`
`Filed on behalf of: Mylan Pharmaceuticals Inc.
`By: Steven W. Parmelee (sparmelee@wsgr.com)
`
`Michael T. Rosato (mrosato@wsgr.com)
`
`Jad A. Mills (jmills@wsgr.com)
`
`Wilson Sonsini Goodrich & Rosati
`
`
`Paper No. ____
`Filed: November 22, 2016
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`ICOS CORPORATION,
`Patent Owner.
`
`_____________________________
`
`Case No. IPR2017-00323
`Patent No. 6,943,166
`
`_____________________________
`
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 6,943,166
`
`
`
`
`
`
`I.
`
`Page
`Introduction .................................................................................................. 1
`
`Table of Contents
`
`A.
`
`Brief Overview of the ’166 Patent....................................................... 3
`
`B.
`
`Brief Overview of the Prosecution History ......................................... 5
`
`C.
`
`Brief Overview of the Scope and Content of the Prior Art .................. 7
`
`D.
`
`Brief Overview of the Level of Skill in the Art ................................. 15
`
`E.
`
`Background Knowledge in the Art Prior to April 30, 1999 ............... 18
`
`II.
`
`Grounds for Standing .................................................................................. 24
`
`III. Mandatory Notices under 37 C.F.R. § 42.8 ................................................. 24
`
`IV. Statement of the Precise Relief Requested for Each Claim Challenged ....... 27
`
`V.
`
`Claim Construction ..................................................................................... 27
`
`A.
`
`“up to a maximum total dose” ........................................................... 28
`
`B.
`
`“female arousal disorder” .................................................................. 29
`
`C.
`
`“free drug” ........................................................................................ 29
`
`VI. Detailed Explanation Of Grounds For Unpatentability ................................ 30
`
`A.
`
`[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
`
`VII. The Claimed Dosing Method Does Not Produce Unexpected Results ......... 46
`
`-i-
`
`
`
`
`
`VIII. Conclusion .................................................................................................. 62
`VIII.
`Conclusion ................................................................................................ ..62
`
`IX. Certificate of Compliance ........................................................................... 65
`Certificate of Compliance ......................................................................... ..65
`
`X.
`
`Payment of Fees under 37 C.F.R. §§ 42.15(a) and 42.103........................... 66
`Payment of Fees under 37 C.F.R. §§ 42.15(a) and 42.103 ......................... ..66
`
`XI. Appendix – List of Exhibits ........................................................................ 67
`XI.
`Appendix — List of Exhibits ...................................................................... ..67
`
`
`
`-ii-
`
`
`
`
`
`I.
`
`INTRODUCTION
`
`Pursuant to the provisions of 35 U.S.C. § 311 and § 6 of the Leahy-Smith
`
`America Invents Act (“AIA”), and to 37 C.F.R. Part 42, Mylan Pharmaceuticals
`
`Inc., (“Petitioner”) hereby requests inter partes review of United States Patent No.
`
`6,943,166 to Pullman (“the ’166 patent,” EX1001), which issued on September 13,
`
`2005, and is currently assigned to ICOS Corp., which is owned by Eli Lilly and Co.
`
`(collectively “Patent Owner”).
`
`The ’166 patent is directed to a dosing regimen for treating sexual
`
`dysfunction using a prior art compound now known as tadalafil, a
`
`phosphodiesterase type 5 (PDE5) inhibitor with previously reported and previously
`
`claimed utility for treating sexual dysfunction. The dosing regimen claimed in
`
`the ’166 is the administration of about 1 to about 20 mg of tadalafil, where the total
`
`maximum daily dose is no larger than 20 mg. The art taught not only the
`
`compound tadalafil itself, but that (i) orally administered tadalafil was useful in
`
`treating sexual dysfunction at daily dosages as low as 0.5 mg (EX1007); and (ii)
`
`tadalafil was nearly twice as potent as sildenafil citrate (Viagra®), another inhibitor
`
`of the same PDE5 enzyme that gained FDA approval in March 1998. EX1008.
`
`Sildenafil (25 mg, 50 mg, and 100mg) was approved, as a once-daily
`
`treatment for male erectile dysfunction, and it was known to produce only minor
`
`adverse events at the approved once-daily doses of 25 and 50 mg. As tadalafil was
`
`-1-
`
`
`
`
`
`nearly twice as potent as sildenafil for the same PDE5 enzyme, the person of
`
`ordinary skill in the art would have been motivated to adjust the dosing of tadalafil
`
`proportionately based on known data regarding the approved doses of sildenafil.
