UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
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`INTELGENX CORP.
`Petitioner
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`v.
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`ICOS CORP.
`Patent Owner
`
`U.S. Patent No. 6,943,166
`_____________________
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`Inter Partes Review Case No. Unassigned
`_____________________
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`DECLARATION OF WAYNE J.G. HELLSTROM, M.D., FACS
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`Inter Partes Review of USPN 6,943,166
`Declaration of Wayne J.G. Hellstrom, M.D., FACS (INX1005)
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`TABLE OF CONTENTS
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`I.
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`Introduction...................................................................................................... 1
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`II. My background and qualifications .................................................................. 2
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`III. Summary of opinions ....................................................................................... 5
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`IV. List of Documents I Considered in Formulating My Opinions ....................10
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`V.
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`Person of ordinary skill in the art ..................................................................13
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`VI. The '166 patent ...............................................................................................14
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`VII. Claim construction .........................................................................................17
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`VIII. State of the art before April 30, 1999 ............................................................19
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`A.
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`B.
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`Sexual dysfunction was a well known disorder .................................. 19
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`Selective PDE-5 inhibitors were known to effectively treat
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`sexual dysfunction ............................................................................... 22
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`C.
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`Tadalafil was a known, highly selective, and potent PDE-5
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`inhibitor ............................................................................................... 25
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`D.
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`It was routine practice in the art to identify an optimal dose
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`range for a new drug ............................................................................ 27
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`IX. Summary chart of analysis over the art .........................................................35
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`X.
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`The basis of my analysis with respect to obviousness ..................................35
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`Inter Partes Review of USPN 6,943,166
`Declaration of Wayne J.G. Hellstrom, M.D., FACS (INX1005)
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`A. Ground 1: Daugan '675 would have provided a reason to
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`arrive at the method of claims 1-12 with a reasonable
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`expectation of success ......................................................................... 37
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`B. Ground 2: Daugan '675 and the SNDA would have
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`provided a reason to arrive at the invention of claims 1-12
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`with a reasonable expectation of success ............................................ 62
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`C.
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`Secondary considerations of non-obviousness ................................... 82
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`1.
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`No unexpectedly superior results ..............................................83
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`(a)
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`The efficacy and side effects data discussed in
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`the Sides declarations and the '166 patent
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`would not have been surprising to a POSA ....................85
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`(i) A POSA would not have been surprised
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`by the side effects data discussed in the
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`first Sides declaration ........................................... 85
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`(ii) A POSA would not have been surprised
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`by the efficacy data discussed in the
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`second Sides declaration and the '166
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`patent .................................................................... 87
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`(b)
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`ICOS' data is not superior over the closest
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`prior art ...........................................................................91
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`Inter Partes Review of USPN 6,943,166
`Declaration of Wayne J.G. Hellstrom, M.D., FACS (INX1005)
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`(c)
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`The evidence provided by ICOS during
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`prosecution of the '166 patent is not equal in
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`scope to the claims ..........................................................92
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`2.
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`3.
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`4.
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`5.
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`No teaching away ......................................................................94
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`No long-felt, unmet need ..........................................................94
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`Commercial success ..................................................................96
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`Other objective evidence...........................................................96
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`XI. Conclusion .....................................................................................................97
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`Inter Partes Review of USPN 6,943,166
`Declaration of Wayne J.G. Hellstrom, M.D., FACS (INX1005)
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`I, Wayne Hellstrom, MD, FACS, hereby declare as follows.
`I.
`
`Introduction
`I am over the age of eighteen and otherwise competent to make this
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`1.
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`declaration.
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`2.
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`I have been retained as an expert witness on behalf of INTELGENX
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`CORP. ("INTELGENX") for the above-captioned inter partes review (IPR). I am
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`being compensated for my time in connection with this IPR at my standard
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`consulting rate, which is $750 per hour.
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`3.
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`I understand that the petition for inter partes review involves U.S.
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`Patent No. 6,943,166 ("the '166 patent"), INX1001, which resulted from U.S.
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`Patent Application No. 10/031,556 ("the '556 application"), which is a national
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`stage entry application of PCT Application Publication No. WO 00/66099 ("the
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`'099 PCT application"), filed April 26, 2000. I also understand that the '166
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`patent's earliest possible priority date is April 30, 1999, the filing date of U.S.
