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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`____________________________________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`____________________________________________
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`ARGENTUM PHARMACEUTICALS LLC,
`Petitioner,
`
`
`v.
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`ICOS CORPORATION,
`Patent Owner.
`
`
`
`Case No. IPR2017-01762
`Patent No. 6,943,166 B1
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 6,943,166
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`
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`TABLE OF CONTENTS
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`I.
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`INTRODUCTION ............................................................................................... 1
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`A. Brief Overview of the ’166 Patent .................................................................... 4
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`B. Brief Overview of the Prosecution History ...................................................... 6
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`C. Brief Overview of the Scope and Content of the Prior Art .............................. 8
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`D. Brief Overview of the Level of Skill in the Art .............................................. 16
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`E. Background Knowledge in the Art Prior to April 30, 1999 ........................... 19
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`II. GROUNDS FOR STANDING .......................................................................... 25
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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
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`CLAIM CHALLENGED ......................................................................................... 28
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`V. CLAIM CONSTRUCTION .............................................................................. 28
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`A. “up to a maximum total dose” ........................................................................ 29
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`B. “female arousal disorder” ............................................................................... 30
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`C. “free drug” ...................................................................................................... 30
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`VI. DETAILED EXPLANATION OF GROUNDS FOR UNPATENTABILITY
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`31
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`A. [Ground 1] Claims 1-12 are Obvious under 35 U.S.C. § 103 over the ’675
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`PCT (EX1007) in view of the Sildenafil NDA (EX1008) and FDA Guideline
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`(EX1009). ............................................................................................................. 31
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`VII. NO OBJECTIVE INDICIA OF NON-OBVIOUSNESS ............................... 48
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`A. Legal Standard ................................................................................................ 48
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`B. The Claimed Dosing Method Does Not Produce Unexpected Results .......... 49
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`C. No Long-Felt Need for the Claimed Dosing Regimen ................................... 63
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`VIII. CONCLUSION .............................................................................................. 65
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`IX. CERTIFICATE OF COMPLIANCE ............................................................. 66
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`X. PAYMENT OF FEES UNDER 37 C.F.R. §§ 42.15(A) AND 42.103 ................ 66
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`XI. APPENDIX – LIST OF EXHIBITS ............................................................... 67
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`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, Argentum
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`Pharmaceuticals LLC, (“Petitioner”) hereby requests inter partes review of
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`United States Patent No. 6,943,166 to Pullman (“the ’166 patent,” EX1001),
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`which issued on September 13, 2005, and is currently assigned to ICOS Corp.,
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`which is owned by Eli Lilly and Co. (collectively “Patent Owner”). Inter partes
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`review of Claims 1-12 of the ’166 patent was instituted in IPR2017-00323 on
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`June 12, 2017, based on a petition filed by Mylan Pharmaceuticals Inc. (“Mylan
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`IPR”). Argentum hereby files its own Petition on the same ground instituted in
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`the Mylan IPR and concurrently seeks to join the instituted Mylan IPR. A motion
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`for joinder with IPR2017-00323 is being filed concurrently with this Petition.
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`This petition is accompanied by declarations from Dr. Culley C. Carson III, M.D.
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`(Ex. 1037) and Dr. Jackie Corbin, Ph.D. (Ex. 1038) indicating that they have
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`reviewed the declarations of Dr. George Grass, Pharm.D., Ph.D. and Dr. Muta M.
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`Issa, M.D., M.B.A., which are Exs. 1002, 1004 in IPR2017-00323 and in this
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`IPR. Additionally, Drs. Carson and Corbin indicated in their declarations that
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`they agree with the opinions and reasoning in the declarations of Drs. Grass and
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`Issa and have adopted the same opinions and reasoning.
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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
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`previously claimed utility for treating sexual dysfunction. The dosing regimen
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`claimed in the ’166 is the administration of about 1 to about 20 mg of tadalafil,
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`where the total maximum daily dose is no larger than 20 mg. The art taught not
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`only the compound tadalafil itself, but that (i) orally administered tadalafil was
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`useful in treating sexual dysfunction at daily dosages as low as 0.5 mg
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`(EX1007); and (ii) tadalafil was nearly twice as potent as sildenafil citrate
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`(Viagra®), another inhibitor of the same PDE5 enzyme that gained FDA
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`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
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`was 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
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`tadalafil proportionately based on known data regarding the approved doses of
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`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
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`dose- response plateau as a preferred daily dosage. In accordance with this, and
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`as discussed in detail below, a 25 mg daily dose of sildenafil falls near the top of
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`the dose-response curve but below its plateau. EX1008 at 0070. In other words,
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`the dose response curve generated for sildenafil identified that daily dose as
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`within the optimal dose range with respect to efficacy and adverse events.
