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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`DR. REDDY’S LABORATORIES, INC.
`Petitioner,
`
`v.
`
`ICOS CORP.
`Patent Owner.
`
`
`
`U.S. Patent No. 6,943,166
`
`
`
`
`DECLARATION OF FATEMEH AKHLAGHI, PHARM.D., PH.D.
`
`
`
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`DRL - EXHIBIT 1002
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`
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`TABLE OF CONTENTS
`
`Page
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`Qualifications ................................................................................................. 1
`I.
`Scope of Work ................................................................................................ 2
`II.
`III. Overview of the ’166 Patent .......................................................................... 3
`IV. Brief Summary of the File History of the ’166 Patent ................................... 6
`Legal Standards ............................................................................................ 15
`V.
`VI. Level of Ordinary Skill and Relevant Time ................................................. 18
`VII. Claim Construction ...................................................................................... 20
`VIII. The State of the Art ...................................................................................... 22
`IX. The Asserted References Disclose or Suggest Each of the Claimed
`Features of the ’166 Patent ........................................................................... 29
`The Claimed Dosing Method Does Not Produce Unexpected Results ....... 49
`X.
`XI. Concluding Statements ................................................................................. 64
`XII. Appendix – List of Exhibits ......................................................................... 66
`
`
`
`
`i
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`
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`I, Fatemeh Akhlaghi, declare as follows:
`
`I.
`
`QUALIFICATIONS
`
`1. My name is Fatemeh Akhlaghi. I am a Professor of Pharmacokinetics
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`and Ernest Mario Distinguished Chair of Pharmaceutics in the College of
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`Pharmacy, University of Rhode Island. I have over 18 years of experience in
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`clinical pharmacology research and an extensive history of collaboration with
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`academia and the pharmaceutical industry.
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`2.
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`I received a Pharm. D. from the University of Mashhad, Iran, in 1990,
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`and a Ph.D. in Pharmaceutical Sciences from the University of Sydney, Australia,
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`in 1997.
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`3. My primary areas of technical expertise are drug development, drug
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`delivery, and pharmacokinetics, including computational simulations and modeling
`
`of pharmacokinetic processes. I completed a post-doctoral fellowship at the
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`University of Sydney in 1998 and another post-doctoral fellowship at the
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`University of Cambridge, United Kingdom, in 2001 before joining the University
`
`of Rhode Island.
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`4.
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`I joined the University of Rhode Island as a tenure track Assistant
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`Professor in 2001. In 2006 I became an Associate Professor with tenure and in
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`July 2011 was promoted to Full Professor. In July 2010, I also joined the faculty
`
`of Brown University Medical School as an Adjunct Associate Professor, and in
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`
`
`1
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`
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`2014, I was promoted to Adjunct Professor.
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`5. My research interests include the general area of pharmaceutical
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`sciences with a focus on pharmacokinetic/pharmacodynamics modeling, clinical
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`pharmacology, translational sciences, drug metabolism, and pharmacogenomics. I
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`have authored more than 70 full-length peer-reviewed articles and 100 abstracts in
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`these areas. In addition, I have given more than 30 invited presentations and have
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`consulted with multiple pharmaceutical companies involving clinical research,
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`design of pharmacokinetic studies and pharmacokinetic/pharmacodynamics
`
`modeling.
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`6.
`
`A summary of my experience, education, publications and other
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`qualifications is provided in my CV, a copy of which is submitted separately.
`
`EX1003.
`
`II.
`
`SCOPE OF WORK
`
`7.
`
`I understand that a petition is being filed with the United States
`
`Patent and Trademark Office for Inter Partes Review of U.S. Patent No. 6,943,166
`
`(“the ’166 patent,” EX1001). I have been retained by Dr. Reddy’s Laboratories,
`
`Inc. as a technical expert to provide analysis and opinions regarding the ’166
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`patent. I have reviewed the ’166 patent and sections of its prosecution history in
`
`the United States Patent and Trademark Office. EX1006. I have also reviewed
`
`and considered various other documents in arriving at my opinions, and I cite
`
`
`
`2
`
`
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`them in this declaration. For convenience, documents cited in this declaration are
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`listed in the Appendix in Section XIII.