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`Provisional Patent Application No. 60/132,036. The '166 patent names William
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`Ernest Pullman and John Steven Whitaker as the inventors. The '166 patent issued
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`on September 13, 2005, from the '556 application. I understand that, according to
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`the United States Patent and Trademark Office ("USPTO") records, the '166
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`patent is currently assigned to ICOS Corp. I also understand that ICOS Corp. is
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`owned by Eli Lilly & Co. The patentee is referred to herein as "ICOS."
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`Inter Partes Review of USPN 6,943,166
`Declaration of Wayne J.G. Hellstrom, M.D., FACS (INX1005)
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`4.
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`The
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`'166 patent
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`is directed generally
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`to
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`the
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`field of
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`phosphodiesterase (PDE) inhibitors, and more specifically to methods of using
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`cyclic guanosine 3',5'-monophosphate specific phosphodiesterase type 5 (PDE-5)
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`inhibitors for treating sexual dysfunction. INX1001, 1, Abstract. The methods of
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`the '166 patent utilize a unit dose containing from about 1 to about 20 mg of
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`(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
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`("tadalafil"). INX1001, 2:58-63, 14:65 to 15:17.
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`5.
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`In preparing this Declaration, I have reviewed the '166 patent and
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`each of the documents cited herein, in light of general knowledge in the art. In
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`formulating my opinions, I have relied upon my experience, education, history of
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`involvement, and knowledge in the relevant art. In formulating my opinions, I
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`have also considered the viewpoint of a person of ordinary skill in the art
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`("POSA") (i.e., a person of ordinary skill in the field of chemistry, pharmacology,
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`or in a related field in the biological or chemical sciences defined further below in
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`Section V) before April 30, 1999.
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`II. My background and qualifications
`I am an expert in the field of urology and male sexual dysfunction,
`6.
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`and I have been an expert in this field since before April 30, 1998. I am presently
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`employed by Tulane University School of Medicine. I obtained a Bachelor of
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`Science degree in Physiology from McGill University in 1977 and a Doctor of
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`Inter Partes Review of USPN 6,943,166
`Declaration of Wayne J.G. Hellstrom, M.D., FACS (INX1005)
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`Medicine and Master of Surgery degree from McGill Medical School in 1981. I
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`was a resident in general surgery at Montreal General and Royal Victoria
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`Hospital, McGill University, in Montreal, Canada from 1982-1983. I was then a
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`Resident and Chief Resident in urology at the University of California, San
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`Francisco, from 1983-1985 and from 1985-1986, respectively. I was also a
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`Fellow in andrology (male infertility and sexual dysfunction) at the University of
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`California, Davis, from 1986-1988.
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`7.
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`I served as an instructor in the Department of Urology at the
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`University of California, Davis, from 1986-1988. I subsequently served as an
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`Assistant Professor from 1988-1992 and an Associate Professor from 1992-1999
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`at Tulane University School of Medicine in New Orleans, Louisiana. I was also a
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`Chief in the Section of Urology at Charity Hospital of New Orleans from 1989-
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`2005 and a Research Affiliate at Delta Regional Primate Research Center in
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`Covington, Louisiana from 1989-1998.
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`8.
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`I currently hold the position of Professor of Urology at Tulane
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`University School of Medicine and have held this position since 1999.
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`9. My curriculum vitae is provided as INX1006.
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`10.
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`I have significant experience with treating male sexual dysfunction
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`disorders, specifically erectile dysfunction. I have experience in microsurgical
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`reconstruction, diagnostic ultrasound, advanced male infertility procedures, and
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`Inter Partes Review of USPN 6,943,166
`Declaration of Wayne J.G. Hellstrom, M.D., FACS (INX1005)
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`the latest therapeutic modalities for erectile dysfunction. My practice is
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`specialized in the diagnosis and treatment of sexual dysfunction including
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`Peyronie's disease, surgical and vascular reconstruction, prosthetic surgery, male
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`infertility (both surgical and medical therapies), benign prostatic hyperplasia
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`(BPH), and urethral stricture disease. I have been the editor for several books on
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`sexual dysfunction, including "Male Infertility and Sexual Dysfunction" and "The
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`Handbook of Sexual Dysfunction," and associate editor for several journals
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`dealing with sexual medicine, including the Journal of Sexual Medicine, Current
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`Sexual Health Reports, and Issues in Sexual Medicine. I am currently an associate
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`editor for several journals, including Urology (Gold Journal), Andrology, and
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`Journal of Urology, where I serve on the editorial board.
