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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_________________________
`
`
`DR. REDDY’S LABORATORIES, INC.
`Petitioner,
`
`v.
`
`ICOS CORPORATION
`Patent Owner.
`
`_________________________
`
`U.S. Patent No. 6,943,166
`_________________________
`
`
`DECLARATION OF ANTHONY SLIWINSKI, M.D.
`
`
`
`
`DRL - EXHIBIT 1004
`
`

`

`TABLE OF CONTENTS
`
`Page
`
`QUALIFICATIONS ........................................................................................ 1
`I.
`SCOPE OF WORK ......................................................................................... 2
`II.
`III. OVERVIEW OF THE ’166 PATENT ............................................................ 2
`IV. BRIEF SUMMARY OF THE FILE HISTORY OF THE ’166
`PATENT .......................................................................................................... 5
`LEGAL STANDARDS ................................................................................... 5
`V.
`VI. LEVEL OF ORDINARY SKILL AND RELEVANT TIME ......................... 8
`VII. CLAIM CONSTRUCTION ............................................................................ 9
`VIII. THE STATE OF THE ART .............................................................................10
`IX. THE ASSERTED REFERENCES DISCLOSE OR SUGGEST
`EACH OF THE CLAIMED FEATURES OF THE ’166 PATENT ............. 14
`A. Brief Overview of the Asserted References ......................................... 14
`
`1.
`The ’675 PCT. ............................................................................ 14
`
`2.
`Sildenafil NDA. ......................................................................... 15
`
`3.
`FDA Guideline. .......................................................................... 15
`B. Detailed Analysis of the Claims ........................................................... 16
`1.
`The Teachings of the ‘675 PCT in view of Sildenafil NDA
`and FDA Guideline Make the Therapeutic Indications of
`Claims 1-3 Obvious. .................................................................. 16
`THERE WAS NO LONG-FELT NEED FOR THE CLAIMED
`DOSING REGIMEN ..................................................................................... 21
`XI. CONCLUDING STATEMENTS ................................................................. 23
`XII. APPENDIX – LIST OF EXHIBITS .............................................................. 24
`
`X.
`
`i
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`

`

`
`I.
`
`
`I, Anthony Sliwinski, declare as follows:
`
`QUALIFICATIONS
`1. My name is Anthony Sliwinski. I am a Board certified urologist with
`
`over 30 years of experience. I am currently the co-director of Men’s Wellness at
`
`Virginia Urology, where I have been practicing since 1994. Before I joined
`
`Virginia Urology Center, I was employed at the McGuire Clinic from 1991 to 1994.
`
`2.
`
`I received an M.D. from Georgetown University School of Medicine in
`
`Washington D.C. in 1986. I completed an Internship in Surgery (1986-1987), and
`
`was Junior Assistant Resident in Surgery (1987-1988) at the Medical College of
`
`Virginia in Richmond, Virginia. I also received my urological training from the
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`Medical College of Virginia as Assistant Resident in Urology (1988-1989), Senior
`
`Assistant Resident in Urology (1989-1990), and Chief Resident in Urology (1990-
`
`1991).
`
`3.
`
`During my career I have given numerous presentations in the field of
`
`urology, which include multiple presentations regarding sexual/erectile dysfunction.
`
`4.
`
`I have extensive experience as a principal investigator involving
`
`research in the urological field, which include multiple studies concerning
`
`sexual/erectile dysfunction.
`
`5.
`
`I have over 26-years of experience as a practicing urologist, which
`
`
`
`1
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`