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`As explained by Dr. George Grass, a pharmacokineticist with over 30
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`years of experience in drug development and drug delivery, to determine an
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`appropriate daily dose of tadalafil a person of ordinary skill would have
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`compared the potency data for tadalafil and sildenafil (consisting of IC50 values
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`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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`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
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`events reported for a once-daily dose of 25 mg sildenafil would have been
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`expected by the skilled artisan to be approximately equivalent to those occurring
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`with a once-daily dose of roughly 15 mg of tadalafil. Id. From the Patent Owner’s
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`own press releases, it was already known in the art that tadalafil had been used
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`for treating sexual dysfunction in a variety of clinical trials in Europe and the
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`U.S., that the drug was safe and well tolerated, and that patients showed
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`significant 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
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`Generally, the ’166 patent is directed to a dosing regimen used in methods
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`to treat sexual dysfunction with tadalafil, a highly-selective PDE5 inhibitor. See,
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`e.g., EX1001, abstract. The ’166 patent has only one independent claim, claim 1,
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`which recites:
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`1. A method of treating sexual dysfunction in a patient in
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`need thereof comprising orally administering one or more
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`unit dose
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`containing about 1 to about 20 mg, up to a maximum total dose of 20
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`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
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`dosage values that are to be administered once per day. Dependent claims 2 and 3
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`recite 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
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`the unit dose is to be given (i.e., formulated as a liquid, tablet, capsule or gelcap,
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`or as 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 ans that such compounds are potent
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`PDE5 inhibitors, have an “oral doage” 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
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`compound.” Id. at 2:12-22 (citing disclosures that include tadalafil). The ’166
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`patent also acknowledges that no significant adverse side effects are disclosed for
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`these prior 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
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`believed to be indicative of PDE5 inhibition can be reduced to clinically
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`insignificant levels 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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`Grass (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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`B.
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`Brief Overview of the Prosecution History
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`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.
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`6,943,166. The ’556 application was a national stage entry of PCT/US00/11129,
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`which claims priority to Provisional Application No. 60/132,036, filed on April
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`30, 1999. The 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
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`dosage within the recited range” of the “the instant compound and a method of
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`using it to treat sexual dysfunction.” EX1006 at 0385. In response, applicants
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`argued that the range of about 1-20 mg “is critical because this dose range
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`exhibits the surprising and unexpected results of low adverse events and still
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`being unexpectedly 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
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`to efficacy (id. at 0035) despite the fact that the Sides declarations did not provide
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`a statistical analysis. The examiner also stated that “the adverse side effects at 20
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`mg are dramatically reduced when compared to 50 mg” and concluded that the
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`data was sufficient to show unexpected results. Id.; EX1002, ¶21.
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`As shown in this Petition and by the supporting evidence, the data
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`presented during prosecution and in the specification of the ’166 patent do not
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`establish unexpected results. In fact, they merely confirm the predictable results
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`of routine dose optimization studies. Moreover, the data comparison used in the
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`Sides declarations suffer from various defects that undermine any legitimate
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`conclusion of unexpected results. As such, Petitioner respectfully submits that the
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`examiner’s acquiescence to Patent Owner’s one-sided attorney argument and
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`accompanying declarations regarding unexpected results should receive little if
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`any deference by the Board.
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`C. Brief Overview of the Scope and Content of the Prior Art
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`In obviousness cases, Graham v. John Deere Co. of Kansas City, requires
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`an evaluation of any differences between the claimed subject matter and the
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`asserted prior art. 383 U.S. 1, 17-18 (1966). As noted in KSR Int’l Co. v. Teleflex
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`Inc., the obviousness inquiry may account for inferences that would be employed
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`by a person of ordinary skill in the art. 550 U.S. 398, 418 (2007).
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`1.
`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).
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`The ’675 PCT prominently discloses Compound A ((6R,12aR)-
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`2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-
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`pyrazino[2’,1’:6,1]pyrido[3,4-b]indole-1,4-dione)( EX1007 at 3, lines 24-25),
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`now known, and referred to herein as tadalafil (see, “Cialis® label,” EX1010), as
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`one of two “highly selective” PDE5 inhibitors that are useful in the treatment of
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`male sexual dysfunction disorders, including erectile dysfunction, as well as
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`female sexual dysfunction disorders. EX1007 at 3-4; EX1002, ¶¶57-60; EX1004,
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`¶37, 39.