`
`8.
`
`I am compensated at the rate of $400/hour for my work. I have no
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`financial interest in the outcome of this matter.
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`III. OVERVIEW OF THE ’166 PATENT
`
`9.
`
`The ’166 patent issued on September 13, 2005. The ’166 patent is
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`titled “Compositions Comprising Phosphodiesterase Inhibitors for the Treatment of
`
`Sexual Dysfunction.” The first page of the patent states that an application for the
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`’166 patent (U.S. Application No. 10/031,556), was filed as a national stage entry
`
`application of PCT/US00/11129 and claims priority to provisional U.S.
`
`Application No. 60/132,036, filed on April 30, 1999.
`
`10. The ’166 patent is generally directed to the treatment of sexual
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`dysfunction, including male erectile dysfunction and female arousal disorder using
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`the compound (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, referred to
`
`herein for convenience as “tadalafil,” and also referred to in the ’166 patent as
`
`Compound I. EX1001, 2:58-63. Tadalafil is marketed under the trademark Cialis®.
`Cialis® Approved Label (“Cialis® Label,” EX1010).The ’166 patent states:
`
`The biochemical, physiological, and clinical effects of cyclic
`guanosine 3’,5’-monophosphate specific phosphodiesterase
`(cGMP-specific PDE) inhibitors suggest their utility in a variety of
`3
`
`
`
`
`
`disease states in which modulation of smooth muscle, renal,
`hemostatic, inflammatory, and/or endocrine function is desired.
`Type 5 cGMP-specific phosphodiesterase (PDE5) is the major
`cGMP hydrolyzing enzyme in vascular smooth muscle, and its
`expression in penile corpus cavernosum has been reported. Thus,
`PDE5 is an attractive target in the treatment of sexual dysfunction.
`
`Id. at 1:29-40 (citations omitted).
`
`11. The ’166 patent also identifies that other PDE5 inhibitors were known
`
`in the art:
`
`A pharmaceutical product, which provides a PDE5 inhibitor, is
`currently available and marketed under the trademark VIAGRA®.
`The active ingredient in VIAGRA® is sildenafil. … The package
`insert provides that sildenafil is a more potent inhibitor of PDE5
`than other known phosphodiesterases … While sildenafil has
`obtained significant commercial success, it has fallen short due to
`its significant adverse side effects[.]
`
`Id. at 1:33-60.
`
`12.
`
`The specification of the ’166 patent states: “Applicants have
`
`discovered that [tadalafil] … can be administered in a unit dose that provides an
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`effective treatment without the side effects associated with the presently marketed
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`PDE5 inhibitor, sildenafil.” EX1001, 2:22:32.
`
`13.
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`The specification of the ’166 patent states that “a unit dose of about 1
`
`to about 20 mg, preferably about 2 to about 20 mg, more preferably about 5 to
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`
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`4
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`
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`about 20 mg, and most preferably about 5 to about 15 mg, of Compound (I) [i.e.,
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`tadalafil], administered up to a maximum of 20 mg per 24-hour period, both
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`effectively treats ED [(erectile dysfunction)] and minimizes or eliminates the
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`occurrence of adverse side effects.” EX1001, 14:43-49.
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`14.
`
`The ’166 patent has twelve claims, each directed to treating sexual
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`dysfunction. Claim 1, the only independent claim, provides:
`
`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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`15. Claims 2 and 3 depend from claim 1 and provide that the sexual
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`dysfunction is male erectile dysfunction and female arousal disorder, respectively.
