UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`MYLAN PHARMACEUTICALS INC.
`Petitioner,
`
`v.
`
`ICOS CORP.
`Patent Owner.
`
`_____________________________
`
`Patent No. 6,943,166
`
`_____________________________
`
`DECLARATION OF MUTA M. ISSA, M.D., M.B.A
`
`ARGENTUM EX1004
`Page 1
`
`
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`MYLAN PHARMACEUTICALS INC.
`Petitioner,
`
`v.
`
`ICOS CORP.
`Patent Owner.
`
`_____________________________
`
`Patent No. 6,943,166
`
`_____________________________
`
`DECLARATION OF MUTA M. ISSA, M.D., M.B.A
`
`ARGENTUM EX1004
`Page 1
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`
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`TABLE OF CONTENTS
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`I.
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`II.
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`Qualifications................................................................................................ 1
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`Scope of Work .............................................................................................. 3
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`III. Overview of the ’166 Patent ......................................................................... 4
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`IV. Brief Summary of the File History of the ’166 Patent ................................... 6
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`V.
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`Legal Standards ............................................................................................ 7
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`VI.
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`Level of Ordinary Skill and Relevant Time ................................................. 10
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`VII. Claim Construction ..................................................................................... 11
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`VIII. The State of the Art ..................................................................................... 12
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`IX.
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`The Asserted References Disclose or Suggest Each of the Claimed
`
`Features of the ’166 Patent .......................................................................... 15
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`X.
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`There Was No Long-Felt Need for the Claimed Dosing Regimen............... 23
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`XI. Concluding Statements ............................................................................... 25
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`XIII. Appendix – List Of Exhibits ....................................................................... 31
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`-i-
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`I.
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`I, Muta M. Issa, declare as follows:
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`QUALIFICATIONS
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`1. My name is Muta M. Issa. I am currently a tenured Professor of
`
`Urology in the School of Medicine at Emory University. I am also Chief of
`
`Urology at the Atlanta Veterans Affairs Medical Center and a Senior Faculty
`
`Member at the Emory Clinic and Emory University Hospital. Before I joined
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`Emory as an Assistant Professor in 1997, I was an Assistant Professor of Urology
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`at Stanford University School of Medicine.
`
`2.
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`I received an M.D. Magna Cum Laude from the Royal College of
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`Surgeons in Ireland in 1983. I completed an internship in Medicine (1983-1984),
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`instructorship in Physiology (1984-1985) and surgical training (1985-1987), which
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`included general surgery, accident and emergency medicine and cardiothoracic
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`surgery at the Royal College of Surgeons in Ireland. I received my urological
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`training from Johns Hopkins University Hospital (1987-1988) and Stanford
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`University Medical Center (1988-1993).
`
`3.
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`During my career I have served on numerous committees and panels,
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`including President of the Atlanta Urological Association, Member of a Special
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`Task Force commission by the National Pharmacy Benefit Management and
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`Strategic Healthcare, Department of Veterans Affairs the VA Policy Guidelines on
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`-1-
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`Page 3
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`Erectile Dysfunction “The Primary Care Management of Erectile Dysfunction”
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`
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`(USA Publication), Consultant (ad hoc) to Agency of Healthcare Research and
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`Quality (AHRQ), US Health & Human Services, President Elect of the Urological
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`Society for American Veterans, as a member of the Advisory/Steering Committee
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`and Chair of the Organizing Committee of the VA Forum of the American
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`Urological Association, and a member of the Scientific Committee of the
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`International Scientific Committee of Radionuclides in Nephro-urology. Among
`
`other things, I have served on the editorial boards of the journals The Scientific
`
`World Journal of Urology and Urologists in Cancer Care. I have also served as a
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`manuscript reviewer for many journals, including The Journal of Urology,
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`Investigative Urology, Urology, Journal of Endourology, British Journal of
`
`Urology International, European Urology, Prostate Cancer and Prostatic
`
`Diseases, and International Journal of Urology.
`
`4.
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`I am an inventor on ten issued U.S. Patents describing a resectoscope
`
`electrode assembly, the treatment of urinary strictures, a method and instrument for
`
`effecting anastomosis, as well as a catheter assembly and anchors for anastomosis.
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`I have authored or co-authored more than 100 peer-reviewed journal articles
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`pertaining to the field of urology. I have taught undergraduate, graduate and
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`medical school courses in urology including topics on the development and uses of
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`therapeutic agents for urological applications.
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`5.