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`Compound A (Tadalafil)
`The '675 PCT; EX1007
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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.” EX1007 at 17; EX1002, ¶59; EX1004, ¶38.
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`The ’675 PCT teaches that tadalafil may be administered orally, for
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`example using “individual tablets or capsules [which] contain from 0.2-400mg of
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`active 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.”
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`EX1007 at 5; EX1002, ¶¶57, 60. The ’675 PCT also notes that “[f]or human use,
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`compounds of formula (I), and in particular compounds A [(tadalafil)] and B [(3-
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`methyl-tadalafil)] can be administered alone, but will generally be administered in
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`admixture with a pharmaceutical carrier[.]” EX1007 at 5; EX1002, ¶60.
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`2.
`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 SNDA
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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:
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`Sildenafil is a selective inhibitor of phosphodiesterase, an enzyme that
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`catalyzes cleavage of cAMP or cGMP. Different tissues have different
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`forms of this enzyme, and these different forms have different
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`affinities for sildenafil. Sildenafil has the lowest IC50 for PDE5 . . .
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`PDE5 is found in the corpus cavernosum, platelets, skeletal muscle,
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`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
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`administration of sildenafil. Id.; EX1002, ¶48. As phosphodiesterase enzymes are
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`found in a variety of tissues throughout the body, the on-target effects of PDE
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`inhibition are predictable adverse events:
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`On the basis of the proposed mechanism of action, relative affinities
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`of sildenafil for different forms of phosphodiesterase, and the
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`distribution of phosphodiesterase in different tissues, there are
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`effects of sildenafil that can be predicted. These effects include (a)
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`penile erection resulting from relaxation of smooth muscle
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`controlling inflow of blood to the corpus cavernosum, (b) systemic
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`vasodilation and, possibly hypotension, (c) inhibition of platelet
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`aggregation and increased risk of hemorrhage, (d) skeletal muscle
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`weakness, (e) reduced activity of the gastrointestinal tract, and (f)
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`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,
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`and 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.
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`The Sildenafil NDA also teaches that maximum recommended dosing schedule
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`is once per day. EX1008 at 0126, 0132, 0139, 0146, 0155, 0217, 0223, 0238,
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`0245, 0251; EX1002, ¶63.The Sildenafil NDA also notes where the tested
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`dosages fall along a dose-response curve, noting, “[t]he 25 mg-placebo
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`difference is more than half of the 100 mg-placebo difference; this suggests that
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`the 25-mg dose is already fairly high on the dose-response curve.” EX1008 at
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`0070.
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`b)
`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
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`of 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.
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`2d 897, 898-899 (Fed. Cir. 1986) (internal quotes omitted). Public accessibility
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`is proven “upon a satisfactory showing that such document has been
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`disseminated or otherwise made available to the extent that persons interested
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`and ordinarily skilled in the subject matter or art exercising reasonable diligence,
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`can locate it.” Id. (quoting SRI Int'l, Inc. v. Internet Sec. Sys. Inc., 511 F.3d
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`1186, 1194 (Fed. Cir. 2008)).
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`Public accessibility of a printed publication is evaluated on a “case-by-
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`case basis.” Id. (citing In re Cronyn, 890 F. 2d 1158, 1161 (Fed. Cir 1989)).
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`Notably, public availability does not require a “show[ing] that particular
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`members of the public actually received the information.” Constant v. Advanced
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`Micro-Devices, Inc., 848 F.2d 1560, 1569 (Fed. Cir. 1988) (Finding “[e]vidence
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`of routine business practice” sufficient for proving public accessibility.); see
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`also In re Wyer, 655 F. 2d 221, 226-227 (C.C.P.A. 1981) (Finding “actual
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`viewing or dissemination of any copy of the application” unnecessary to prove
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`public accessibility “given that there [was] also no genuine issue as to whether
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`the application was properly classified, indexed, or abstracted.”); In re Hall, 781
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`F. 2d at 899 (Dissertation was publicly accessible based on a showing of “routine
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`business practice” of “cataloging and 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,
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`NDA application documents are accessible to the public immediately upon
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`approval. 21 C.F.R. § 314.430(e) (“After FDA sends an approval letter to the
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`applicant” certain data and information associated with that application become
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`“immediately available for public disclosure.”). These data and information
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`available to the public include a “summary or summaries of the safety and
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`effectiveness data and information submitted with or incorporated by reference
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`in the [new drug] application” and a “Summary Basis of Approval (SBA)
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`document that contains a summary of the safety and effectiveness data and
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`information evaluated by FDA during the drug approval process.” See 21 C.F.R.
