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
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`U.S. Patent No. 6,943,166
`_____________________
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`Inter Partes Review Case No. Unassigned
`_____________________
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`DECLARATION OF DOUGLAS REID PATTERSON, D.V.M, PH.D
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`_____________________
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`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 DOUGLAS REID PATTERSON, D.V.M, PH.D
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`Inter Partes Review of USPN 6,943,166
`Declaration of Douglas Reid Patterson, D.V.M., Ph.D. (INX1007)
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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 .......................... 8
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`V.
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`Person of ordinary skill in the art ..................................................................10
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`VI. The '166 patent ...............................................................................................11
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`VII. Dose optimization before April 30, 1999 ......................................................13
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`VIII. The Daugan '675 application .........................................................................19
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`IX. No unexpectedly superior results ..................................................................20
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`A.
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`The efficacy and side effects data discussed in the Sides
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`declarations and the '166 patent would not have been
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`surprising to a POSA ........................................................................... 22
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`1.
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`A POSA would not have been surprised by the side
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`effects data discussed in the first Sides declaration ..................22
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`2.
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`A POSA would not have been surprised by the
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`efficacy data discussed
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`in
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`the second Sides
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`declaration and the '166 patent..................................................24
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`B.
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`ICOS' data is not superior over the closest prior art ........................... 28
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`Inter Partes Review of USPN 6,943,166
`Declaration of Douglas Reid Patterson, D.V.M., Ph.D. (INX1007)
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`C.
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`The evidence provided by ICOS during prosecution of the
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`'166 patent is not equal in scope to the claims .................................... 29
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`X.
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`Conclusion .....................................................................................................31
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`Inter Partes Review of USPN 6,943,166
`Declaration of Douglas Reid Patterson, D.V.M., Ph.D. (INX1007)
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`I, Douglas Reid Patterson, DVM, Ph.D, 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 $350 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 Douglas Reid Patterson, D.V.M., Ph.D. (INX1007)
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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, Abstract. The methods of the
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`'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, and
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`knowledge in the relevant art. In formulating my opinions, I have also considered
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`the viewpoint of a person of ordinary skill in the art ("POSA") (i.e., a person of
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`ordinary skill in the field of chemistry, pharmacology, or in a related field in the
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`biological or chemical sciences defined further below in Section V) before April
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`30, 1999.
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`II. My background and qualifications
`I am an expert in the fields of clinical pharmacology, preclinical drug
`6.
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`development, and toxicology, and I have been an expert in these fields since
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`before April 30, 1999. I am currently the President of Reid Patterson Consulting,
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`Inc. I obtained a Bachelor of Science degree from Texas A&M University in
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`Inter Partes Review of USPN 6,943,166
`Declaration of Douglas Reid Patterson, D.V.M., Ph.D. (INX1007)
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`1968, a Doctor of Veterinary Medicine degree from Texas A&M University in
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`1969, and a Ph.D. in comparative pathology from the University of Missouri in
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`1976. I was a resident in laboratory animal medicine at the University of Missouri
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`from 1971-1975. I was board certified as a Diplomate by the American College of
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`Laboratory Animal Medicine in 1976, the American College of Veterinary
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`Pathologists in 1978, and the American Board of Toxicology in 1981. I was also
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`recognized as a Fellow by the Academy of Toxicological Sciences in 2000 and by
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`the International Academy of Toxicologic Pathology in 2001.
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`7.
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`I served as a pathologist in and Head of the Department of Pathology
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`at Hazelton Labs, Europe, from 1975-1978 and 1978-1980, respectively. I
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`subsequently served as Director in the Department of Medicine at Hazelton Labs,
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`America from 1980-1981. I served as Supervisor in Pathology, Teratology &
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`Reproductive Toxicology at Shell Development Co. from 1981-1984. I was also
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`the Director of Pathology/Toxicology and of the Division of Drug Safety and
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`Evaluation at Abbot Laboratories from 1984-1987 and 1987-1990, respectively. I
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`then served as Head of the Neuroscience Venture, Divisional Vice President of
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`Drug Safety Evaluation, and Divisional Vice President of Global Preclinical
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`Safety at Abbot Laboratories from 1992-1993, 1991-2001, and 2001-2003,
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`respectively.