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`11.
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`I have received several honors in my career, including First Prize for
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`Clinical Research in 1988 by the American Urological Association, the Young
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`Andrologist Award in 1994 by the American Society of Andrology, the award for
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`Best Presentation on MSD (preclinical) in 2002 at the 5th Congress of the
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`European Society for Sexual and Impotence Research (ESSM) in Hamburg,
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`Germany, and the award for Best Presentation on Male Sexual Dysfunction
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`(clinical) in 2006 at ESSM in Vienna, Austria. I was also inducted into the Tulane
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`AOA Honor Society in 2013, and I became a member of the American
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`Association of Genitourinary Surgeons in 2014. In addition, I have served as
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`Inter Partes Review of USPN 6,943,166
`Declaration of Wayne J.G. Hellstrom, M.D., FACS (INX1005)
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`President of the American Society of Andrology, the Sexual Medicine Society of
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`North America, and am currently President of the International Society of Sexual
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`Medicine (ISSM).
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`12. During my nearly 30 years of experience in urology and sexual
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`dysfunction, I have authored or co-authored over 400 peer- reviewed scientific
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`articles. Each publication is listed in my curriculum vitae, INX1006.
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`13.
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`I have also been the mentor for countless students, residents, and
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`more than 20 fellows.
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`14. Accordingly, I am an expert in the field of urology and sexual
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`dysfunction.
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`III. Summary of opinions
`In this declaration, I consider the methods of treating sexual
`15.
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`dysfunction of the '166 patent in relation to the state of the art before April 30,
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`1999. The prior art references that I considered when comparing the claims of the
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`'166 patent to the state of the art include, but are not limited to, PCT Application
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`Publication No. WO 97/03675 ("Daugan '675") (INX1002) and the Sildenafil
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`Citrate Approval Package for New Drug Application No. 020895 ("SNDA")
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`(INX1003). I also considered the file history of the '166 patent (INX1024),
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`including the Declarations of Dr. Gregory D. Sides (INX1024, 615-620, 860-864)
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`and the data cited therein. I understand that ICOS submitted the Sides Declaration
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`Inter Partes Review of USPN 6,943,166
`Declaration of Wayne J.G. Hellstrom, M.D., FACS (INX1005)
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`to the USPTO to support the purported patentability of the '166 patent claims. A
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`summary of my opinions follows.
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`16. Claims 1-12 of the '166 patent are directed to methods of treating
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`sexual dysfunction, including male erectile dysfunction and female arousal
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`disorder, that include administering one or more unit doses containing about 1 to
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`about 20 mg of tadalafil, once or more per day. INX1001, 14:65 to 16:20.
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`17. Claims 1-12 would have been obvious in view of the prior art.
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`Daugan '675 teaches methods of treating sexual dysfunction, including male and
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`female sexual dysfunction, by orally administering tadalafil to a patient in need
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`thereof. INX1002, 3-5. Daugan '675 also teaches a range of tadalafil doses (0.2–
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`400 mg) suitable for treating sexual dysfunction—a range that encompasses the
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`dose range recited in the claims of the '166 patent. INX1002, 5.
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`18. According to the '166 patent's file history, ICOS argued that a POSA
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`would not have been motivated to use tadalafil doses on the lower end of a 0.2–
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`400 mg dose range. INX1024, 547, 592. I disagree that a POSA would not have
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`used lower tadalafil doses. A POSA would have had a reason to use tadalafil
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`doses from the lower end of Daugan '675's 0.2–400 mg range, because (i) Daugan
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`'675 teaches a method of treating sexual dysfunction that encompasses every step
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`recited in claims 1-12 of the '166 patent; (ii) Daugan '675 provides guidance on
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`dose formulation, stating that "other doses" and "other strengths" can be prepared,
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`Inter Partes Review of USPN 6,943,166
`Declaration of Wayne J.G. Hellstrom, M.D., FACS (INX1005)
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`and that "higher or lower dose ranges may be merited"; and (iii) a POSA would
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`have known that a less potent PDE-5 inhibitor, sildenafil, exhibits dose-dependent
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`therapeutic effectiveness in treating sexual dysfunction at doses as low as 5 and
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`10 mg. INX1002, 4-5, 14, 16; INX1009, 51, Figure 4; INX1003, 126-128, 215-
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`218; INX1004, 33-35, 39-42.