`
`Dose response analyses of sildenafil for treatment of sexual dysfunction
`
`were documented in the prior art. See, e.g., EX1008 at 0070. Skilled artisans
`
`routinely produced these dose-response curves to inform dosage decisions and,
`
`following FDA Guidelines (e.g., EX1009), routinely selected doses below a dose-
`
`response plateau as a preferred daily dosage. In accordance with this, and as
`
`discussed in detail below, a 25 mg daily dose of sildenafil falls near the top of the
`
`dose-response curve but below its plateau. EX1008 at 0070. In other words, the
`
`dose response curve generated for sildenafil identified that daily dose as within the
`
`optimal dose range with respect to efficacy and adverse events.
`
`As explained by Dr. George Grass, a pharmacokineticist with over 30 years
`
`of experience in drug development and drug delivery, to determine an appropriate
`
`daily dose of tadalafil a person of ordinary skill would have compared the potency
`
`data for tadalafil and sildenafil (consisting of IC50 values for the PDE5 enzyme)
`
`that were reported in the prior art. Based on this comparison (3.5 nM to 2.0 nM),
`
`tadalafil would have been expected to be nearly twice as potent as sildenafil, and
`
`the dose response for tadalafil would have been expected to be analogous to that
`
`reported for sildenafil except similar efficacies would be obtained at lower doses of
`
`-2-
`
`
`
`
`
`tadalafil. Thus, the efficacy and adverse events reported for a once-daily dose of
`
`25 mg sildenafil would have been expected by the skilled artisan to be
`
`approximately equivalent to those occurring with a once-daily dose of roughly 15
`
`mg of tadalafil. Id. From the Patent Owner’s own press releases, it was already
`
`known in the art that tadalafil had been used for treating sexual dysfunction in a
`
`variety of clinical trials in Europe and the U.S., that the drug was safe and well
`
`tolerated, and that patients showed significant improvement.
`
`Administering a once-daily dose of 15 mg of tadalafil to a patient with
`
`sexual dysfunction satisfies each element of claim 1 of the ’166 patent, including
`
`that that the unit dose contains about 1 to about 20 mg of tadalafil, and that the
`
`daily dose is no larger than 20 mg. Moreover, each of claims 1-12 of the ʼ166
`
`patent merely recite doses that would have been expected to be efficacious and
`
`cause only minimal adverse events based on comparison to sildenafil’s known
`
`potency and approved dosing. EX1008.
`
`A. Brief Overview of the ’166 Patent
`
`Generally, the ’166 patent is directed to a dosing regimen used in methods to
`
`treat sexual dysfunction with tadalafil, a highly-selective PDE5 inhibitor. See, e.g.,
`
`EX1001, abstract. The ’166 patent has only one independent claim, claim 1, which
`
`recites:
`
`1. A method of treating sexual dysfunction in a patient in need
`
`thereof comprising orally administering one or more unit dose
`
`-3-
`
`
`
`
`
`containing about 1 to about 20 mg, up to a maximum total dose of 20
`
`mg per day, of a compound having the structure
`
`CH3
`
`N
`
`H
`
`N
`
`O
`
`O
`
`O
`
`O
`
`
`
`H
`
`N H
`
`Dependent claims 4, 5, 8, and 12 recite specific dosage values within the 1-
`
`20 mg range, and dependent claims 6, 9, and 10 additionally recite specific dosage
`
`values that are to be administered once per day. Dependent claims 2 and 3 recite
`
`that the sexual dysfunction is male erectile dysfunction and female arousal disorder,
`
`respectively. Dependent claims 7 and 11 recite dosage forms in which the unit dose
`
`is to be given (i.e., formulated as a liquid, tablet, capsule or gelcap, or as a free
`
`drug).
`
`The ’166 patent admits that the prior art had previously identified “certain
`
`tetracyclic derivatives” including tadalafil ans that such compounds are potent
`
`PDE5 inhibitors, have an “oral doage” of “0.58 mg daily for an average adult
`
`patient (70 kg),” and have unit doses between “0.2 to 400 mg of active compound.”
`
`Id. at 2:12-22 (citing disclosures that include tadalafil). The ’166 patent also
`
`acknowledges that no significant adverse side effects are disclosed for these prior
`
`art tetracyclic derivatives. Id.