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`§ 314.430(e)(2)(ii); see also, 21 C.F.R. § 312.130 (Availability for public
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`disclosure of data and information in an Investigation New Drug (IND)
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`application). In the case of sildenafil, the data and information accessible to the
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`public includes over 500 pages of information relevant to the “FDA's Clinical,
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`Statistical and Biopharmacological Review of Viagra Clinical Development.”
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`EX1008; Viagra (Sildenafil) NDA 020895 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 (VIAGR® ) on March 27, 1998. EX1008 at 1;FDA
`A
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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
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`higher Friday on news that the U.S. Food and Drug Administration has approved
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`its treatment for impotence.”); Pfizer’s Eagerly Anticipated Impotence Drug
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`Viagra Wins FDA Approval, Dow Jones Online News, March 27, 1998 (“Dow
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`Jones 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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`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
`
`sildenafil’s approval because of the intense publicity the event garnered and
`
`could have requested and obtained the documents containing the safety and
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`effectiveness information contained within the NDA (i.e. the Sildenafil NDA,
`
`EX1008) on March 27, 1998. Id. Thus, the Sildenafil NDA is prior art under 35
`
`U.S.C. § 102(b) because it was publically available more than one year before
`
`April 30, 1999.
`
`3.
`Dose-Response Information to Support Drug Registration
`(“FDA Guideline,” EX1009)
`
`FDA Guideline, which was originally authored by the International
`
`Conference on Harmonisation (ICH) and was then adopted and published by FDA
`
`in the Federal Register on November 9, 1994 (EX1009 at 55972), is prior art to
`
`the claims of the ’166 patent under 35 U.S.C. § 102(b). FDA Guideline discloses
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`that dose-response information “help[s] identify an appropriate starting dose, the
`
`best way to adjust dosage to the needs of a particular patient, and a dose beyond
`
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`15
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`IPR2017-01762 Petition
`Patent No. 6,943,166
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`which increases would be unlikely to provide added benefit or would produce
`
`unacceptable side effects.” EX1009 at 55972; EX1002, ¶65; EX1004, ¶43. FDA
`
`Guideline advocates use of dose-ranging studies to identify doses that are
`
`sufficient for clinical effect without subjecting patients to unnecessary or
`
`excessive dosing. EX1009 at 55973.
`
`FDA Guideline provides examples of dose-ranging study procedures that
`
`may be used to obtain dose-response data and further recommends “choos[ing]
`
`as wide a range of doses as is compatible with practicality and patient safety to
`
`discern clinically meaningful differences.” Id. at 55974. FDA Guideline
`
`cautions against using excessive doses, described as being “well onto the
`
`plateau of the dose-response curve[.]” Id. at 55973. FDA Guideline notes that
`
`using a dosage well onto the plateau in the past has resulted in adverse patient
`
`effects that were only realized post-marketing. Id.; EX1002, ¶65.
`
`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
`
`likely have some combination of (a) experience with the research or development
`
`of pharmaceuticals; (b) the ability to gather and interpret pharmacokinetic and
`
`pharmacodynamics data including dose-response curves; and (c) the ability to
`
`understand results and findings presented or published by others in the field,
`
`including the references discussed in this Petition. EX1002, ¶¶38-39; EX1004,
`
`
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`16
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`IPR2017-01762 Petition
`Patent No. 6,943,166
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`¶¶24-25. Typically this person would have, or would be a member of a team with
`
`individuals having, a Pharm.D. or Ph.D. with experience in clinical
`
`pharmacology, medicinal chemistry, or in a related field, or less education but
`
`considerable professional experience in one or more of these fields. Id. at ¶38.
`
`The skilled artisan may also have, or have access as part of a team to a person
`
`having, an M.D. with experience in the field of urology, with specific experience
`
`in sexual dysfunction.
`
`This Petition is supported by the declaration of Dr. George Grass. Dr.
`
`Grass received a Pharm.D. from the University of Nebraska in 1980 and a Ph.D.
`
`in pharmaceutics from the University of Wisconsin, Madison in 1985. EX1002,
`
`¶2; EX1003 (CV). In 1985, Dr. Grass began a research position at the Institute of
`
`Pharmaceutical Sciences in Palo Alto, California, where he worked on the
`
`development of early stage compounds for oral delivery. Id. at ¶3; EX1003. By
`
`1991, Dr. Grass was serving as a pharmaceutical industry consultant. Id. Dr.