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`I have 24-years of experience as an academic urologist in the field of
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`
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`academic urology that includes such areas as research design, methodology, data
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`analysis, reporting and publishing. In parallel, I have experience as a practicing
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`urologist in the field of clinical urology that includes areas such as male sexual and
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`erectile dysfunction, diagnostic ultrasonography, potency preserving surgical
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`procedures and reconstructive genito-urinary surgery.
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`6.
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`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.
`
`EX1005.
`
`II.
`
`SCOPE OF WORK
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`7.
`
`I am informed that a petition is being filed with the United States
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`Patent and Trademark Office for Inter Partes Review of U.S. Patent No. 6,943,166
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`(“the ’166 patent,” EX1001). I have been retained as a technical expert to provide
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`analysis and opinions regarding the ’166 patent. I have reviewed the ’166 patent
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`and portions of its prosecution history at the U.S. Patent Office. EX1006. I have
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`also considered other documents cited in this declaration, which are listed in the
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`Appendix in Section XIII.
`
`8.
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`I am being compensated at the rate of $600/hour for my time. I have
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`no financial interest in the outcome of this matter.
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`III. OVERVIEW OF THE ’166 PATENT
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`9.
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`The ’166 patent, entitled “Compositions Comprising
`
`
`
`Phosphodiesterase Inh[i]bitors for the Treatment of Sexual D[y]sfunction” issued
`
`on September 13, 2005. I understand that the earliest claimed priority date of the
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`’166 patent is April 30, 1999.
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`10. The ’166 patent discusses treatment of sexual dysfunction, including
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`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-
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`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,
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`which can be sold under the trade name Cialis®, through my clinical practice.
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`11. Tadalafil belongs to a class of compounds called PDE5 inhibitors.
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`The ’166 patent provides a description of the role of PDE5 inhibitors in the body:
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`The biochemical, physiological, and clinical effects of cyclic
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`guanosine 3’,5’-monophosphate specific phosphodiesterase
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`(cGMP-specific PDE) inhibitors suggest their utility in a variety of
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`disease states in which modulation of smooth muscle, renal,
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`hemostatic, inflammatory, and/or endocrine function is desired.
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`Type 5 cGMP-specific phosphodiesterase (PDE5) is the major
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`cGMP hydrolyzing enzyme in vascular smooth muscle, and its
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`expression in penile corpus cavernosum has been reported. Thus,
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`PDE5 is an attractive target in the treatment of sexual dysfunction.
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`Id. at 1:29-40 (citations omitted).
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`
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`12. The ’166 patent also discusses sildenafil, another PDE-5 inhibitor that
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`can be sold under the trade name Viagra®:
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`A pharmaceutical product, which provides a PDE5 inhibitor, is
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`currently available and marketed under the trademark VIAGRA®.
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`The active ingredient in VIAGRA® is sildenafil. . . . The package
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`insert provides that sildenafil is a more potent inhibitor of PDE5
`
`than other known phosphodiesterases . . . While sildenafil has
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`obtained significant commercial success, it has fallen short due to
`
`its significant adverse side effects[.]
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`Id. at 1:33-60. The ’166 patent acknowledges that other tetracyclic compounds
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`were known in the art to be potent inhibitors of PDE5 and that significant adverse
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`effects had not been attributed to these compounds. EX1001, 2:12-21. Tadalafil is
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`specifically disclosed in the art acknowledged by the ’166 patent. Id., 2:22-32.
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`13. Claim 1 of the ’166 patent states:
`
`1. A method of treating sexual dysfunction in a patient in need
`
`thereof comprising orally administering one or more unit dose
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`containing about 1 to about 20 mg, up to a maximum total dose of
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`20 mg per day, of a compound having the structure
`
`
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`-5-
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`Page 7
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`CH3
`
`N
`
`H
`
`N
`
`O
`
`O
`
`O
`
`O
`
`
`
`H
`
`NH
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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.
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`IV. BRIEF SUMMARY OF THE FILE HISTORY OF THE ’166 PATENT
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`15. During prosecution, claims were rejected under 35 U.S.C. 103(a) over
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`U.S. Patent No. 6,140,329, which disclosed “the instant compound and a method
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`of using it to treat sexual dysfunction,” including “oral administration and a dosage
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`within the recited range.” EX1006 at 0385. The applicants submitted two
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`declarations of Dr. Gregory Sides, an employee of the Patent Owner Eli Lilly. Dr.
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`Sides asserted there was an unexpected reduction of side effects associated with
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`lowering the unit dosage level from 50 mg to 20 mg, and compared the efficacies
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`of these two dosage levels. EX1006 at 0296-0301, 0058-62. The examiner stated
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`that “no statistical difference [was] seen in the change in efficacy between 20 mg
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`and 50 mg . . . However, the adverse side effects at 20 mg are dramatically reduced
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`when compared to 50 mg . . . This demonstrates unexpected results of the 20 mg
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`dose of tadalafil over the 50 mg dose.” EX1006 at 0035. A Notice of Allowability
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`followed. Id. at 0034-36.