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`Inter Partes Review of USPN 6,943,166
`Declaration of Douglas Reid Patterson, D.V.M., Ph.D. (INX1007)
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`8.
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`I am currently the President of Reid Patterson Consulting, Inc. and
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`have held this position since 2003.
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`9. My full background is detailed in my curriculum vitae. INX1008.
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`10.
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`I have significant experience with drug development and toxicologic
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`pathology. While at Abbot Laboratories, I directed clinical development of new
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`drug candidates, and I led up to 400 people in toxicology, pathology, comparative
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`medicine, metabolism, pharmacokinetics, analytical chemistry, and drug analysis.
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`I also have experience managing pathology and reproductive toxicology in the
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`petrochemical industry. I have been directly involved in 25 successful new drug
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`applications with small molecules and biologicals for numerous indications.
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`11.
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`I have received several honors in my career, including the
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`Doerenkamp-Zbinden Honour Award in 2009 from the Doerenkamp-Zbinden
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`Foundation in Switzerland, the 2009 CAAT Recognition Award from Johns
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`Hopkins University, the Distinguished Alumnus Award from Texas A&M
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`College of Veterinary Medicine in 2006, and Abbott's PPD R&D Champion
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`Award in 1990. I have served as an officer for many different professional
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`organizations, including President of the American College of Veterinary
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`Pathologists, President of the Society for Toxicologic Pathologists, President of
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`the Regulatory and Safety Evaluation and founding President of the Exploratory
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`and Toxicologic Pathology Subsections of the Society of Toxicology, and Board
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`of Directors for the Charles L. Davis, D.V.M. Foundation for Advancement in
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`Inter Partes Review of USPN 6,943,166
`Declaration of Douglas Reid Patterson, D.V.M., Ph.D. (INX1007)
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`Veterinary Pathology.
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`12. During my nearly 36 years of experience in pharmaceutical research
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`and development, preclinical drug development, and toxicology, I have authored
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`or co-authored numerous scientific articles, a book chapter, and abstracts. I have
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`also been an invited speaker for scientific and regulatory presentations, including
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`57 presentations with the Food and Drug Administration (FDA). Each
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`publication, abstract, and presentation is listed in my curriculum vitae, INX1008.
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`13. Accordingly, I am an expert in the fields of clinical pharmacology,
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`preclinical drug development, and toxicology and have been an expert since
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`before April 30, 1999.
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`III. Summary of opinions
`In this declaration, I consider the methods of treating sexual
`14.
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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. I also considered the file history of the '166 patent (INX1024), including
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`the Declarations of Dr. Gregory D. Sides (INX1024, 615-620, 860-864) and the
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`data cited therein. I understand that ICOS submitted the Sides Declarations to the
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`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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`Inter Partes Review of USPN 6,943,166
`Declaration of Douglas Reid Patterson, D.V.M., Ph.D. (INX1007)
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`15.
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`I understand from the prosecution history of the '166 patent that
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`ICOS alleged that the claimed methods provided "unexpected results" because
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`administering a lower dose of tadalafil resulted in lower side effects without a
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`loss of efficacy. INX1024, 543-544. I disagree that these results would have been
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`surprising or unexpectedly superior.
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`16. First, ICOS' data do not show any unexpected results over the prior
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`art. Before April 30, 1999, artisans routinely used dose-response curves to
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`identify a drug's optimal therapeutic dose range. Using routine dose-response
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`curves, a POSA would have known that drug doses at the top of the curve provide
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`comparable therapeutic efficacy, while doses along the shoulder and slope of the
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`curve provide dose-dependent therapeutic efficacy. Here, ICOS' tadalafil data and
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`the Sides declarations show nothing more than data points from a routine dose-
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`response curve. A POSA would not have been surprised that the data show a
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`dose-dependent decrease in side effects from a 100 mg dose to a 2 mg dose,
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`comparable efficacy for doses at the top of the dose response curve (e.g., 20 mg
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`and 50 mg), and dose-dependent decrease in therapeutic efficacy for doses along
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`the shoulder and slope of the curve. INX1024, 619-620, 863-864; INX1001, 14:1-
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`16, 14:22-37.