`
`-4-
`
`
`
`
`
`The ’166 patent then states: “Applicants have discovered that one such
`
`tetracyclic derivative, [tadalafil], can be administered in a unit dose that provides
`
`an effective treatment without the side effects associated with the presently
`
`marketed PDE5 inhibitor, sildenafil.” Id. at 2:23-32. The ’166 patent
`
`subsequently states: “The present invention is based on detailed experiments and
`
`clinical trials, and the unexpected observations that side effects previously believed
`
`to be indicative of PDE5 inhibition can be reduced to clinically insignificant levels
`
`by the selection of a compound and unit dose.” Id. at 5:15-19.
`
`As discussed in this Petition and in the accompanying declaration of Dr.
`
`Grass (EX1002), however, the compound and claimed dosing regimens were both
`
`disclosed and suggested in the art. At most, the unit dose containing about 1 to
`
`about 20 mg, up to a maximum total dose of 20 mg per day as claimed in the ’166
`
`patent is simply the result of routine optimization. EX1002, ¶¶22-28.
`
`B.
`
`Brief Overview of the Prosecution History
`
`U.S. Patent Application No. 10/031,556 (“the ’556 application”) was filed
`
`on April 26, 2000 and issued on September 13, 2005 as U.S. Patent No. 6,943,166.
`
`The ’556 application was a national stage entry of PCT/US00/11129, which claims
`
`priority to Provisional Application No. 60/132,036, filed on April 30, 1999. The
`
`earliest claimed priority date of the ’166 patent is April 30, 1999.
`
`-5-
`
`
`
`
`
`During prosecution, the examiner rejected claims under 35 U.S.C. § 103(a)
`
`over U.S. Patent No. 6,140,329, which discloses “oral administration and a dosage
`
`within the recited range” of the “the instant compound and a method of using it to
`
`treat sexual dysfunction.” EX1006 at 0385. In response, applicants argued that the
`
`range of about 1-20 mg “is critical because this dose range exhibits the surprising
`
`and unexpected results of low adverse events and still being unexpectedly
`
`efficacious in treating sexual dysfunction.” EX1006 at 0053.
`
`As purported evidence of alleged unexpected results, Applicants submitted
`
`two declarations of Dr. Gregory Sides, an employee of Patent Owner. EX1006 at
`
`0058-62, 0296-0301; EX1002, ¶18-21. Dr. Sides compared the efficacy and
`
`adverse events associated with 20 mg to 50 mg of tadalafil, but he did not submit
`
`data sufficient to permit any conclusion of statistical significance, nor did he
`
`provide a statistical analysis of the data. EX1002, ¶21. A Notice of Allowability
`
`followed thereafter. Id. at 0034-36. In the “Reasons for Allowance,” the examiner
`
`stated that there was no statistical difference between the two doses with respect to
`
`efficacy (id. at 0035) despite the fact that the Sides declarations did not provide a
`
`statistical analysis. The examiner also stated that “the adverse side effects at 20 mg
`
`are dramatically reduced when compared to 50 mg” and concluded that the data
`
`was sufficient to show unexpected results. Id.; EX1002, ¶21.
`
`-6-
`
`
`
`
`
`As shown in this Petition and by the supporting evidence, the data presented
`
`during prosecution and in the specification of the ’166 patent do not establish
`
`unexpected results. In fact, they merely confirm the predictable results of routine
`
`dose optimization studies. Moreover, the data comparison used in the Sides
`
`declarations suffer from various defects that undermine any legitimate conclusion
`
`of unexpected results. As such, Petitioner respectfully submits that the examiner’s
`
`acquiescence to Patent Owner’s one-sided attorney argument and accompanying
`
`declarations regarding unexpected results should receive little if any deference by
`
`the Board.
`
`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
`
`evaluation of any differences between the claimed subject matter and the asserted
`
`prior art. 383 U.S. 1, 17-18 (1966). As noted in KSR Int’l Co. v. Teleflex Inc., the
`
`obviousness inquiry may account for inferences that would be employed by a
`
`person of ordinary skill in the art. 550 U.S. 398, 418 (2007).
`
`1.
`International Patent Publication No. WO 1997/03675
`(“the ’675 PCT”) (EX1007).
`
`The ’675 PCT published on February 6, 1997, and is prior art to the claims
`
`of the ’166 patent under 35 U.S.C. § 102(b).