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`19. Accordingly, based on the disclosures in Daugan '675 and the
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`general knowledge in the art, the claims of the '166 patent would have been
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`obvious. And, a POSA would have had a reasonable expectation of success in
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`arriving at the claimed methods because Daugan '675 teaches every step recited in
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`claims 1-12, and the prior art taught that the PDE-5 inhibitor approved by the
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`FDA to treat sexual dysfunction, sildenafil, exhibits a degree of therapeutic
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`effectiveness in some patients at doses as low as 5 mg. INX1001, 14:65 to 16:20;
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`INX1002, 3-5, 17; INX1009, 51, Figure 4; INX1003, 37, 126-128, 215-218;
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`INX1004, 33-35, 39-42.
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`20. Though Daugan '675 alone would have provided sufficient teachings
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`and guidance for a POSA to readily arrive at the claimed methods with a
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`reasonable expectation of success, a POSA would have found further guidance
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`and motivation in the SNDA document, which teaches that a potent, selective
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`PDE-5 inhibitor, sildenafil, exhibits dose-dependent therapeutic effectiveness at
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`doses as low as 5 mg. INX1003, 37, 126-128, 215-218; INX1004, 33-35, 39-42.
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`Inter Partes Review of USPN 6,943,166
`Declaration of Wayne J.G. Hellstrom, M.D., FACS (INX1005)
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`As discussed in this Declaration, a POSA would have had a reason to combine the
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`method disclosed in Daugan '675 with the teachings in the SNDA, and a POSA
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`would have had a reasonable expectation of successfully arriving at the claimed
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`methods.
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`21.
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`I understand that ICOS argued during prosecution of the '166 patent
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`that the claimed methods provided "unexpected results" and satisfied a "long felt
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`need." INX1024, 541-547, 855. I disagree that the methods of the '166 patent
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`provided unexpected results or satisfied a long-felt, but unmet need.
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`22. First, ICOS' dose-dependent therapeutic efficacy and toxicity would
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`not have been surprising or unexpected to a POSA. Before April 30, 1999,
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`artisans routinely used dose-response curves to identify a drug's optimal
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`therapeutic dose range. INX1030, 68-69, Figure 4-3. See also INX1032, 404 and
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`406; INX1033, 26. Using routine dose-response curves, a POSA would have
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`known that drug doses at the top of the curve provide comparable therapeutic
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`efficacy, while doses along the shoulder and slope of the curve provide dose-
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`dependent therapeutic efficacy. See INX1030, 67-69, Figures 4-2 and 4-3;
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`INX1032, 404; INX1023, 54; INX1034, 27-28; INX1040, 13. Thus, a POSA
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`would not have been surprised that ICOS' data and the Sides declarations show a
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`dose-dependent decrease in side effects from a 100 mg dose to a 2 mg dose of
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`tadalafil. INX1024, 619-620; INX1001, 14:22-37. Furthermore, a POSA would
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`Inter Partes Review of USPN 6,943,166
`Declaration of Wayne J.G. Hellstrom, M.D., FACS (INX1005)
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`not have been surprised that ICOS's data and the Sides declarations show
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`comparable efficacy between two doses at the top of the dose-response curve, 20
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`mg and 50 mg; and a dose-dependent decrease in efficacy for doses along the
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`shoulder and slope of the dose-response curve. INX1024, 863-864; INX1001,
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`14:1-16.
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`23. Second, ICOS' data and the Sides declarations do not provide
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`unexpectedly superior results over the closest prior art. Daugan '675 specifically
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`teaches methods of treating sexual dysfunction using a range of tadalafil doses
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`(0.2–400 mg), which encompasses the doses described in the Sides declarations
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`and the '166 patent. INX1002, 5. A POSA would not have considered ICOS' data
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`surprising or superior over the teachings in Daugan '675.