`

`includes treating over 4000 patients with sexual/erectile dysfunction, and
`
`prescribing both Viagra® and Cialis®. In addition, I have broad knowledge
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`concerning the development in the treatment of sexual/erectile dysfunction and
`
`pharmaceutical products, as I have stayed current with publications concerning the
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`same, and have incorporated such knowledge into my practice.
`
`6.
`
`A summary of my experience, education, and other qualifications is
`
`provided in my CV, a copy of which is submitted separately. EX1005.
`
`II.
`
`SCOPE OF WORK
`
`7.
`
`I am informed 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 as a technical expert to provide
`
`analysis and opinions regarding the ’166 patent. I have reviewed the ’166 patent
`
`and portions of its prosecution history at the U.S. Patent Office. EX1006. I have
`
`also considered other documents cited in this declaration, which are listed in the
`
`Appendix in Section XIII.
`
`8.
`
`I am being compensated at the rate of $500/hour for my time. I have no
`
`financial interest in the outcome of this matter.
`
`III. OVERVIEW OF THE ’166 PATENT
`The ’166 patent, entitled “Compositions Comprising Phosphodiesterase
`9.
`
`Inh[i]bitors for the Treatment of Sexual D[y]sfunction” issued on September 13,
`
`
`
`2
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`

`

`2005. I understand that the earliest claimed priority date of the ’166 patent is April
`
`30, 1999.
`
`10. The ’166 patent discusses treatment of sexual dysfunction, including
`
`male erectile dysfunction and female arousal disorder. Specifically, the ’166 patent
`
`discusses such treatment by administration of (6R,12aR)-2,3,6,7,12,12a- hexahydro-
`
`2-methyl-6-(3,4-methylenedioxyphenyl)pyrazino[2',1':6,1]-pyrido[3,4- b]indole-1,4-
`
`dione, which I understand is the chemical name for “tadalafil.” EX1001, 2:58-63;
`
`see also, e.g., EX1001, abstract. I am familiar with tadalafil, which can be sold
`
`under the trade name Cialis®, through my clinical practice.
`
`body:
`
`
`11. Tadalafil belongs to a class of compounds called PDE5 inhibitors.
`
`The ’166 patent provides a description of the role of PDE5 inhibitors in the
`
`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 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).
`
`
`
`
`3
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`

`

`12. The ’166 patent also discusses sildenafil, another PDE-5 inhibitor that
`
`can be sold under the trade name Viagra®:
`
`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. The ’166 patent acknowledges that other tetracyclic compounds were
`
`known in the art to be potent inhibitors of PDE5 and that significant adverse effects
`
`had not been attributed to these compounds. EX1001, 2:12-21. Tadalafil is
`
`specifically disclosed in the art acknowledged by the ’166 patent. Id., 2:22-32.
`
`13. Claim 1 of the ’166 patent states:
`
`A method of treating sexual dysfunction in a patient in need
`1.
`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
`
`
`
`4
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`
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`

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`14. Claims 2 and 3 each depend from claim 1 and respectively state that
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`the sexual dysfunction is male erectile dysfunction or female arousal disorder.
`
`IV. BRIEF SUMMARY OF THE FILE HISTORY OF THE ’166 PATENT
`
`15. During prosecution, claims were rejected under 35 U.S.C. 103(a) over
`
`U.S. Patent No. 6,140,329, which disclosed “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 applicants submitted two
`
`declarations of Dr. Gregory Sides, an employee of the Patent Owner Eli Lilly. Dr.
`
`Sides asserted there was an unexpected reduction of side effects associated with
`
`lowering the unit dosage level from 50 mg to 20 mg, and compared the efficacies of
`
`these two dosage levels. EX1006 at 0296-0301, 0058-62. The examiner stated that
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`“no statistical difference [was] seen in the change in efficacy between 20 mg and 50
`
`mg . . . However, the adverse side effects at 20 mg are dramatically reduced when
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`compared to 50 mg . . . This demonstrates unexpected results of the 20 mg dose of
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`tadalafil over the 50 mg dose.” EX1006 at 0035. A Notice of Allowability followed.
`
`Id. at 0034-36.
`
`V. LEGAL STANDARDS
`
`16.
`
`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
`5
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`