`
`The ’675 PCT prominently discloses Compound A ((6R,12aR)-
`
`2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-
`
`-7-
`
`
`
`
`
`pyrazino[2’,1’:6,1]pyrido[3,4-b]indole-1,4-dione)( EX1007 at 3, lines 24-25), now
`
`known, and referred to herein as tadalafil (see, “Cialis® label,” EX1010), as one of
`
`two “highly selective” PDE5 inhibitors that are useful in the treatment of male
`
`sexual dysfunction disorders, including erectile dysfunction, as well as female
`
`sexual dysfunction disorders. EX1007 at 3-4; EX1002, ¶¶57-60; EX1004, ¶37, 39.
`
`
`
`CH 3
`
`N
`
`H
`
`N
`
`O
`
`O
`
`O
`
`H
`
`NH
`
`O
`Compound A (Tadalaf il)
`The '675 PCT; EX1007
`
`
`
`The ’675 PCT teaches tadalafil has an IC50 of 2 nM for PDE5 and “hence [has]
`
`utility in the treatment of erectile dysfunction substantially as hereinbefore
`
`described.” EX1007 at 17; EX1002, ¶59; EX1004, ¶38.
`
`The ’675 PCT teaches that tadalafil may be administered orally, for example
`
`using “individual tablets or capsules [which] contain from 0.2-400mg of active
`
`compound, in a suitable pharmaceutically acceptable vehicle or carrier, for
`
`administration in single or multiple doses, once or several times per day.” EX1007
`
`at 5; EX1002, ¶¶57, 60. The ’675 PCT also notes that “[f]or human use,
`
`compounds of formula (I), and in particular compounds A [(tadalafil)] and B [(3-
`
`-8-
`
`
`
`
`
`methyl-tadalafil)] can be administered alone, but will generally be administered in
`
`admixture with a pharmaceutical carrier[.]” EX1007 at 5; EX1002, ¶60.
`
`Sildenafil Citrate (VIAGRA®) Approval Package for New Drug
`
`2.
`Application No. 020895 (“Sildenafil NDA,” EX1008).
`
`a)
`
`Brief Description of the SNDA
`
`The Sildenafil NDA is the Center for Drug Evaluation and Research
`
`Approval Package for the use of sildenafil citrate (Viagra®) in the treatment of
`
`erectile dysfunction. The Sildenafil NDA includes a joint clinical review, which
`
`outlines clinical trial data available for sildenafil citrate, as well as
`
`pharmacokinetic, pharmacological, toxicological, safety and efficacy data
`
`compiled for review by FDA for formal drug approval. EX1002, ¶63; EX1004,
`
`¶41, 42.
`
`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.
`
`EX1008 at 0088.
`
`The Sildenafil NDA also teaches that sildenafil’s PDE6 IC50 is only 10-fold
`
`higher (less potent) than its PDE5 IC50. Id. PDE6 is present in ocular tissues,
`
`providing the probable cause of the visual adverse events that sometimes occur
`
`-9-
`
`
`
`
`
`following administration of sildenafil. Id.; EX1002, ¶48. As phosphodiesterase
`
`enzymes are found in a variety of tissues throughout the body, the on-target effects
`
`of PDE inhibition are predictable adverse events:
`
`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.
`
`EX1008 at 0088-89. Accordingly, the Sildenafil NDA concludes that “common
`
`treatment-related adverse events—notably headache, vasodilation, dyspepsia, and
`
`vision disturbance—were clearly dose-related.” EX1008 at 0095.
`
`The Sildenafil NDA states that sildenafil has an IC50 of 3.5 nM for PDE5 (id.
`
`at 0037), that the therapeutic effectiveness of sildenafil is dose-dependent, and that
`
`sildenafil is therapeutically effective for the treatment of erectile dysfunction at
`
`doses as low as 5 mg. EX1008 at 0126-28, 0215-16; EX1002, ¶63; EX1004, ¶44.
`
`The Sildenafil NDA also teaches that maximum recommended dosing schedule is
`
`once per day. EX1008 at 0126, 0132, 0139, 0146, 0155, 0217, 0223, 0238, 0245,
`
`0251; EX1002, ¶63.The Sildenafil NDA also notes where the tested dosages fall
`
`-10-
`
`
`
`
`
`along a dose-response curve, noting, “[t]he 25 mg-placebo difference is more than
`
`half of the 100 mg-placebo difference; this suggests that the 25-mg dose is already
`
`fairly high on the dose-response curve.” EX1008 at 0070.