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`24. Third, ICOS' data is not equal in scope to the claims of the '166
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`patent. The claims of the '166 patent encompass treating sexual dysfunction, in
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`men and in women, by administering tadalafil doses, in one or more unit doses,
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`from 1 mg to 20 mg, once or more per day. INX1001, 14:65 to 16:20. But, ICOS'
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`allegedly "unexpected" data are limited to treating male erectile dysfunction, by
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`administering a single 20 mg unit dose of tadalafil, on demand, not more than
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`once per day. This is not equal in scope to the claims of the '166 patent, which are
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`much broader.
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`Inter Partes Review of USPN 6,943,166
`Declaration of Wayne J.G. Hellstrom, M.D., FACS (INX1005)
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`25. Fourth, I disagree with ICOS' assertion that the claimed methods
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`satisfied a long-felt, unmet need for an oral treatment for ED with fewer side
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`effects than Viagra® (sildenafil). There is no evidence in the '166 patent or its file
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`history showing the existence of a long-felt, unmet need recognized in the art.
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`Moreover, even if a long-felt, unmet need did exist, the need would have been
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`satisfied by disclosures in the prior art before April 30, 1999.
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`26. Finally, after reviewing the '166 patent and its file history, I am not
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`aware of any publicly available objective evidence that would support the claims
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`of the '166 patent.
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`IV. List of Documents I Considered in Formulating My Opinions
`In formulating my opinions, I have considered all the references and
`27.
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`documents cited herein, including those listed below.
`
`IntelGenX
`Exhibit #
`
`1001
`
`Description
`Pullman, W. E.., et al., "Compositions Comprising
`Phosphodiesterase [Inhibitors] for the Treatment of Sexual
`Dysfunction," U.S. Patent No. 6,943,166 (filed on April 26, 2000;
`issued September 13, 2005)
`Daugan, A.C-M.,, "Use of cGMP-Phosphodiesterase Inhibitors to
`Treat Impotence," Int'l Pub. No. WO 97/03675 (filed on July 11,
`1996; published February 6, 1997)
`"Center for Drug Evaluation and Research," Approval Package for
`VIAGRA, Approval Date March 27, 1998 ("SNDA")
`"Center for Drug Evaluation and Research," Approval Package for
`VIAGRA, Approval Date March 27, 1998, pp. i-xxx, 99-103, 183-
`188 ("SNDA Condensed")
`1006 Dr. Wayne J.G. Hellstrom's Curriculum Vitae
`
`1002
`
`1003
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`1004
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`IntelGenX
`Exhibit #
`1007 Declaration of Douglas Reid Patterson, D.V.M, PH.D
`Boolell, M., et al., "Sildenafil: an orally active type 5 cyclic GMP-
`specific phosphodiesterase inhibitor for the treatment of penile
`erectile dysfunction," Int'l J. Impot. Res., 8:47-52 (1996)
`Rosen, R.C., et al., "The International Index of Erectile Function
`(IIEF): A Multidimensional Scale for Assessment of Erectile
`Dysfunction," Urology, 49:822-830 (1997)
`Laumann, E.O., et al., "Sexual Dysfunction in the United States,"
`1011
`JAMA, 281:537-544 (1999)
`1012 Halvorsen, J.G., and Metz, M.E., "Sexual Dysfunction, Part I:
`Classification, Etiology, And Pathogenesis," JABFP, 5:51-61 (1992)
`1013 Goldstein, I., et al., "Oral Sildenafil in the Treatment of Erectile
`Dysfunction," N. Engl. J. Med., 338:1397-1404 (1998)
`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," Bioorg. Med.