`

`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 relevant
`
`art at the time of the invention. As discussed above, I understand that the relevant art
`
`for the purpose of this declaration at least includes references that were published
`
`before April 30, 1999.
`
`17.
`
`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.
`
`18.
`
`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.
`
`19.
`
`I understand that improper hindsight must not be used when comparing
`
`the prior art to the invention for obviousness. Thus, a conclusion of 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.
`
`
`
`6
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`

`20.
`
`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 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
`
`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.
`
`21.
`
`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 combination of
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`prior art elements according to known methods to yield predictable results; (ii) the
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`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
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`same way; (iv) the application of a known technique to a known method or product
`
`ready for improvement to yield predictable results; (v) the application of a technique
`
`or approach that would have been “obvious to try” (e.g., choosing from a finite
`
`number of identified, predictable solutions, with a reasonable expectation of
`
`success); (vi) predictable variations of a known work in one field of endeavor
`
`prompted for use in either the same field or a different field based on design
`
`
`
`7
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`

`

`incentives or other market forces; or (vii) some teaching, 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 arrive at the claimed
`
`invention.
`
`22.
`
`I also understand that “secondary considerations” may be weighed
`
`against evidence of obviousness where appropriate.
`
`23.
`
`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 independent simultaneous
`
`invention within a comparatively short space of time; and (viii) teaching away from
`
`the invention in the prior art. Secondary considerations are relevant where there is a
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`nexus between the evidence and the claimed invention.
`
`VI. LEVEL OF ORDINARY SKILL AND RELEVANT TIME
`
`24.
`
`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
`8
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`

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`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. Unless
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`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
`
`were applied.
`
`25. Because of my education, experience, and training 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 a Pharm.D., or Ph.D. with experience in clinical pharmacology, and
`
`would be capable of understanding publications in the field.
`
`26. The skilled artisan may often have, or consult with, an individual with
`
`an M.D. with experience in the field of clinical urology, with exposure to patients
`
`with sexual/erectile dysfunction.
`
`VII. CLAIM CONSTRUCTION
`
`27.
`
`I have been advised that, in the present proceeding, the ’166 patent
`
`claims 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
`
`
`
`9
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`

`

`these principles in my analysis throughout this declaration. Below I discuss the
`
`meaning of the term “female arousal disorder” as it is used in claim 3 of the ’166
`
`patent.
`
`28. Claim 3 of the ’166 patent identifies the sexual dysfunction as “female
`
`arousal disorder.” EX1001, 15:19-21. The specification of the ’166 patent states:
`
`Specific conditions that can be treated by the present invention,
`include, but are not limited to, male erectile dysfunction and female
`sexual dysfunction, particularly female arousal disorder, also known
`as female sexual arousal disorder. . . . Preferred conditions to be
`treated include sexual dysfunction (including male erectile
`dysfunction; and female sexual dysfunction, and more preferably
`female arousal disorder (FAD)).
`
`EX1001, 3:6-4:26.
`
`29. Thus, in the context of the ’166 patent, I understand “female arousal
`
`disorder” to be a type of sexual dysfunction, and, more specifically, a type of
`
`female sexual dysfunction.
`
`VIII. THE STATE OF THE ART
`
`
`30. Sexual dysfunctions have been described 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).
`
`
`
`10
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`