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`Dependent claims 4-6, 8, and 12 provide that the method involves the
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`administration of a unit dose containing from about 2 to about 20 mg, about 5 mg,
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`about 10 mg, about 2.5 mg, or about 20 mg of tadalafil, respectively. Claim 8
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`(which depends from claim 1), and claims 9 and 10 (which depend from claims 8
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`and 5, respectively), each provide that the unit dose is administered once per day.
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`
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`5
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`
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`Claim 7 depends from claim 1 and provides that the unit dose is a liquid, a tablet, a
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`capsule, or a gel cap. Claim 12 also depends from claim 1 and provides that the
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`compound is administered as a free drug.
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`IV. BRIEF SUMMARY OF THE FILE HISTORY OF THE ’166 PATENT
`16. As noted above, U.S. Patent Application No. 10/031,556 (“the ’556
`
`application) was filed on April 26, 2000, as a national stage entry of
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`PCT/US00/11129 and issued on September 13, 2005 as U.S. Patent No. 6,943,166.
`
`The ’166 patent claims priority to Provisional Application No. 60/132,036, filed on
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`April 30, 1999.
`
`17.
`
`In the first office action the patent examiner rejected all claims under
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`35 U.S.C. § 103(a) over U.S. Patent No. 6,140,329 (“Daugan”). The examiner
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`stated that Daugan discloses “the instant compound and a method of using it to
`
`treat sexual dysfunction,” including “oral administration and a dosage within the
`
`recited range.” EX1006 at 0385. The examiner further indicated that, in the
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`absence of a declaration providing evidence of unexpected results, the claimed
`
`dosing regimen was obvious. EX1006 at 0385.
`
`18. The applicants ultimately submitted two declarations from Dr.
`
`Gregory Sides, an employee of Eli Lilly and the Medical Director on the Cialis®
`
`Product Team. EX1006 at 0058, 0296. The applicants rely on the data within the
`
`Sides declarations to argue that:
`
`
`
`6
`
`
`
`[T]he examiner failed to appreciate the present invention as a
`whole. In particular, while decreasing a dose of drug often
`decreases side effects, it also often decreases efficacy. In contrast,
`the surprising and unexpected results of the present invention
`include at least two factors: the claimed unit dose range of about 1
`to about 20 mg provides substantially decreased adverse side
`effects while still retaining efficacy. The observed divergence of
`retained efficacy from decreased side effects in these substantially
`lower doses is unexpected.
`
`Id. at 0055.
`
`19.
`
`In the first declaration, filed January 15, 2004, Dr. Sides presents
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`adverse events data “pooled from eight Phase 3 studies for placebo, 5 mg, 10 mg,
`
`and 20 mg doses” not disclosed in the specification and three Phase 2 studies for
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`“placebo and the 50 mg dose.” EX1006 at 0300-01 (table reproduced below).
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`From these data, Dr. Sides concludes that there is a “dramatic reduction in adverse
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`events associated with common adverse events, such as headache, dyspepsia and
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`back pain between the 20 mg and 50 mg dosages[.]” Id. at 0301. Dr. Sides further
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`alleges that “[t]his decrease of adverse events coupled with an efficacy across the
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`claimed dose range is an unexpected advance in the art.” Id.
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`
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`7
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`
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`Id. at 0300-01.
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`20.
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`In the second declaration, filed July 26, 2004, Dr. Sides compares
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`efficacy of the 20 mg (not presented in the specification) and 50 mg doses (data
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`from Example 7 of the specification). The data for the 20 mg dose results came
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`from “pooled data from 11 randomized, double-blind, 12-week placebo-controlled
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`trials” and data for the 50 mg dose is pooled from the results of three Phase 2
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`studies. EX1006 at 0061 (table reproduced below). Dr. Sides concludes from these
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`data that “the efficacy of 20 mg dose is comparable to the efficacy of 50 mg dose.”
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`Id. at 0062.
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`
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`8
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`Id.
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`21.