`Chem. Lett., 6:1819-1824 (1996)
`Daugan, A.C-M.,, "Tetracyclic Derivatives, Process of Preparation
`and Use," Int'l Pub. No. WO 95/19978 (filed Jan. 19, 1995;
`published July 27, 1995)
`VIAGRA® Approved Label, 69-5485-00-2, Revised November
`1998, downloaded from the Food and Drug Administration website
`http://www.accessdata.fda.gov/drugsatfda_docs/label/1998/viagrala
`bel2.pdf, last accessed February 18, 2016
`Licht, M.R., "Sildenafil (Viagra) for treating male erectile
`dysfunction," Curr. Drug Ther., 65:301-304 (1998)
`Gingell, C.J.C., et al., "A New Oral Treatment for Erectile
`Dysfunction: A Double-Blind, Placebo-Controlled, Once Daily
`Dose Response Study," J. Urology, 155(Suppl 5):495A, Abstract
`No. 738 (1996)
`de Mey, C., "Opportunities for the Treatment of Erectile
`Dysfunction by Modulation of the NO Axis-Alternatives to
`Sildenafil Citrate," Curr. Med. Res. Opin., 14:187-202 (1998)
`"Lilly/ICOS Joint Venture's PDE5 to Treat Sexual Dysfunction,"
`1020
`Worldwide Biotech, 11(10), pp. 1-2, November 1998
`1021 Michaels, P., "Biotech's Drug Pipeline Ready To Rupture," The
`
`1009
`
`1010
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
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`Inter Partes Review of USPN 6,943,166
`Declaration of Wayne J.G. Hellstrom, M.D., FACS (INX1005)
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`Description
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`Inter Partes Review of USPN 6,943,166
`Declaration of Wayne J.G. Hellstrom, M.D., FACS (INX1005)
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`IntelGenX
`Exhibit #
`
`Description
`
`1022
`
`1023
`1024
`
`1026
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`New America, Investor's Business Daily, p. A7, April 23, 1999
`Edelhart, C., "Lilly venture to create impotency pill, Firm will team
`up with drugmaker in Seattle to create drug to rival Viagra.," The
`Indianapolis Star, pp. D1-D2, October 2, 1998
`COLOR ATLAS OF PHARMACOLOGY, pp. 44-57 (Lüllmann, H., et al.,
`eds., 1993)
`File History for U.S. Patent No. 6,943,166
`Sybertz, E., and Czarniecki, M., "Inhibitors of PDE1 and PDE5
`cGMP phosphodiesterases: patents and therapeutic potential,"
`Expert Opin. Ther. Pat., 7:631-639 (1997)
`Padma-Nathan, H., "Efficacy and Tolerability of Tadalafil, a Novel
`Phosphodiesterase 5 Inhibitor, in Treatment of Erectile
`Dysfunction," Am. J. Cardiol., 92:19M-25M (2003)
`CIALIS® Approved Label, Reference ID: 3820620, Revised
`September 2015, downloaded from the Food and Drug
`Administration website
`http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021368s
`026lbl.pdf, last accessed February 18, 2016
`Nies, A.S., "Principles of Therapeutics" in GOODMAN AND GILMAN'S
`THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Ch. 4, pp. 62-83
`(Gilman, A.G., et al., eds., 8th Ed. 1990)
`Babb, J., et al., "Cancer Phase I Clinical Trials: Efficient Dose
`Escalation with Overdose Control," Statist. Med., 17:1103-1120
`(1998)
`Oates, J.A. and Wilkinson, G.R., "Principles of Drug Therapy," in
`HARRISON'S PRINCIPLES OF INTERNAL MEDICINE, Ch. 66, pp. 393-
`412 (Isselbacher, K.J., et al.,Eds., 13th Ed. 1994)
`THE MERCK MANUAL OF MEDICAL INFORMATION, Ch. 5, pp. 23-27
`(Berkow, R., et al., Eds., Home Edition 1997)
`Bourne, H.R. and Roberts, J.M., "Drug Receptors &
`Pharmacodynamics," in BASIC & CLINICAL PHARMACOLOGY, Ch. 2,
`pp. 9-32 (Katzung, B.G., ed., 6th Ed. 1995)
`Graham, M.A., and Workman, P., "The impact of
`pharmacokinetically guided dose escalation strategies in phase I
`clinical trials: Critical evaluation and recommendations for future
`studies," Ann. Oncol., 3:339-347 (1992)
`
`- 12 -
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`

`
`
`
`
`
`IntelGenX
`Exhibit #
`
`Inter Partes Review of USPN 6,943,166
`Declaration of Wayne J.G. Hellstrom, M.D., FACS (INX1005)
`
`Description
`
`1036
`
`1037
`
`1038
`
`1040
`
`1041
`
`1042
`
`1043
`
`Piantadosi, S., and Liu, G., "Improved Designs for Dose Escalation
`Studies Using Pharmacokinetic Measurements," Stat. Med.,
`15:1605-1618 (1996)
`Rinaldi, D.A., et al., "Initial Phase I Evaluation of the Novel
`Thymidylate Synthase Inhibitor, LY231514, Using the Modified
`Continual Reassessment Method for Dose Escalation," J. Clin.
