`
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`knowledge of publications concerning the developments in the treatment of
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`sexual/erectile dysfunction and pharmaceutical products to treat the same.
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`EX1004, ¶5. Currently, Dr. Sliwinski is the co-director of Men’s Wellness at
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`Virginia Urology. EX1004, ¶1. Dr. Sliwinski is well qualified as an expert,
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`possessing the necessary scientific, technical, and other specialized knowledge and
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`training to assist in an understanding of the evidence presented herein. See
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`EX1005; EX1004, ¶¶ 1-5.
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`Background Knowledge in the Art Prior to April 30, 1999
`E.
`The background publications below reflect knowledge skilled artisans would
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`bring to bear in reading the prior art at the time of the invention, i.e., before the
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`earliest claimed priority date of April 30, 1999, and thereby assist in understanding
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`why one would have been motivated to combine or modify the references as
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`asserted in this Petition. Ariosa Diagnostics v. Verinata Health, Inc., 805 F.3d
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`1359, 1365 (Fed. Cir. 2015). As established in KSR, 550 U.S. at 406, the
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`knowledge of a skilled artisan is part of the store of public knowledge that must be
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`consulted when considering whether a claimed invention would have been
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`obvious. Randall Mfg. v. Rea, 733 F.3d 1355, 1362-63 (Fed. Cir. 2013).
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`Prior to April 30, 1999, sexual dysfunctions were defined as “disturbances in
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`sexual desire and in the psychophysiological changes associated with the sexual
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`response cycle in men and women.” Laumann, E. O., et al., Sexual Dysfunction in
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`
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`18
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`
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`the United States, 281 JAMA 537-544 (Feb. 1999) (“Laumann,” EX1012);
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`EX1002, ¶44. Dysfunctions of this type were identified as belonging to one of four
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`main categories, including desire disorders, arousal disorders, orgasmic disorders
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`and pain disorders. Halvorsen, J. G., et al., Sexual Dysfunction, Part I:
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`Classification, Etiology, and Pathogenesis, 5 J. AM. BOARD FAM. PRACT. (1992) 51-
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`61 (“Halvorsen,” EX1026); EX1004, ¶30. While male sexual dysfunction disorders
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`were more heavily studied (EX1004, ¶¶31-32), those in the art taught that female
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`sexual disorders, such as female arousal disorder, may have similar biological
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`origins as male sexual impotence disorders such as erectile function. EX1026 at
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`56-57; EX1004, ¶32.
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`The biological mechanism governing penile rigidity and its role in sexual
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`dysfunctions such as erectile dysfunction was well established in the art. For
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`example, Boolell teaches that production of cyclic guanosine monophosphate
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`(cGMP) causes relaxation of smooth muscle cells, which in turn results in penile
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`rigidity. Boolell, M., et al., Sildenafil: an orally active type 5 cyclic GMP-specific
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`phosphodiesterase inhibitor for the treatment of penile erectile dysfunction, 8 INT.
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`J. IMPOT. RES., (1996) 47-52 (“Boolell,” EX1015); EX1002, ¶44; EX1004, ¶¶32-33.
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`A group of enzymes known as cyclic nucleotide phosphodiesterase (PDE)
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`isozymes were known to be present in the corpus cavernosum tissues present in the
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`penis, and were known to hydrolyze cGMP. EX1015 at 47. Thus, those in the art
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`
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`19
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`
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`recognized that “a pharmacological agent which inhibits the cGMP-specific
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`phosphodiesterase isozyme, should enhance the action of nitric oxide/cGMP on
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`penile erectile activity and have the potential to enhance penile erections during
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`sexual stimulation.” Id.; EX1002, ¶44.
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`One particular isozyme, PDE5, was identified as “the predominant cGMP
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`[for its] hydrolyzing activity,” and oral “inhibitors of type 5 PDE [which] improve
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`erection” were known to serve as pharmaceutical agents in the treatment of sexual
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`dysfunctions. Terrett, N. K., et al., Sildenafil (ViagraTM), a Potent and Selective
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`Inhibitor of Type 5 cGMP Phosphodiesterase with Utility for the Treatment of
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`Male Erectile Dysfunction, 6 BIOORG. MED. CHEM. LETT. (1996) 1819-1824
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`(“Terrett,” EX1013); EX1002, ¶45; EX1004, ¶32. Sildenafil citrate (Viagra®), was
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`identified as a PDE5 inhibitor and as an “orally active treatment for male erectile
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`dysfunction” prior to 1999. EX1013 at 1819; EX1002, ¶46; EX1
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