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`Following submission of the second declaration of Dr. Sides, the
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`examiner allowed the patent, stating in the reasons for allowance:
`
`No statistical difference seen in the change from the baseline for
`the placebo at 20 mg of tadalafil and 50 mg of tadalafil, which is
`respectively .9 vs. .8. No statistical difference seen in the change in
`efficacy between 20 mg and 50 mg, which is 8.6 vs. 9.8,
`respectively. However, the adverse side effects at 20 mg are
`dramatically reduced when compared to 50 mg. This data has been
`set forth in the showings submitted on July 26, 2004 and January
`15, 2004. This demonstrates unexpected results of the 20 mg dose
`of tadalafil over the 50 mg dose.
`
`EX1006 at 0035. The examiner’s statement that there is no “statistical difference”
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`between placebo groups and the two treatment groups with respect to efficacy is
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`
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`9
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`
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`not an accurate representation of the data within Dr. Sides’ declarations. Dr. Sides
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`presents no statistical analysis of efficacy data nor does he make any conclusions
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`regarding the statistical significance of the presented data. Moreover, the data
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`presented for the 50 mg treatment group were obtained from different clinical trials
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`than the data for the lower dosages. It appears that these two sets of clinical trials
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`used different medical dictionaries for coding adverse events, designating Medical
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`Dictionary for Regulatory Activities for one and the COSTART dictionary for the
`
`other. As a result, it is not clear that direct comparisons are valid.
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`22.
`
`I disagree with the conclusion of Dr. Sides and the patent examiner
`
`that the data show a “dramatic reduction” in adverse events between the 20 mg and
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`50 mg dosages. It is true that the data presented in Example 7 of the ’166 patent
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`(shown below) show that total adverse events decrease with decreasing dosage
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`amount.
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`EX1001, 14:22-37. However, the per mg increase in adverse events is much
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`
`
`10
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`
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`
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`higher for doses below 20 mg than for doses above 20 mg, as evidenced by the
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`steeper slope of the graph below 20 mg than above 20 mg. For example, the
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`change in adverse event per mg tadalafil observed in the Sides declaration between
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`20 mg and 50 mg was 0.63 %/mg ((34%-15%)/30 mg) for headache and 0.33 %.
`
`mg ((20%-10%)/30 mg) for dyspepsia. EX1006 at 0300. Notably, the percentage
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`of patients experiencing headache and dyspepsia at the 20 mg dose as reported in
`
`the Sides declaration (15% and 10%) is lower than the percentage of patients
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`experiencing headache and dyspepsia at the 10 mg dose as reported in the ’166
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`patent (23% and 13%). In contrast, the ’166 patent indicates that the change in the
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`percentage of patients with a headache per mg tadalafil observed between 5 mg
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`and 10 mg was 2.6 %/mg ((23%-10%)/5 mg). EX1001, 14:22-38. Similarly, the
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`’166 patent indicates that the change in the percentage of patients with dyspepsia
`
`per mg tadalafil observed between 2 mg and 10 mg was 3.67 %/mg ((14%-3%)/3
`
`mg). Id. In each case, the increase in adverse events at dosages below 20 mg
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`appears much greater than that observed at dosages above 20 mg. A graphical
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`representation of the data for headache and dyspepsia exemplifies this point.
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`
`
`
`
`11
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`
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`6 0
`D o s e (m g )
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`8 0
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`1 0 0
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`1 2 0
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`D y s p e p s ia
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`H e a d a c h e
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`5 0
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`4 0
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`3 0
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`2 0
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`1 0
`
`0
`
`0
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`2 0
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`4 0
`
`Patients Experiencing Adverse Events (%)
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`
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`As can be seen from the above table and graph, there is no dramatic change in
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`adverse events between 20 mg and 50 mg. Indeed, to the extent the efficacy of the
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`20 mg and 50 mg doses can be deemed “comparable” based on the limited data and
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`analysis provided by Dr. Sides, the same can be said of the adverse events at the 20
`
`mg and 50 mg doses. Moreover, a 20 mg dose was not even tested in the Example
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`7 study.