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`V. LEGAL STANDARDS
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`
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`16.
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`I have been informed that a claimed invention is not patentable under
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`35 U.S.C. § 103, for obviousness, if the differences between the invention and the
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`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
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`the subject matter of the invention pertains. I understand that “a person of ordinary
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`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
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`relevant art for the purpose of this declaration at least includes references that were
`
`published before April 30, 1999.
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`17.
`
`I have been instructed that, a determination of obviousness requires
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`inquiries into (i) the scope and content of the art when the invention was made; (ii)
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`the differences between the art and the claims at issue; (iii) the level of ordinary
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`skill in the pertinent art when the invention was made; and, to the extent they exist,
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`any secondary considerations.
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`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
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`combined the elements as claimed by known methods with no change in their
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`respective functions, and the combination would have yielded nothing more than
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`predictable and expected results to one of ordinary skill in the art.
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`19.
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`I understand that improper hindsight must not be used when
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`
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`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
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`ordinary skill in the art at the time the invention was made.
`
`20.
`
`I have been informed that obviousness may also be shown by
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`demonstrating that it would have been obvious to modify what is taught in a single
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`piece of prior art to create the patented invention. I understand that obviousness
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`may be demonstrated by showing that it would have been obvious to combine the
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`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,
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`there must be some supporting rationale for combining the cited references or
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`teachings as proposed.
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`21.
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`I am informed that the following are examples of principles that may
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`indicate that it would have been obvious to combine multiple teachings, resulting
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`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
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`results; (ii) the simple substitution of one known element for another to obtain
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`predictable results; (iii) the use of a known technique to improve similar methods
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`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
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`to modify the prior art reference or to combine prior art reference teachings to
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`arrive at the claimed invention.
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`22.
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`I also understand that “secondary considerations” may be weighed
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`against evidence of obviousness where appropriate.
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`23.
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`I understand that such secondary considerations, where in evidence,
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`may include: (i) commercial success of a product due to the merits of the claimed
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`invention; (ii) a long-felt, but unsatisfied need for the invention; (iii) failure of
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`others to find the solution provided by the claimed invention; (iv) deliberate
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`copying of the invention by others; (v) unexpected results achieved by the
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`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;
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`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.
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`VI. LEVEL OF ORDINARY SKILL AND RELEVANT TIME
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`24.
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`I have been advised that a person of ordinary skill in the art is a
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`hypothetical person who is presumed to have known the relevant art at the time of
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`the invention. A person of ordinary skill in the art is also a person of ordinary
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`creativity. For the purposes of this declaration, I have assumed that the relevant
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`timeframe for assessing the validity of claims of the ’166 patent is April 30, 1999,
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`the earliest claimed priority date of the application that led to the ’166 patent.
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`Unless otherwise specifically noted, all of my opinions expressed herein regarding
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`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
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`later filing date were applied.
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`25. Because of my education, experience, and training I am familiar with
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`the level of skill in the art of the ’166 patent on and before April 30, 1999. In my
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`opinion, a person of ordinary skill in the relevant field as of April 30, 1999, would
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`typically have a Pharm.D., or Ph.D. with experience in clinical pharmacology, and
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`would be capable of understanding publications in the field.
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`26. The skilled artisan may often have, or consult with, an individual with
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`an M.D. with experience in the field of clinical urology, with exposure to patients
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`with sexual/erectile dysfunction.
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`VII. CLAIM CONSTRUCTION
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`
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`27.
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`I have been advised that, in the present proceeding, the ’166 patent
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`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
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`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
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`have followed these principles in my analysis throughout this declaration. Below I
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`discuss the meaning of the term “female arousal disorder” as it is used in claim 3
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`of the ’166 patent.
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`28. Claim 3 of the ’166 patent identifies the sexual dysfunction as “female
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`arousal disorder.” EX1001, 15:19-21. The specification of the ’166 patent states:
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`Specific conditions that can be treated by the present invention,
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`include, but are not limited to, male erectile dysfunction and
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`female sexual dysfunction, particularly female arousal disorder,
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`also known as female sexual arousal disorder. . . . Preferred
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`conditions to be treated include sexual dysfunction (including male
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`erectile dysfunction; and female sexual dysfunction, and more
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`preferably female arousal disorder (FAD)).
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`EX1001, 3:6-4:26.