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`17. Second, ICOS' data and the Sides declarations do not show that the
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`results are unexpectedly superior over the closest prior art. The prior art
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`specifically discloses methods of treating sexual dysfunction using a range of
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`Inter Partes Review of USPN 6,943,166
`Declaration of Douglas Reid Patterson, D.V.M., Ph.D. (INX1007)
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`tadalafil doses, 0.2-400 mg, encompassing the individual doses listed in the Sides
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`declarations and the '166 patent. INX1002, 5. Given the teachings in the prior art,
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`ICOS's data are neither surprising nor are the data superior over the disclosures in
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`the prior art. Again, the data in the '166 patent and the Sides declarations are
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`nothing more than data points from a routine dose-response curve. INX1040, 2, 5,
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`13. See INX1030, 68-69, Figure 4-3; INX1034, 27-28. Thus, ICOS' therapeutic
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`efficacy and side effects data are not superior over the closest prior art.
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`18. Third, the alleged evidence of unexpectedly superior results is not
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`equal in scope to the claims of the '166 patent. The '166 patent claims encompass
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`administering single or multiple doses containing between 1 and 20 mg of
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`tadalafil, once or more per day, to treat sexual dysfunction in both men and
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`women. See INX1001, 14:65 to 15:20. However, ICOS relied on data from the
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`administration of a single, 20 mg dose of tadalafil, to male patients with erectile
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`dysfunction, on-demand, not more than once per day. INX1001, 12:65 to 13:9
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`and 14:1-16. These data fail to show unexpectedly superior results for the claimed
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`range of about 1 to about 20 mg, which includes doses 10- and 20-times lower
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`than the single 20 mg data point in ICOS's allegedly "unexpected" data. Likewise,
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`these data do not support daily administration of tadalafil and fail to address an
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`entire half of the population, showing no support for treating female arousal
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`Inter Partes Review of USPN 6,943,166
`Declaration of Douglas Reid Patterson, D.V.M., Ph.D. (INX1007)
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`disorder.
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`19. Accordingly, ICOS did not present sufficient data to show
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`unexpected or surprising results for the full scope of the methods claimed in the
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`'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
`20.
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`documents cited herein, including those listed below.
`
`IntelGenX
`Exhibit #
`
`Description
`
`1001
`
`1002
`
`1009
`
`1023
`1024
`
`1028
`
`Pullman, W. E.., et al., "Compositions Comprising
`Phosphodiesterase [Inhibitors] for the Treatment of Sexual
`Disfunction," U.S. Patent No. 6,943,166 (filed on April 26, 2000;
`issued on September 13, 2005)
`Daugan, A.C-M.,, "Use of cGMP-Phosphodiesterase Inhibitors to
`Treat Impotence," Int'l Pub. No. WO 97/03675 (filed July 11, 1996;
`published February 6, 1997)
`1008 Dr. Douglas Reid Patterson's Curriculum Vitae
`Boolell, M., et al., "Sildenafil: an orally active type 5 cyclic GMP-
`specific phosphodiesterase inhibitor for the treatment of penile
`erectile dysfunction," Int. J. Impot. Res., 8:47-52 (1996)
`COLOR ATLAS OF PHARMACOLOGY, pp. 44-57 (Lüllmann, H., et al.,
`eds., 1993)
`File History for U.S. Patent No. 6,943,166
`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
`
`1029
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`Inter Partes Review of USPN 6,943,166
`Declaration of Douglas Reid Patterson, D.V.M., Ph.D. (INX1007)
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`IntelGenX
`Exhibit #
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`Description
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`1030
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`1031
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`1032
`
`1033
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`1034
`
`1035
`
`1036
`
`1037
`
`1040
`
`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)
`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)
`"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
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`Inter Partes Review of USPN 6,943,166
`Declaration of Douglas Reid Patterson, D.V.M., Ph.D. (INX1007)
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`V.