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`23. Differences between the studies themselves may be responsible for
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`the appearance of differences in reported adverse events in the Sides declaration.
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`For example, the data for the 50 mg dosage in Dr. Sides’s declaration comes from
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`Example 7. EX1006 at 0300; EX1001, 14:22-37. The data for the 5 mg, 10 mg and
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`20 mg doses come from a study not presented in the ’166 patent. Comparing the
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`placebo groups for the studies yields a substantial difference, simply between the
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`
`
`12
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`
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`two placebo groups. Id. For instance, in the two placebo groups, the rates for
`
`headache are 2-fold different, and for dyspepsia they are 6-fold different. EX1006
`
`at 0300.
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`24. As discussed in more detail below in Section X, I disagree with the
`
`conclusion of Dr. Sides and the patent examiner that the data presented in his
`
`declarations establish unexpected results associated with the claimed dose range.
`
`25. The purpose of clinical dose-response studies, such as those described
`
`in the declarations of Dr. Sides, is to identify dosages of a drug that maximize
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`clinical benefit while minimizing adverse effects. Dose-Response Information to
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`Support Drug Registration, 59 FEDERAL REGISTER, (November 9, 1994) 55972-
`
`55976 (“FDA Guideline,” EX1009) at 55972. Finding an optimal dosage with
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`respect to benefits and risks is routine in the pharmaceutical industry. Id. The
`
`person of ordinary skill would find based on the data presented in Dr. Side’s
`
`declarations that there is nothing unexpected with respect to administration of
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`maximum daily tadalafil dosages at or below 20 mg.
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`26. The similarity between sildenafil and tadalafil clinical trial results for
`
`the efficacy and adverse events further confirms that the results in Dr. Side’s
`
`declarations would have been considered by the skilled artisan to be expected and
`
`routine. The sildenafil dose ranging studies noted that on-target adverse effects
`
`such as headache and dyspepsia increase with increasing dosage until they plateau.
`
`
`
`13
`
`
`
`Eardley, I., New Oral Therapies for the Treatment of Erectile Dysfunction, 81 BR.
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`J. UROL. (1998) 122-27 (“Eardley,” EX1011) at 125.
`
`27. The clinical studies described by Dr. Sides are said to show that the 20
`
`mg and 50 mg dosages of tadalafil have comparable efficacies in the treatment of
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`sexual dysfunctions such as erectile dysfunction. No descriptions of the various
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`clinical studies are provided, as would be needed to support a conclusion that the
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`results from the dosages are in fact “comparable.” As discussed in more detail
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`below in Section X, the data presented by Dr. Sides, taken at face value, suggest
`
`that 20 mg is near the top of the dose-response curve where clinical effect is less
`
`sensitive to further increases in dosage amount. This effect may reflect that
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`interactions between the drug and its target have become saturated (i.e. the plateau
`
`of the dose-response curve had been reached), and is not an “unexpected” effect.
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`Rather, increasing the dose beyond this point would have been expected by the
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`person of ordinary skill to yield little to no additional clinical benefit due to the
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`saturation of the drug with its molecular PDE5 target. As similar effect would be
`
`expected for on-target adverse events.
`
`28. The specification of the ’166 patent states that “detailed experiments
`
`and clinical trials” (EX1001, 5:15-19) led to the “unexpected” results, however
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`there is no discussion of any experiments or clinical trials that were not routine.