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`29. Thus, in the context of the ’166 patent, I understand “female arousal
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`
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`disorder” to be a type of sexual dysfunction, and, more specifically, a type of
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`female sexual dysfunction.
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`VIII. THE STATE OF THE ART
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`30. Sexual dysfunctions have been described as “disturbances in sexual
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`desire and in the psychophysiological changes associated with the sexual response
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`cycle in men and women.” Laumann, E. O., et al., Sexual Dysfunction in the
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`United States, 281 JAMA 537-544 (Feb.1999) (“Laumann,” EX1012).
`
`31. These disturbances can be classified as sexual desire disorders, sexual
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`arousal disorders, orgasmic disorders, and sexual pain disorders. Halvorsen, J. G.,
`
`et al., Sexual Dysfunction, Part I: Classification, Etiology, and Pathogenesis, 5 J.
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`AM. BOARD FAM. PRACT. (1992) 51-61 (“Halvorsen,” EX1026) at 51. Halvorsen
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`teaches that sexual arousal disorders include:
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`(1) [F]emale sexual arousal disorder, characterized by failure to attain
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`or maintain the lubrication-swelling response of sexual excitement
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`until completion of the sexual activity or by lack of a subjective sense
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`of sexual excitement and pleasure during sexual activity; and (2) male
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`erectile disorder, marked by failure to attain or maintain erection until
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`completion of sexual activity or by lack of a subjective sense of sexual
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`excitement and pleasure during sexual activity.
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`EX1026 at 52.
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`Page 14
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`32. Erectile dysfunction is correlated with an increased report of “anxiety,
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`loss of self-esteem, lack of self-confidence, tension and difficulty in the
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`relationship” with a patient’s partner. Boolell, M., et al., Sildenafil: an orally
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`active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of
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`penile erectile dysfunction, 8 INT. J. IMPOT. RES. (1996) 47-52 (“Boolell,”
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`EX1015).
`
`33. Halvorsen teaches over 100 distinct “organic origins” of male sexual
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`impotence involved in sexual arousal disorders, noting that female sexual arousal
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`disorders, while not studied as extensively, may have similar origins. EX1026 at
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`56-57. In the case of male erectile dysfunction, the biological pathway for penile
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`erections was known to be a hemodynamic event, “dependent upon relaxation of
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`the smooth muscle cells of the corpus cavernosum and of its associated arterioles,
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`with consequential increase in arterial flow into the trabecular spaces of the
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`corpora cavernosa.” EX1015 at 47. The blood flow results in distention,
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`compressing the venules between the sinusoids and tunica albuginea, and resulting
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`in increased penile pressure, and thus, penile rigidity. Id.
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`34. The initial relaxation of the smooth muscle cells was known to be
`
`mediated by nitric oxide, which stimulates the production of cyclic guanosine
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`monophosphate (cGMP), causing the smooth muscle cells to relax, ultimately
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`resulting in penile rigidity. Id. Phosphodiesterase enzymes convert cGMP to GMP
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`and, as a result, decrease physiologic actions mediated by cGMP such as smooth
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`muscle relaxation. Conversely, inhibition of phosphodiesterases increase cGMP
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`levels and, as a result, increase physiologic actions mediated by cGMP such as
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`smooth muscle relaxation. Given the distribution of cyclic nucleotide
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`phosphodiesterase (PDE) isozymes throughout the penile tissues, those in the art
`
`understood 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. Prior to 1999, those in the art understood that type 5 PDE
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`was “the predominant cGMP [for] hydrolysing activity,” and that oral “inhibitors
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`of type 5 PDE [would] improve erection” and thus serve as pharmaceutical agents
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`in the treatment of sexual dysfunctions such as erectile dysfunction. Terrett, N. K.,
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`et al., Sildenafil (ViagraTM), a Potent and Selective Inhibitor of Type 5 cGMP
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`Phosphodiesterase with Utility for the Treatment of Male Erectile Dysfunction, 6
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`BIOORG. MED. CHEM. Lett. (1996) 1819-1824 (“Terrett,” EX1013).
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`35. Sildenafil citrate (Viagra®) is a PDE-5 inhibitor that became the first
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`FDA-approved “orally active treatment for male erectile dysfunction.” EX1013 at
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`1819. Doses of 25 mg, 50 mg, and 100 mg of sildenafil were approved for the
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`treatment of erectile dysfunction with a “maximum recommended dosing
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`frequency of once per day.” Viagra® Approved Label, EX1014 at 17.