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`Person of ordinary skill in the art
`I understand that a person of ordinary skill in the art ("POSA") is a
`21.
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`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
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`reviewed the '166 patent claims and specification, and in my opinion, a POSA
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`would typically have had an M.D. specializing in urology, including sexual
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`dysfunction, with at least about two years of experience in clinical pharmacology;
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`a Ph.D. in chemistry, pharmacology, or in a related field in the biological or
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`chemical sciences, and at least about two years of experience in clinical
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`pharmacology; or a Master's degree in chemistry, pharmacology, or in a related
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`field in the biological or chemical sciences, and at least about five years of
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`experience in clinical pharmacology.
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`22. A POSA typically would have worked as part of a multidisciplinary
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`team and drawn upon not only his or her own skills, but also taken advantage of
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`certain specialized skills of others in the team to solve a given problem. For
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`example, a physician having experience in treating sexual dysfunction may have
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`been part of the team that includes Ph.D. or Master's level artisans described
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`above. Before April 30, 1999, I personally worked on such multidisciplinary
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`teams. As of April 30, 1999, the state of the art included the teachings provided
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`by the references discussed in this declaration. Additionally, a POSA would have
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`been aware of other
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`Inter Partes Review of USPN 6,943,166
`Declaration of Douglas Reid Patterson, D.V.M., Ph.D. (INX1007)
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`important
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`information and references relating
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`to
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`phosphodiesterase 5 inhibitors and the treatment of sexual dysfunction.
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`VI. The '166 patent
`I understand that this declaration is being submitted together with a
`23.
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`petition for inter partes review of claims 1-12 of the '166 patent.
`
`24.
`
`Independent claim 1 of the '166 patent is directed to a method of
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`treating sexual dysfunction comprising orally administering a unit dose
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`containing from about 1 mg to about 20 mg of a compound having the structure
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`,
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`which is referred to as "Compound (I)" and has the chemical names (6R,12aR)-
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`2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)pyrazino[2',1':
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`6,1]pyrido[3,4-b]indole-1,4-dione
`
`and
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`(6R-trans)-6-(1,3-benzodioxol-5-yl)-
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`2,3,6,7,12,12a-hexahydro-2-methylpyrazino-[1',2':1,6]pyrido[3,4-b]indole-1,4-
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`dione. INX1001, 2:25-28, 2:60-62, 5:32-47, and 14:65 to 15:17. This compound
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`is also known as tadalafil. INX1029, 111. Claim 1 encompasses administering any
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`Inter Partes Review of USPN 6,943,166
`Declaration of Douglas Reid Patterson, D.V.M., Ph.D. (INX1007)
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`dose between 1 and 20 mg, in single or multiple doses, once or more per day, to
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`treat sexual dysfunction in both men and women. See INX1001, 14:65 to 15:17.
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`Dependent claims 2-12 further narrow the dose range of tadalafil or add
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`limitations to the method, such as treating a specific form of sexual dysfunction,
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`requiring once per day administration, or requiring a specific formulation of
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`tadalafil. INX1001, 15:18 to 16:20.
`
`25.
`
`I have also reviewed the file history of the '166 patent. INX1024.
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`During prosecution of the '166 patent, ICOS submitted two declarations to the
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`USPTO from Dr. Gregory Sides. See INX1024, 615-620, 860-864. These
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`declarations pertained to clinical data, including data related to the efficacy and
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`side effects of various tadalafil doses. INX1024, 615-620, 860-864.
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`26. Dr. Sides' first declaration alleges that a decrease in tadalafil dosage
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`results in fewer side effects. INX1024, 615-620. Dr. Sides' second declaration
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`describes data regarding therapeutic efficacy of 20 and 50 mg doses of tadalafil.