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`The specification notes that the “[a]ctivity of PDE5 can be measured by standard
`
`
`
`14
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`
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`assays in the art.” Id. at 6:46-48. Moreover, the specification describes a routine
`
`clinical study in which efficacy and adverse events are measured over a 2-100 mg
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`range of unit doses of tadalafil. EX1001, 13:10-14:42. The clinical trial mentioned
`
`in the specification used the International Index of Erectile Function (IIEF) to
`
`measure efficacy, which is the same efficacy measure used in sildenafil clinical
`
`trials. See, e.g., EX1008 at 0062-70. Similar types and frequencies of adverse
`
`events were reported for tadalafil as compared to sildenafil. Compare EX1001,
`
`14:20-36 with Morales, A., et al., Clinical safety of oral sildenafil citrate
`
`(VIAGRATM) in the treatment of erectile dysfunction, 10 INT. J. IMPOT. RES.,
`
`(1998) 69-74 (“Morales,” EX1018) at 71. Thus, the Patent Owner presented
`
`efficacy and adverse events data that would have been expected and unsurprising
`
`to a skilled artisan, and obtained these results by employing standard assays and
`
`routine clinical trial protocols.
`
`V. LEGAL STANDARDS
`
`29.
`
`I have been informed that a claimed invention is not patentable under
`
`35 U.S.C. § 103, for obviousness, if the differences between the invention and the
`
`prior art are such that the subject matter as a whole would have been obvious at the
`
`time the invention was made to “a person having ordinary skill in the art” to which
`
`the subject matter of the invention pertains. I understand that “a person of ordinary
`
`skill in the art” is a hypothetical person who is presumed to have known the
`
`
`
`15
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`
`
`relevant art at the time of the invention. As discussed above, I understand that the
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`relevant art for the purpose of this declaration at least includes references that were
`
`effective before April 30, 1999.
`
`30.
`
`I have been instructed that, a determination of obviousness requires
`
`inquiries into (i) the scope and content of the art when the invention was made; (ii)
`
`the differences between the art and the claims at issue; (iii) the level of ordinary
`
`skill in the pertinent art when the invention was made; and, to the extent they exist,
`
`any secondary considerations.
`
`31.
`
`I understand that a claim can be found to be obvious if all the claimed
`
`elements were known in the prior art and one skilled in the art could have
`
`combined the elements as claimed by known methods with no change in their
`
`respective functions, and the combination would have yielded nothing more than
`
`predictable and expected results to one of ordinary skill in the art.
`
`32.
`
`I understand that improper hindsight must not be used when
`
`comparing the prior art to the invention for obviousness. Thus, a conclusion of
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`obviousness must be firmly based on the knowledge and skill of a person of
`
`ordinary skill in the art at the time the invention was made.
`
`33.
`
`I have been informed that obviousness may also be shown by
`
`demonstrating that it would have been obvious to modify what is taught in a single
`
`piece of prior art to create the patented invention. I understand that obviousness
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`
`
`16
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`
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`may be demonstrated by showing that it would have been obvious to combine the
`
`teachings of more than one item of prior art. I understand that in order for a
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`combination of references or teachings to render the claimed invention obvious,
`
`there must be some supporting rationale for combining the cited references or
`
`teachings as proposed.
`
`34.
`
`I am informed that the following are examples of principles that may
`
`indicate that it would have been obvious to combine multiple teachings, resulting
`
`in the claimed combination, if the claimed combination involves: (i) the
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`combination of prior art elements according to known methods to yield predictable
`
`results; (ii) the simple substitution of one known element for another to obtain
`
`predictable results; (iii) the use of a known technique to improve similar methods
`
`or products in the same way; (iv) the application of a known technique to a known
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`method or product ready for improvement to yield predictable results; (v) the
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`application of a technique or approach that would have been “obvious to try” (e.g.,
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`choosing from a finite number of identified, predictable solutions, with a
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`reasonable expectation of success); (vi) predictable variations of a known work in
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`one field of endeavor prompted for use in either the same field or a different field
`
`based on design incentives or other market forces; or (vii) some teaching,
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`suggestion, or motivation in the prior art that would have led one of ordinary skill
`
`to modify the prior art reference or to combine prior art reference teachings to
`
`
`
`17
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`
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`arrive at the claimed invention.
`
`35.
`
`I also understand that “secondary considerations” may be weighed
`
`against evidence of obviousness where appropriate.
`
`36.