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`31. These disturbances can be classified as sexual desire disorders, sexual
`
`arousal disorders, orgasmic disorders, and sexual pain disorders. Halvorsen, J. G., et
`
`al., Sexual Dysfunction, Part I: Classification, Etiology, and Pathogenesis, 5 J. AM.
`
`BOARD FAM. PRACT. (1992) 51-61 (“Halvorsen,” EX1026) at 51. Halvorsen teaches
`
`that sexual arousal disorders include:
`
`(1) [F]emale sexual arousal disorder, characterized by failure to attain
`or maintain the lubrication-swelling response of sexual excitement
`until completion of the sexual activity or by lack of a subjective sense
`of sexual excitement and pleasure during sexual activity; and (2) male
`erectile disorder, marked by failure to attain or maintain erection until
`completion of sexual activity or by lack of a subjective sense of
`sexual excitement and pleasure during sexual activity.
`
`EX1026 at 52.
`
`
`32. Erectile dysfunction is correlated with an increased report of “anxiety,
`
`loss of self-esteem, lack of self-confidence, tension and difficulty in the
`
`relationship” with a patient’s partner. Boolell, M., et al., Sildenafil: an orally active
`
`type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile
`
`erectile dysfunction, 8 INT. J. IMPOT. RES. (1996) 47-52 (“Boolell,” EX1015).
`
`33. Halvorsen teaches over 100 distinct “organic origins” of male sexual
`
`impotence involved in sexual arousal disorders, noting that female sexual arousal
`
`disorders, while not studied as extensively, may have similar origins. EX1026 at 56-
`
`57. In the case of male erectile dysfunction, the biological pathway for penile
`11
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`
`

`

`erections was known to be a hemodynamic event, “dependent upon relaxation of the
`
`smooth muscle cells of the corpus cavernosum and of its associated arterioles, with
`
`consequential increase in arterial flow into the trabecular spaces of the corpora
`
`cavernosa.” EX1015 at 47. The blood flow results in distention, compressing the
`
`venules between the sinusoids and tunica albuginea, and resulting in increased penile
`
`pressure, and thus, penile rigidity. Id.
`
`34. The initial relaxation of the smooth muscle cells was known to be
`
`mediated by nitric oxide, which stimulates the production of cyclic guanosine
`
`monophosphate (cGMP), causing the smooth muscle cells to relax, ultimately
`
`resulting in penile rigidity. Id. Phosphodiesterase enzymes convert cGMP to GMP
`
`and, as a result, decrease physiologic actions mediated by cGMP such as smooth
`
`muscle relaxation. Conversely, inhibition of phosphodiesterases increase cGMP
`
`levels and, as a result, increase physiologic actions mediated by cGMP such as
`
`smooth muscle relaxation. Given the distribution of cyclic nucleotide
`
`phosphodiesterase (PDE) isozymes throughout the penile tissues, those in the art
`
`understood 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.” Id. Prior to 1999, those in the art understood that type 5 PDE
`
`was “the predominant cGMP [for] hydrolysing activity,” and that oral “inhibitors of
`
`
`
`12
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`

`

`type 5 PDE [would] improve erection” and thus serve as pharmaceutical agents in
`
`the treatment of sexual dysfunctions such as erectile dysfunction. Terrett, N. K., et
`
`al., Sildenafil (ViagraTM), a Potent and Selective Inhibitor of Type 5 cGMP
`
`Phosphodiesterase with Utility for the Treatment of Male Erectile Dysfunction, 6
`
`BIOORG. MED. CHEM. Lett. (1996) 1819-1824 (“Terrett,” EX1013).
`
`35.
`
`Sildenafil citrate (Viagra®) is a PDE-5 inhibitor that became the first
`
`FDA-approved “orally active treatment for male erectile dysfunction.” EX1013 at
`
`1819. Doses of 25 mg, 50 mg, and 100 mg of sildenafil were approved for the
`
`treatment of erectile dysfunction with a “maximum recommended dosing frequency
`of once per day.” Viagra® Approved Label, EX1014 at 17.
`
`36. Sildenafil was as a potent inhibitor of PDE-5, having an IC50 of 0.0039
`
`µM (i.e., 3.9 nM). EX1015 at 50. It was also known to be much more selective for
`
`PDE5 than PDE1-4. EX1015 at 50. Patients taking sildenafil experience non-serious
`
`adverse events, including headaches, flushing, dyspepsia, also known as indigestion,
`
`rhinitis, and visual disturbances. Goldstein, I., et al., Oral Sildenafil in the Treatment
`
`of Erectile Dysfunction, 338 N. ENGL. J. MED., (1998) 1397-1404 (“Goldstein,”
`
`EX1028) at 1403; see also, Licht, M. R., Sildenafil (Viagra) for treating male erectile
`
`dysfunction, 65 CLEVE. CLIN. J. MED., (1998) 301-304 (“Licht,” EX1016) at 303.
`
`However, Goldstein notes that few subjects discontinued treatment and states that
`
`Viagra has “minimal side effects.” EX1028 at 1403. Sildenafil was also known to
`13
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`