`
`b)
`The Sildenafil NDA was publically available at least as
`early as March 27, 1998.
`
`Under 35 U.S.C. § 102(b), “a person shall be entitled to a patent unless …
`
`the invention was patented or described in a printed publication … more than one
`
`year prior to the date of the application for patent in the United States.” Because
`
`of the variety of ways in which a publication may be disseminated, “public
`
`accessibility has been called the touchstone in determining whether a reference
`
`constitutes a printed publication bar under 35 U.S.C. § 102(b).” Kyocera Wireless
`
`Corp. v. ITC, 545 F.3d 1340, 1350 (Fed. Cir. 2008) (quoting In re Hall, 781 F.
`
`2d 897, 898-899 (Fed. Cir. 1986) (internal quotes omitted). Public accessibility
`
`is proven “upon a satisfactory showing that such document has been
`
`disseminated or otherwise made available to the extent that persons interested
`
`and ordinarily skilled in the subject matter or art exercising reasonable diligence,
`
`can locate it.” Id. (quoting SRI Int'l, Inc. v. Internet Sec. Sys. Inc., 511 F.3d 1186,
`
`1194 (Fed. Cir. 2008)).
`
`Public accessibility of a printed publication is evaluated on a “case-by-
`
`case basis.” Id. (citing In re Cronyn, 890 F. 2d 1158, 1161 (Fed. Cir 1989)).
`
`Notably, public availability does not require a “show[ing] that particular
`
`-11-
`
`
`
`
`
`members of the public actually received the information.” Constant v. Advanced
`
`Micro-Devices, Inc., 848 F.2d 1560, 1569 (Fed. Cir. 1988) (Finding “[e]vidence
`
`of routine business practice” sufficient for proving public accessibility.); see
`
`also In re Wyer, 655 F. 2d 221, 226-227 (C.C.P.A. 1981) (Finding “actual
`
`viewing or dissemination of any copy of the application” unnecessary to prove
`
`public accessibility “given that there [was] also no genuine issue as to whether
`
`the application was properly classified, indexed, or abstracted.”); In re Hall, 781
`
`F. 2d at 899 (Dissertation was publicly accessible based on a showing of
`
`“routine business practice” of “cataloging and shelving before the critical date.”).
`
`The Sildenafil NDA became publicly available on March 27, 1998, a date
`
`more than one year before the April 30, 1999 priority date. Under FDA rules,
`
`NDA application documents are accessible to the public immediately upon
`
`approval. 21 C.F.R. § 314.430(e) (“After FDA sends an approval letter to the
`
`applicant” certain data and information associated with that application become
`
`“immediately available for public disclosure.”). These data and information
`
`available to the public include a “summary or summaries of the safety and
`
`effectiveness data and information submitted with or incorporated by reference
`
`in the [new drug] application” and a “Summary Basis of Approval (SBA)
`
`document that contains a summary of the safety and effectiveness data and
`
`information evaluated by FDA during the drug approval process.” See 21 C.F.R.
`
`-12-
`
`
`
`
`
`§ 314.430(e)(2)(ii); see also, 21 C.F.R. § 312.130 (Availability for public
`
`disclosure of data and information in an Investigation New Drug (IND)
`
`application). In the case of sildenafil, the data and information accessible to the
`
`public includes over 500 pages of information relevant to the “FDA's Clinical,
`
`Statistical and Biopharmacological Review of Viagra Clinical Development.”
`
`EX1008; Viagra (Sildenafil) NDA 020895 Approval Package Access Data,
`
`http://www.accessdata.fda.gov/drugsatfda_docs/NDA/98/viagra/viagra_toc.cfm
`
`(Sildenafil NDA Access Data, “EX1031”) (indicating the files were created on
`
`March 27, 1998).
`
`®) on March 27, 1998. EX1008 at 1;
`FDA approved sildenafil (VIAGRA
`
`FDA Approval Letter, Sildenafil (Viagra®) NDA 020895, March 27, 1998
`
`(“Sildenafil Approval Letter,” EX1032). FDA approval of the sildenafil NDA
`
`was publicized broadly that same day. See, e.g., Drug company’s shares rise on
`
`FDA approval of pill to treat impotence, CNNMoney.com, March 27, 1998
`
`(“CNN Article,” EX1033) reporting: “Shares of pharmaceutical giant Pfizer Inc.