`
`I understand that such secondary considerations, where in evidence,
`
`may include: (i) commercial success of a product due to the merits of the claimed
`
`invention; (ii) a long-felt, but unsatisfied need for the invention; (iii) failure of
`
`others to find the solution provided by the claimed invention; (iv) deliberate
`
`copying of the invention by others; (v) unexpected results achieved by the
`
`invention; (vi) praise of the invention by others skilled in the art; (vii) lack of
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`independent simultaneous invention within a comparatively short space of time;
`
`and (viii) teaching away from the invention in the prior art. Secondary
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`considerations are relevant where there is a nexus between the evidence and the
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`claimed invention.
`
`VI. LEVEL OF ORDINARY SKILL AND RELEVANT TIME
`
`37.
`
`I have been advised that a person of ordinary skill in the art is a
`
`hypothetical person who is presumed to have known the relevant art at the time of
`
`the invention. A person of ordinary skill in the art is also a person of ordinary
`
`creativity. For the purposes of this declaration, I have assumed that the relevant
`
`timeframe for assessing the validity of claims of the ’166 patent is April 30, 1999,
`
`the earliest claimed priority date of the application that led to the ’166 patent.
`
`
`
`18
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`
`
`Unless otherwise specifically noted, all of my opinions expressed herein regarding
`
`a person of ordinary skill in the art apply to a person of ordinary skill in the art as
`
`of April 30, 1999. However, the outcome of my opinion would not change if a later
`
`filing date was applied.
`
`38.
`
`I am familiar with the level of skill in the art of the ’166 patent on and
`
`before April 30, 1999. In my opinion, a person of ordinary skill in the relevant
`
`field as of April 30, 1999, would typically 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. One of
`
`ordinary skill in the art would also be capable of understanding work published in
`
`the field, including the publications discussed in this declaration. In addition, as
`
`pharmaceutical development is an inherently collaborative process, the skilled
`
`artisan would have access to, or be part of a team including, other skilled
`
`individuals such as an M.D. with experience in the field of urology, with specific
`
`experience in sexual dysfunction, medicinal chemists, organic chemists,
`
`pharmacologists, toxicologists, formulators, and clinicians.
`
`39.
`
`In particular, one of ordinary skill in the art would likely have some
`
`combination of the following skills and experience: (i) experience with the
`
`research or development of pharmaceuticals; (ii) the ability to gather and interpret
`
`
`
`19
`
`
`
`pharmacokinetic and pharmacodynamics data including dose-response curves; and
`
`(iii) the ability understand results and findings presented or published by others in
`
`the field, including the publications discussed in this declaration.
`
`VII. CLAIM CONSTRUCTION
`
`40.
`
`I have been advised that, in the present proceeding, the claims of the
`
`’166 patent are to be given their broadest reasonable interpretation to one of
`
`ordinary skill in the art in view of the specification. I also understand that, absent
`
`some reason to the contrary, claim terms are typically given their ordinary and
`
`accustomed meaning as would be understood by one of ordinary skill in the art. I
`
`have followed these principles in my analysis throughout this declaration. The ’166
`
`patent defines some of its terms. Many of its terms are used conventionally.
`
`Certain claim terms are not defined in the ’166 patent. Below I discuss
`
`constructions of a few terms from the patent.
`
`A.
`
`“Administering One or More Unit Dose Containing About 1 to
`About 20 mg, Up to a Maximum Total Dose of 20 mg Per Day”
`41. Claim 1 recites that the method requires “administering one or more
`
`unit dose containing about 1 to about 20 mg, up to a maximum total dose of 20 mg
`
`per day.” EX1001, 14:66-15:1. This phrase means that the unit dose is in the range
`
`of 1 to 20 mg and the daily dose is no larger than 20 mg. The “preferred” dosing
`
`regimens set out in the ’166 patent are encompassed by this construction. For
`
`instance, the ’166 patent states that “the dose administered is about 5 to about 20
`
`
`
`20
`
`
`
`mg/day, more preferably about 5 to about 15 mg/day. Most preferably, a 10 mg
`
`dosage form is administered once per day.” EX1001, 4:19-21. The most preferred
`
`dosing schedule — a 10 mg dosage form that is administered once per day —
`
`satisfies the dosing limitations of claim 1 because the unit dose and total daily dose
`
`are each within the claimed ranges (single daily dose of 10 mg is a unit dose
`
`between 1 and 20 mg and is a daily dose that is no larger than “20 mg per day”).