`Oncol., 13:2842-2850 (1995)
`"What's hot Impotency drugs," Discount Store News, p. 35, June 22,
`1998
`"Guideline for Industry Dose-Response Information to Support
`Drug Registration," ICH-E4, November 1994, downloaded from the
`Food and Drug Administration website
`http://www.fda.gov/downloads/drugs/guidancecomplianceregulator
`yinformation/guidances/ucm073115.pdf, last accessed February 18,
`2016
`Morales, A., et al., "Clinical safety of oral sildenafil citrate
`(VIAGRATM) in the treatment of erectile dysfunction," Int'l J.
`Impot. Res., 10:69-74 (1998)
`Zippe, C.D., et al., "Treatment of Erectile Dysfunction After
`Radical Prostatectomy with Sildenafil Citrate (Viagra)," Urology,
`52:963-966 (1998)
`Svejgaard, E., "Double-Blind Trial of Miconazole in
`Dermatomycosis," Acta Dermatovener, 53:497-500 (1973)
`
`V.
`
`Person of ordinary skill in the art
`I understand that a person of ordinary skill in the art ("POSA") is a
`28.
`
`hypothetical person who is presumed to be aware of all pertinent art, thinks along
`
`conventional wisdom in the art, and is a person of ordinary creativity. I have
`
`reviewed the '166 patent claims and specification, and in my opinion, a POSA
`
`would typically have had an M.D. specializing in urology, including sexual
`
`dysfunction, with at least about two years of experience in clinical pharmacology;
`
`
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`- 13 -
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`
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`
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`a Ph.D. in chemistry, pharmacology, or in a related field in the biological or
`
`Inter Partes Review of USPN 6,943,166
`Declaration of Wayne J.G. Hellstrom, M.D., FACS (INX1005)
`
`chemical sciences, and at least about two years of experience in clinical
`
`pharmacology; or a Master's degree in chemistry, pharmacology, or in a related
`
`field in the biological or chemical sciences, and at least about five years of
`
`experience in clinical pharmacology.
`
`29. A POSA typically would have worked as part of a multidisciplinary
`
`team and drawn upon not only his or her own skills, but also taken advantage of
`
`certain specialized skills of others in the team to solve a given problem. For
`
`example, a physician having experience in treating sexual dysfunction may have
`
`been part of the team that includes Ph.D. or Master's level artisans described
`
`above. Before April 30, 1999, I personally worked on such multidisciplinary
`
`teams. As of April 30, 1999, the state of the art included the teachings provided
`
`by the references discussed in this declaration. Additionally, a POSA would have
`
`been aware of other
`
`important
`
`information and references relating
`
`to
`
`phosphodiesterase 5 inhibitors and the treatment of sexual dysfunction.
`
`VI. The '166 patent
`I understand that this declaration is being submitted together with a
`30.
`
`petition for inter partes review of claims 1-12 of the '166 patent.
`
`31.
`
`I have considered the disclosure of the '166 patent in light of general
`
`knowledge in the art and the teachings of the scientific literature before the
`
`
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`- 14 -
`
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`
`
`
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`earliest possible priority date of the '166 patent, which I understand to be April
`
`Inter Partes Review of USPN 6,943,166
`Declaration of Wayne J.G. Hellstrom, M.D., FACS (INX1005)
`
`30, 1999.