`

`be “strictly contraindicated in patients using oral or transdermal nitrates, as it
`
`dangerously potentiates the hypotensive effect of these drugs,” as well as in patients
`
`with cardiovascular disease. EX1016 at 304; see also, de Mey, C., Opportunities for
`
`the Treatment of Erectile Dysfunction by Modulation of the NO Axis-Alternatives to
`
`Sildenafil Citrate, 14 CURR. MED. RES. OPIN., (1998) 187-202 (“de Mey,” EX1029)
`
`at 188.
`
`IX. THE ASSERTED REFERENCES DISCLOSE OR SUGGEST
`EACH OF THE CLAIMED FEATURES OF THE ’166 PATENT
`
`
`
`
`
`A. Brief Overview of the Asserted References
`
`37.
`
`I have reviewed the asserted references discussed below and I
`
`understand that they may be applied in assessing the validity of the ’166 patent.
`
`
`
`1.
`
`The ’675 PCT
`
`38.
`
`International Patent Publication No. WO 1997/03675 (“the ’675 PCT”)
`
`(EX1007) discloses the PDE5 tadalafil (Compound A), and that it may be
`
`administered orally for the treatment of sexual dysfunction. EX1007 at 3-4.
`
`39.
`
`The ’675 PCT teaches that tadalafil an IC50 of 2 nM and an EC50 of 0.2
`
`µm for PDE5, and notes these values “demonstrates the ability of the subject
`
`compounds of the invention to inhibit cGMP PDE, and hence [have] utility in the
`
`treatment of erectile dysfunction substantially as hereinbefore described.” Id. at 17.
`
`The ’675 PCT also notes that tadalafil, “may also be useful for the treatment of
`
`
`
`14
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`female sexual dysfunction[.]” Id. at 4.
`
`40.
`
`I understand that the ’675 PCT can be applied in assessing the validity
`
`of the ’166 patent claims.
`
`
`
`2.
`
`Sildenafil NDA
`
`41. The Sildenafil Citrate Approval Package for New Drug Application
`
`No. 020895 (Viagra®) (“Sildenafil NDA,” EX1008) at 0001, indicates that
`
`sildenafil was approved on March 27, 1998. I understand that the Sildenafil NDA
`
`can be applied in assessing the validity of the ’166 patent claims.
`
`42. The Sildenafil NDA is the Center for Drug Evaluation and Research
`
`Approval Package for sildenafil citrate, an erectile dysfunction drug that can be sold
`
`as Viagra®. The Sildenafil NDA includes data compiled for formal FDA review for
`
`regulatory approval. The Sildenafil NDA identifies the IC50 of sildenafil for PDE5
`
`as 3.5 nM (id. at 0037) and teaches that sildenafil exhibits dose-dependent
`
`therapeutic effectiveness at doses of 5 mg, 10 mg, 25 mg, 50 mg, and 100 mg.
`
`EX1008 at 0126-28, 0214-16.
`
`
`
`3.
`
`FDA Guideline
`
`43. Dose-Response Information to Support Drug Registration (“FDA
`
`Guideline,” EX1009) was published by the U.S. Government on November 9, 1994. I
`
`understand that FDA Guideline can be applied in assessing the patentability of the
`
`’166 patent claims.
`
`
`
`15
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`