`
`Likewise, the other preferred dosing schedules (e.g., 5 to 20 mg and 5 to 15 mg)
`
`satisfy the dosing limitations of claim 1 because they recite unit doses between 1
`
`and 20 mg and, when administered once per day, yield daily doses no larger than
`
`20 mg.
`
`B.
`
`“Free Drug”
`
`42. Claim 11 of the ’166 patent recites that the compound “is
`
`administered as a free drug.” EX1001, 16:16-17. The ’166 patent specification
`
`states that “free drug” means “solid particles of drug not intimately embedded in a
`
`polymeric coprecipitate.” Id. at 4:1-2. Although the customary and ordinary
`
`meaning of “free drug” may vary depending on the context in which the term is
`
`used, I understand that the patent drafter may define terms in the patent, and that
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`claim terms in this proceeding are given their broadest reasonable interpretation to
`
`the person of ordinary skill in the art in view of the specification. The broadest
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`reasonable interpretation of “free drug” as that term is broadly defined in the ’166
`
`
`
`21
`
`
`
`patent would thus include, but not be limited to, solid drug particles administered
`
`in the absence of a carrier or excipient, i.e., administered alone. It would also
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`include solid drug particles administered with a polymeric coprecipitate, so long as
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`the drug particles were not embedded in said coprecipitate, consistent with the
`
`definition provided in the ’166 patent.
`
`VIII. THE STATE OF THE ART
`
`43. Below I describe some of the relevant aspects of what was generally
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`known in the art as of April 30, 1999.
`
`44. Sexual dysfunctions were known in the art before April 30, 1999, and
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`thus were characterized as “disturbances in sexual desire and in the
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`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, (1999) 537-544 (“Laumann,” EX1012). In the case of male erectile
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`dysfunction, the biological pathway for penile erections was well known to involve
`
`cyclic nucleotide phosphodiesterase (PDE) isozymes. Those in the art appreciated
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`that “a pharmacological agent which inhibits the cGMP-specific phosphodiesterase
`
`isozyme, should enhance the action of nitric oxide/cGMP on penile erectile activity
`
`and have the potential to enhance penile erections during sexual stimulation.”
`
`Boolell, M., et al., Sildenafil: an orally active type 5 cyclic GMP-specific
`
`phosphodiesterase inhibitor for the treatment of penile erectile dysfunction, 8 INT.
`
`
`
`22
`
`
`
`J. IMPOT. RES., (1996) 47-52 (“Boolell,” EX1015) at 47.
`
`45.
`
`Indeed, prior to 1999 those in the art had identified type 5 PDE as “the
`
`predominant cGMP hydrolyzing activity” in the corpus cavernosum, and had
`
`identified oral “inhibitors of type 5 PDE [that] improve erection” and thus served
`
`as pharmaceutical agents in the treatment of sexual dysfunctions such as erectile
`
`dysfunction. 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
`
`Male Erectile Dysfunction, 6 BIOORG. MED. CHEM. LETT. (1996) 1819-1824
`
`(“Terrett,” EX1013).
`
`46. Sildenafil citrate (Viagra®), is one such PDE5 inhibitor, and is an
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`“orally active treatment for male erectile dysfunction.” EX1013 at 1819. Dosage
`
`units of 25, 50, and 100 mg of sildenafil were approved by the FDA for the
`
`treatment of erectile dysfunction with a 25 mg dose being recommended for
`
`patients over the age of 65, and a “maximum recommended dosi
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