`
`were pushed higher Friday on news that the U.S. Food and Drug Administration
`
`has approved its treatment for impotence.”); Pfizer’s Eagerly Anticipated
`
`Impotence Drug Viagra Wins FDA Approval, Dow Jones Online News, March
`
`27, 1998 (“Dow Jones Article,” EX1034) reporting: “The Food and Drug
`
`Administration Friday announced approval of a long-awaited impotence drug,
`
`-13-
`
`
`
`
`
`Pfizer Inc.’s Viagra, which is the first pill for the disorder.” (original formatting
`
`removed)). Thus, as of March 27, 1998, the general public and skilled artisans
`
`alike would have been aware that FDA had approved the sildenafil NDA.
`
`FDA sent Pfizer the approval letter on March 27, 1998, and this event
`
`resulted in “immediate” public availability of the Sildenafil NDA documents.
`
`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
`
`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 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 which
`
`increases would be unlikely to provide added benefit or would produce
`
`-14-
`
`
`
`
`
`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.
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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
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`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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`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. George Grass. Dr. Grass
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`received a Pharm.D. from the University of Nebraska in 1980 and a Ph.D. in
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`pharmaceutics from the University of Wisconsin, Madison in 1985. EX1002, ¶2;
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`EX1003 (CV). In 1985, Dr. Grass began a research position at the Institute of
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`Pharmaceutical Sciences in Palo Alto, California, where he worked on the
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`development of early stage compounds for oral delivery. Id. at ¶3; EX1003. By
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`1991, Dr. Grass was serving as a pharmaceutical industry consultant. Id. Dr. Grass
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`has also served as the Senior Vice President of Research and Development at
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`Sorbent Therapeutics, overseeing the development of novel technologies and
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`product formulation strategies. EX1002, ¶4; EX1003. Currently, Dr. Grass is
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`President of a consulting business, G2 Research Inc., and Senior Vice President of
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`Non-Clinical Development for NeuroVia, Inc. EX1002, ¶1.
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`Dr. Grass has authored dozens of peer-reviewed journal articles, including
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`articles dealing with oral drug absorption predictions, pharmacokinetic simulation
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`modeling, and predictive pharmacokinetic simulation models for drug discovery,
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`and is listed as an inventor on at least twelve issued U.S. Patents. EX1002, ¶3, 5;
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`EX1003. Dr. Grass is well qualified as an expert, possessing the necessary
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`scientific, technical, and other specialized knowledge and training to assist in an
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`understanding of the evidence presented herein, as well as possessing the expertise
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`necessary to determine and explain the level of ordinary skill in the art as of April
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`30, 1999. See EX1003.
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`This Petition is also supported by the declaration of Dr. Muta M. Issa.
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`EX1004. Dr. Issa is a tenured Professor of Urology in the School of Medicine at
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`Emory University, and also serves as Chief of Urology at the Atlanta Veterans
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`Affairs Medical Center. EX1004, ¶1. Dr. Issa received his M.D. from the Royal
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`College of Surgeons in Ireland in 1983, after which he became Chief Resident in
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`Urology at Stanford Medical Center. EX1004, ¶2; EX1005 (CV).
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`Dr. Issa has served on the editorial boards of peer-reviewed publications
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`such as The Scientific World Journal of Urology and Urologists in Cancer Care.
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`EX1004, ¶3. Dr. Issa has also authored more than 100 peer-reviewed journal
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`articles, pertaining to the field of urology, and is listed as an inventor on at least ten
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`issued U.S. Patents. EX1004, ¶4; EX1005. Dr. Issa 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, ¶5.
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`E.
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`Background Knowledge in the Art Prior to April 30, 1999
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`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 obvious.
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`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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`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)
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`51-61 (“Halvorsen,” EX1026); EX1004, ¶30. While male sexual dysfunction
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`disorders were more heavily studied (EX1004, ¶¶31-32), those in the art taught that
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`female sexual disorders, such as female arousal disorder, may have similar
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`biological origins as male sexual impotence disorders such as erectile function.
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`EX1026 at 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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`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; EX1004, ¶34. Those
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`in the art noted sildenafil exhibited dose-dependent efficacy in the treatment of
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`erectile dysfunction, showing effectiveness over placebo at doses at least as low as
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`5-10 mg. EX1015 at