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`1 INX1029 is a true and correct copy of a document entitled "CIALIS®
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`Approved Label," which I downloaded from the Food and Drug Administration's
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`website,
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`http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021368s
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`026lbl.pdf.
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`INX1024, 860-864. As I discuss in more detail in Section IX, I disagree with Dr.
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`Inter Partes Review of USPN 6,943,166
`Declaration of Douglas Reid Patterson, D.V.M., Ph.D. (INX1007)
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`Side's conclusions because the data provided in the declarations would not have
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`been surprising to a POSA, nor are they superior over the closest prior art.
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`VII. Dose optimization before April 30, 1999
`27. Before April 30, 1999, artisans optimized dosage for new drug
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`candidates during Phase 1 clinical trials. INX1031, 1103. To begin, artisans
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`routinely generated dose-response curves to identify the optimal therapeutic dose
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`range for a drug. INX1030, 68-69, Figure 4-3; INX1040, 5, 13. See also
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`INX1032, 404 and 406; INX1033, 26. For example, the industry-accepted ICH2
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`Guideline for Industry stated in 1994 that "[a]ssessment of dose-response should
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`be an integral component of drug development" and "[c]onducting dose-response
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`studies at an early stage of clinical development may reduce the number of failed
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`Phase 3 trials, speeding the drug development process and conserving
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`development resources." INX1040, 5, 73. A POSA would have known that dose-
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`2 ICH is the International Conference on Harmonisation of Technical
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`Requirements for the Registration of Pharmaceuticals for Human Use. INX1040,
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`1. The ICH Guideline for Industry would have provided guidance to a POSA on
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`accepted industry practices.
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`3 INX1040 is a true and correct copy of a document entitled " Guideline for
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`Industry Dose-Response Information to Support Drug Registration," which I
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`response curves measure physiological responses, such as therapeutic efficacy or
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`Inter Partes Review of USPN 6,943,166
`Declaration of Douglas Reid Patterson, D.V.M., Ph.D. (INX1007)
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`toxicity, to varying doses of drug. INX1030, 68-69, Figure 4-3; INX1034, 27-28.
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`See INX1032, 397, 404, 406; INX1040, 2, 13; INX1033, 26.
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`28. Before April 30, 1999, a POSA would have understood the concept
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`and the significance of identifying a drug's therapeutic ratio (also known as the
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`therapeutic index or therapeutic window), which is the margin between doses of
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`drug that provide therapeutic efficacy and doses that provide toxicity. INX1030,
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`68-69, Figure 4-3; INX1040, 2; INX1032, 394 and 404; INX1033, 26; INX1034,
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`29. As the ICH Guideline for Industry stated in 1994, "[w]hat is most helpful in
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`choosing the starting dose of a drug is knowing the shape and location of the
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`population (group) average dose-response curve for both desirable and
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`undesirable effects." INX1040, 2.
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`29. An example dose-response curve from the prior art is shown below:
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`downloaded
`from
`the Food
`and Drug Administration's website,
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`http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/
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`guidances/ucm073115.pdf.
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`Inter Partes Review of USPN 6,943,166
`Declaration of Douglas Reid Patterson, D.V.M., Ph.D. (INX1007)
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`INX1030, 69, Figure 4-3. In the above example, the curve labeled "hypnosis"
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`represents the therapeutic effect, which increases with dosage amount until a
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`peak, or maximum therapeutic efficacy occurs. INX1030, 69, Figure 4-3. The
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`curve labeled "death" represents the occurrence of side effects or adverse events,
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`which begin to increase once the maximum therapeutic efficacy is reached.
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`INX1030, 69, Figure 4-3. This particular sample curve measures the percentage
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`of individuals responding to a particular dose of the drug. INX1030, 69, Figure 4-
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`3. The therapeutic ratio, or index, is labeled as the margin between the therapeutic
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`effect curve and the side effects or adverse events curve. INX1030, 69, Figure 4-
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`3. See INX1034, 29.