`
`32. The
`
`'166 patent
`
`is directed generally
`
`to
`
`the
`
`field of
`
`phosphodiesterase (PDE) inhibitors, and more specifically to methods of using
`
`cyclic guanosine 3',5'-monophosphate specific phosphodiesterase type 5 (PDE-5)
`
`inhibitors for treating sexual dysfunction. INX1001, 1, Abstract. Independent
`
`claim 1 of the '166 patent is directed to a method of treating sexual dysfunction
`
`comprising orally administering a unit dose containing from about 1 mg to about
`
`20 mg of a compound having the structure
`
`,
`
`which is referred to as "Compound (I)" and has the chemical names (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
`
`and
`
`(6R-trans)-6-(1,3-benzodioxol-5-yl)-
`
`2,3,6,7,12,12a-hexahydro-2-methylpyrazino-[1',2':1,6]pyrido[3,4-b]indole-1,4-
`
`dione. INX1001, 2:25-28, 2:58-63, 5:32-47, 14:65 to 15:17. This compound is
`
`
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`

`
`
`
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`also known as tadalafil. INX1029, 111. Claim 1 encompasses administering any
`
`Inter Partes Review of USPN 6,943,166
`Declaration of Wayne J.G. Hellstrom, M.D., FACS (INX1005)
`
`dose between 1 and 20 mg, in single or multiple doses, once or more per day, to
`
`treat sexual dysfunction in both men and women. See INX1001, 14:65 to 15:17.
`
`Dependent claims 2-12 further narrow the dose range of tadalafil or add
`
`additional limitations to the method, such as treating a specific form of sexual
`
`dysfunction, requiring once per day administration, or specifying the formulation
`
`of tadalafil. INX1001, 15:18 to 16:20.
`
`33. The '166 patent specification acknowledges that several tetracyclic
`
`compounds, including tadalafil, were known in the art as potent inhibitors of
`
`PDE-5. INX1001, 2:12-21. The '166 patent specification further acknowledges
`
`that both the use of these compounds to treat sexual dysfunction, and dosage
`
`forms containing between 0.2 to 400 mg of these compounds, were known in the
`
`art. INX1001, 2:12-21.
`
`34. According to the file history of the '166 patent, (INX1024), ICOS
`
`submitted two declarations from Dr. Gregory Sides to the USPTO during
`
`
`1 INX1029 is a true and correct copy of a document entitled "CIALIS®
`
`Approved Label," which I downloaded from the Food and Drug Administration's
`
`website,
`
`http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021368s
`
`026lbl.pdf.
`
`
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`
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`prosecution. Dr. Sides' declarations pertained to clinical data, including data
`
`Inter Partes Review of USPN 6,943,166
`Declaration of Wayne J.G. Hellstrom, M.D., FACS (INX1005)
`
`related to the efficacy and side effects of various tadalafil doses. INX1024, 615-
`
`620, 860-864. Dr. Sides' first declaration alleged that a decrease in dosage of
`
`tadalafil resulted in a decrease in side effects. INX1024, 615-620. Dr. Sides'
`
`second declaration disclosed data regarding therapeutic efficacy of 20 and 50 mg
`
`doses of tadalafil. INX1024, 860-864. As I discuss in more detail in Section X.C.,
`
`I disagree with Dr. Sides' conclusions that ICOS' data would have been surprising
`
`and unexpected to a POSA. Nor would a POSA have considered ICOS' data
`
`superior over the closest prior art.
`
`VII. Claim construction
`I understand that terms of the claims are to be given their broadest
`35.
`
`reasonable interpretation in light of the language of the claims and the
`
`specification of the '166 patent.
`
`36.
`
`"Compound Having the Structure . . ." Claim 1 recites a method of
`
`treating sexual dysfunction with a compound having the following structure:
`
`
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`

`
`
`
`
`INX1001, 14:65 to 15:17. The specification of the '166 patent states that "[t]he
`
`Inter Partes Review of USPN 6,943,166
`Declaration of Wayne J.G. Hellstrom, M.D., FACS (INX1005)
`
`present
`
`invention provides a pharmaceutical dosage
`
`form
`
`for human
`
`pharmaceutical use, comprising about 1 to about 20 mg 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 in a unit dosage form suitable for oral
`
`administration." INX1001, 2:58-63. The specification also states that this
`
`compound
`
`is
`
`"alternatively
`
`named
`
`(6R-trans)-6-(1,3-benzodioxol-5-yl)-
`
`2,3,6,7,12,12a-hex