`44. FDA Guideline teaches that a dose-response assessment should be an
`
`integral part of drug-development, and may be performed to “identify an appropriate
`
`starting dose.” EX1009 at 55972. In addition, FDA Guideline teaches that a dose-
`
`response assessment can identify “a dose beyond which increases would be unlikely
`
`to provide added benefit or would produce unacceptable side effects.” Id. Doses
`
`“well onto the plateau of the dose-response curve for the desired effect” are
`
`referenced as excessive. Id. at 55973.
`
`
`
`B. Detailed Analysis of the Claims
`
`1.
`
`The Teachings of the ’675 PCT in view of Sildenafil NDA
`and FDA Guideline Make the Therapeutic Indications of
`Claims 1-3 Obvious.
`45. As discussed above, the ’675 PCT (EX1007), the Sildenafil NDA
`
`(EX1008), and FDA Guideline (EX1009) can be considered in assessing the
`
`patentability of the ’166 patent.
`
`Claim 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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`16
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`
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`46. The ’675 PCT teaches compounds which are “potent and selective
`
`inhibitors of cyclic guanosine 3’,5’-monophosphate specific phosphodiesterase
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`(cGMP specific PDE) in the treatment of impotence.” EX1007 at 1. The ’675 PCT
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`calls out Compound A (tadalafil) and Compound B (3-methyl-tadalafil) as the
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`“specific compounds of the invention.” EX1007 at 3.
`
`47. The ’675 PCT teaches that impotence, “can be defined as a lack of
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`power, in the male, to copulate and may involve an inability to achieve penile
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`erection or ejaculation, or both. More specifically, erectile impotence or dysfunction
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`may be defined as an inability to obtain or sustain an erection adequate for
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`intercourse.” EX1007 at 1. Thus, the ’675 PCT teaches that tadalafil is useful in the
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`treatment of sexual dysfunctions, including erectile dysfunction.
`
`48. The ’675 PCT states that:
`
`Reports of well-controlled clinical trials in man are few and the
`efficacy of orally administered drugs is low. Although many different
`drugs have been shown to induce penile erection, they are only
`effective after direct injection into the penis, e.g. intraurethrally or
`
`17
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`intracavernosally (i.c.), and are not approved for erectile dysfunction.
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`Id. In addition, the ’675 PCT notes that penile prostheses have been used to assist
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`achievement of erection, but can have several drawbacks including infection and
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`ischaemia, “mak[ing] this type of treatment a final option rather than first-line
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`therapy.” Id.
`
`49. The ’675 PCT teaches that tadalafil may be “administered orally,
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`thereby obviating the disadvantages associated with i.c. [(intracavernosal)]
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`administration.” Id. at 3-4. The ’675 PCT also teaches a daily dose range of 0.5-800
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`mg for tadalafil in the treatment of sexual dysfunction disorders. Id. at 5. It was
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`routine in the art to identify a wide dosage range, as FDA Guideline teaches that a
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`wide range can be used in a dose-ranging study to “discern clinically meaningful
`
`differences” at different dosage levels, and to “identify an appropriate starting dose.”
`
`EX1009 at 55974. Indeed, such routine studies were performed in the development
`
`of sildenafil citrate, also known as Viagra®, and a person of ordinary skill would
`
`have looked to such studies to inform the identification of appropriate dosage levels
`
`of tadalafil. See EX1008.
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`50. Thus, from the teachings of the ʼ675 PCT, the Sildenafil NDA, and
`
`FDA Guideline, a person of ordinary skill in the art would have known that tadalafil
`
`was intended to be administered orally in the treatment of a sexual dysfunction
`
`disorder in a patient in need thereof, as recited in claim 1.
`
`
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`18
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`Claim 2:
`The method of claim 1 wherein the sexual dysfunction is male
`erectile dysfunction.