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`Page 16
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`36. Sildenafil was as a potent inhibitor of PDE-5, having an IC50 of
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`
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`0.0039 µM (i.e., 3.9 nM). EX1015 at 50. It was also known to be much more
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`selective for PDE5 than PDE1-4. EX1015 at 50. Patients taking sildenafil
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`experience non-serious adverse events, including headaches, flushing, dyspepsia,
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`also known as indigestion, rhinitis, and visual disturbances. Goldstein, I., et al.,
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`Oral Sildenafil in the Treatment of Erectile Dysfunction, 338 N. ENGL. J. MED.,
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`(1998) 1397-1404 (“Goldstein,” EX1028) at 1403; see also, Licht, M. R., Sildenafil
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`(Viagra) for treating male erectile dysfunction, 65 CLEVE. CLIN. J. MED., (1998)
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`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 be “strictly contraindicated in patients using
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`oral or transdermal nitrates, as it dangerously potentiates the hypotensive effect of
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`these drugs,” as well as in patients with cardiovascular disease. EX1016 at 304; see
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`also, de Mey, C., Opportunities for the Treatment of Erectile Dysfunction by
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`Modulation of the NO Axis-Alternatives to Sildenafil Citrate, 14 CURR. MED. RES.
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`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
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`A. Brief Overview of the Asserted References
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`-15-
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`Page 17
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`37.
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`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.
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`39. The ’675 PCT teaches that tadalafil an IC50 of 2 nM and an EC50 of
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`0.2 µm for PDE5, and notes these values “demonstrates the ability of the subject
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`compounds of the invention to inhibit cGMP PDE, and hence [have] utility in the
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`treatment of erectile dysfunction substantially as hereinbefore described.” Id. at 17.
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`The ’675 PCT also notes that tadalafil, “may also be useful for the treatment of
`
`female sexual dysfunction[.]” Id. at 4.
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`40.
`
`I understand that the ’675 PCT can be applied in assessing the validity
`
`of the ’166 patent claims.
`
`2.
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`Sildenafil NDA
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`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
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`can be applied in assessing the validity of the ’166 patent claims.
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`Page 18
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`42. The Sildenafil NDA is the Center for Drug Evaluation and Research
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`
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`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.
`
`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
`-17-
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`Page 19
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`
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`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
`
`H
`
`N
`
`O
`
`O
`
`O
`
`O
`
`
`
`CH3
`
`N
`
`
`
`H
`
`NH
`
`46. The ’675 PCT teaches compounds which are “potent and selective
`
`inhibitors of cyclic guanosine 3’,5’-monophosphate specific phosphodiesterase
`
`(cGMP specific PDE) in the treatment of impotence.” EX1007 at 1. The ’675 PCT
`
`calls out Compound A (tadalafil) and Compound B (3-methyl-tadalafil) as the
`
`“specific compounds of the invention.” EX1007 at 3.
`
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`-18-
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`Page 20
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`
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`47. The ’675 PCT teaches that impotence, “can be defined as a lack of
`
`
`
`power, in the male, to copulate and may involve an inability to achieve penile
`
`erection or ejaculation, or both. More specifically, erectile impotence or
`
`dysfunction may be defined as an inability to obtain or sustain an erection adequate
`
`for intercourse.” EX1007 at 1. Thus, the ’675 PCT teaches that tadalafil is useful in
`
`the 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 intracavernosally (i.c.), and are not approved for
`
`erectile dysfunction.
`
`Id. In addition, the ’675 PCT notes that penile prostheses have been used to assist
`
`achievement of erection, but can have several drawbacks including infection and
`
`ischaemia, “mak[ing] this type of treatment a final option rather than first-line
`
`therapy.” Id.
`
`49. The ’675 PCT teaches that tadalafil may be “administered orally,
`
`thereby obviating the disadvantages associated with i.c. [(intracavernosal)]
`
`administration.” Id. at 3-4. The ’675 PCT also teaches a daily dose range of 0.5-
`
`800 mg for tadalafil in the treatment of sexual dysfunction disorders. Id. at 5. It
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`-19-
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`Page 21
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`
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`was routine in the art to identify a wide dosage range, as FDA Guideline teaches
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`
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`that a 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.
`
`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.
`
`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
`
`’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, 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
`
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`-20-
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`Page 22
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`
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`in the treatment indication recited in claim 2, where the sexual dysfunction is
`
`
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`“male sexual dysfunction.”
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`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 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, placebo controlled, two way crossover study to
`
`investigate the efficacy of single doses of UK-92,480 (sildenafil) in patients with
`
`erectile dysfunction with no 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 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
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`person of ordinary skill in the art prior to April 30, 1999.
`
`Claim 3:
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`-21-
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`Page 23
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`
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`The method of claim 1 wherein the sexual dysfunction is female
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`
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`arousal disorder.
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`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
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