`
`Grass has also served as the Senior Vice President of Research and Development
`
`at Sorbent Therapeutics, overseeing the development of novel technologies and
`
`product formulation strategies. EX1002, ¶4; EX1003. Currently, Dr. Grass is
`
`President of a consulting business, G2 Research Inc., and Senior Vice President
`
`of Non-Clinical Development for NeuroVia, Inc. EX1002, ¶1.
`
`Dr. Grass has authored dozens of peer-reviewed journal articles, including
`
`
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`17
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`IPR2017-01762 Petition
`Patent No. 6,943,166
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`articles dealing with oral drug absorption predictions, pharmacokinetic
`
`simulation modeling, and predictive pharmacokinetic simulation models for drug
`
`discovery, and is listed as an inventor on at least twelve issued U.S. Patents.
`
`EX1002, ¶3, 5; EX1003. Dr. Grass is well qualified as an expert, possessing the
`
`necessary scientific, technical, and other specialized 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 level of ordinary skill in the
`
`art as of April 30, 1999. See EX1003.
`
`This Petition is also supported by the declaration of Dr. Muta M. Issa.
`
`EX1004. Dr. Issa is a tenured Professor of Urology in the School of Medicine at
`
`Emory University, and also serves as Chief of Urology at the Atlanta Veterans
`
`Affairs Medical Center. EX1004, ¶1. Dr. Issa received his M.D. from the Royal
`
`College of Surgeons in Ireland in 1983, after which he became Chief Resident in
`
`Urology at Stanford Medical Center. EX1004, ¶2; EX1005 (CV).
`
`Dr. Issa has served on the editorial boards of peer-reviewed publications
`
`such as The Scientific World Journal of Urology and Urologists in Cancer Care.
`
`EX1004, ¶3. Dr. Issa has also authored more than 100 peer-reviewed journal
`
`articles, pertaining to the field of urology, and is listed as an inventor on at least
`
`ten issued U.S. Patents. EX1004, ¶4; EX1005. Dr. Issa is well qualified as an
`
`expert, possessing the necessary scientific, technical, and other specialized
`
`
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`18
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`IPR2017-01762 Petition
`Patent No. 6,943,166
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`knowledge and training to assist in an understanding of the evidence presented
`
`herein. See EX1005; EX1004, ¶5.
`
`E.
`
`Background Knowledge in the Art Prior to April 30, 1999
`
`The background publications below reflect knowledge skilled artisans
`
`would bring to bear in reading the prior art at the time of the invention, i.e.,
`
`before the earliest claimed priority date of April 30, 1999, and thereby assist in
`
`understanding why one would have been motivated to combine or modify the
`
`references as asserted in this Petition. Ariosa Diagnostics v. Verinata Health,
`
`Inc., 805 F.3d 1359, 1365 (Fed. Cir. 2015). As established in KSR, 550 U.S. at
`
`406, the knowledge of a skilled artisan is part of the store of public knowledge
`
`that must be consulted when considering whether a claimed invention would
`
`have been obvious. Randall Mfg. v. Rea, 733 F.3d 1355, 1362-63 (Fed. Cir.
`
`2013).
`
`Prior to April 30, 1999, sexual dysfunctions were defined as “disturbances
`
`in sexual desire and in the psychophysiological changes associated with the
`
`sexual response cycle in men and women.” Laumann, E. O., et al., Sexual
`
`Dysfunction in the United States, 281 JAMA 537-544 (Feb. 1999) (“Laumann,”
`
`EX1012); EX1002, ¶44. Dysfunctions of this type were identified as belonging
`
`to one of four main categories, including desire disorders, arousal disorders,
`
`orgasmic disorders and pain disorders. Halvorsen, J. G., et al., Sexual
`
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`19
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`Patent No. 6,943,166
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`Dysfunction, Part I: Classification, Etiology, and Pathogenesis, 5 J. AM. BOARD
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`FAM. PRACT. (1992) 51-61 (“Halvorsen,” EX1026); EX1004, ¶30. While male
`
`sexual dysfunction disorders were more heavily studied (EX1004, ¶¶31-32),
`
`those in the art taught that female sexual disorders, such as female arousal
`
`disorder, may have similar biological origins as male sexual impotence disorders
`
`such as erectile function. EX1026 at 56-57; EX1004, ¶32.
`
`The biological mechanism governing penile rigidity and its role in sexual
`
`dysfunctions such as erectile dysfunction was well established in the art. For
`
`example, Boolell teaches that production of cyclic guanosine monophosphate
`
`(cGMP) causes relaxation of smooth muscle cells, which in turn results in penile
`
`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
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`INT. J. IMPO
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