`51. The ’675 PCT states that tadalafil is “envisaged primarily for the
`
`treatment of erectile dysfunction or male sexual dysfunction[.]” EX1007 at 4. The
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`’675 PCT also states that tadalafil can be used “for the manufacture of a medicament
`
`for the curative or prophylactic treatment of erectile dysfunction in a male animal,
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`including man.” Id. at 6. Based on this disclosure a person of ordinary skill would
`
`have been motivated to use the tadalafil as recited in claim 1
`
`in the treatment indication recited in claim 2, where the sexual dysfunction is “male
`
`sexual dysfunction.”
`
`52. Moreover, the Sildenafil NDA describes multiple studies evaluating the
`
`efficacy of sildenafil, also a PDE-5 inhibitor, as a drug for the treatment of erectile
`
`dysfunction. For example, this included a “randomised, double-blind, placebo
`
`controlled, parallel-group, fixed-dose, multicentre, long-term dose- response study to
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`access the efficacy and safety of sildenafil (UK-92,480) administered prior to sexual
`
`activity to male patients with erectile dysfunction.” EX1008 at 0126. Another study
`
`described in the Sildenafil NDA was a “double blind, randomised placebo
`
`controlled, four way crossover study followed by a double blind, randomised,
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`placebo controlled, two way crossover study to investigate the efficacy of single
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`doses of UK-92,480 (sildenafil) in patients with erectile dysfunction with no
`19
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`established organic cause.” EX1008 at 0215. As the ’675 PCT teaches that tadalafil
`
`is a PDE-5 inhibitor (EX1007 at, e.g., cover page), and the Sildenafil NDA provides
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`clinical data on the efficacy of that PDE-5 inhibitor for male erectile dysfunction, the
`
`person of ordinary skill would have had good reason to believe that tadalafil would
`
`be similarly useful for the same indication. Thus, the method recited in claim 2
`
`would have been obvious to a person of ordinary skill in the art prior to April 30,
`
`1999.
`
`Claim 3:
`The method of claim 1 wherein the sexual dysfunction is female
`arousal disorder.
`
`53. While the ’675 PCT specifically highlights tadalafil’s usefulness in the
`
`treatment of male erectile disorder, it also teaches its use for the treatment of female
`
`sexual dysfunction. For example, the ’675 PCT states that tadalafil “may also be
`
`useful for the treatment of female sexual dysfunction including orgasmic dysfunction
`
`related to clitoral disturbances.” Id. at 4. As noted above in section VII, female
`
`arousal disorder is a female sexual dysfunction. Based on the teachings of the ʼ675
`
`PCT, the skilled artisan would have been motivated to use tadalafil in the treatment
`
`of female sexual dysfunction disorders such as female arousal disorder.
`
`54. The skilled artisan would have reasonably expected tadalafil to be
`
`useful in the treatment of female arousal disorder, as it was recognized in the art that
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`the female-based disorders likely have similar origins to those in men. EX1026 at
`20
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`56-57. In addition, female arousal disorder was identified as the female- equivalent
`
`to male erectile dysfunction, with both being categorized as their respective gender’s
`
`main sexual arousal disorder. Id. at 52. Thus, a person of ordinary skill in the art
`
`would have found it obvious to utilize the PDE5 inhibitor tadalafil for the treatment
`
`of female arousal disorder, as recited in claim 3 of the ’166 patent.
`
`X. THERE WAS NO LONG-FELT NEED FOR THE CLAIMED
`DOSING REGIMEN
`
`
`
`55. During the prosecution of the ’166 patent, the applicants asserted that a
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`long-felt need existed for an orally available treatment for erectile dysfunction that
`
`presented fewer side effects than sildenafil (Viagra®). EX1006 at 0327, 0348-I have
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`been asked to opine as to whether there was a long-felt need on April 30, 1999, the
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`earliest claimed priority date of the ’166 patent, for an orally available treatment for
`
`erectile dysfunction that presented fewer side effects than sildenafil, that would have
`
`been recognized in the art by a person of ordinary skill in the art. I have also been
`
`asked whether any such need had been satisfied before the claimed priority date, and
`
`whether the claimed invention of the ’166 patent did, in fact, satisfy the long-felt
`
`need. I also been asked to opine regarding whether any satisfaction of any unmet
`
`need