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`30. When identifying a drug's optimal dose range for therapeutic
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`efficacy, a POSA would have sought to identify the top of the therapeutic dose-
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`response curve. See INX1030, 67-69, Figures 4-2 and 4-3; INX1040, 2, 13;
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`- 15 -
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`INX1032, 404; INX1023, 54. A POSA would have understood that when the top
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`Inter Partes Review of USPN 6,943,166
`Declaration of Douglas Reid Patterson, D.V.M., Ph.D. (INX1007)
`
`of the curve (maximum efficacy) is reached, additional increases in the dose
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`provide little to no benefit but may increase side effects. See INX1030, 67-69,
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`Figures 4-2 and 4-3; INX1040, 2, 13; INX1032, 396, 404, and 406; INX1023, 52,
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`54; INX1033, 26; INX1034, 27-28. For example, the ICH Guideline for Industry
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`specifically advised investigators to "[i]dentify a dose, or response (desirable or
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`undesirable), beyond which titration should not ordinarily be attempted because
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`of a lack of further benefit or an unacceptable increase in undesirable effects."
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`INX1040, 13.
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`31. Artisans routinely used dose escalation studies to generate dose-
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`response curves and identify a drug's therapeutic ratio. See INX1009, 49;
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`INX1035, 339-340; INX1040, 2. A POSA would have understood that dose-
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`escalation studies begin with a low starting dose and gradually increase the
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`dosage amount to a pre-defined endpoint. See INX1009, 49; INX1035, 339-340;
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`INX1036, 1605; INX1031, 1103; INX1037, 2844. For some drugs, such as highly
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`toxic cancer drugs, a POSA would have escalated the dose until reaching the
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`maximum tolerated dose (MTD) as the endpoint. INX1037, 2844; INX1035, 340.
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`For other types of drugs, a POSA would have escalated the dose until reaching
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`the top of the dose-response curve—i.e., maximum therapeutic efficacy—as the
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`endpoint. See INX1040, 2, 13; INX1009, 49-50. For example, Boolell reported an
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`"escalating single oral dose study" where oral doses of a PDE-5 inhibitor,
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`Inter Partes Review of USPN 6,943,166
`Declaration of Douglas Reid Patterson, D.V.M., Ph.D. (INX1007)
`
`sildenafil, were escalated from 1.25 mg to 90 mg, and then up to 200 mg in an
`
`extension study. INX1009, 49. Boolell stated that "[t]he main adverse events
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`reported [followed] doses of 90 mg and above . . . ." INX1009, 50-51.
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`Accordingly, generating dose-response curves based on dose-escalation studies
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`was routine practice before April 30, 1999. See INX1040, 2, 5, 13; INX1009, 49-
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`50; INX1035, 339-340; INX1037, 2844; INX1031, 1103-1104; INX1036, 1605-
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`1606.
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`32.
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`In general, a POSA would have known that "[t]he effect of a
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`substance depends on the amount administered, i.e., the dose." INX1023, 52.
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`Thus, a POSA would have understood that the amount of active ingredient in a
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`dosage form is a results-effective variable—i.e., that varying the amount of active
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`ingredient in a dosage form affects results such as therapeutic efficacy and
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`toxicity. INX1023, 52. See INX1030, 68-69, Figure 4-3; INX1032, 396 and 404.
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`A POSA would have known that increasing the dose of a drug can increase the
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`therapeutic efficacy. INX1023, 52. See INX1030, 68-69, Figure 4-3; INX1032,
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`396 and 404. However, if the drug's therapeutic ratio is small, an increase in
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`dosage can also result in an increase in side effects. INX1030, 68-69, Figure 4-3;
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`INX1032, 396, 404; INX1040, 2. See INX1023, 52. Therefore, depending on the
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`therapeutic ratio, a POSA would have understood that an increase in dosage of an
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`- 17 -
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`active ingredient can increase therapeutic efficacy, but can also increase toxicity
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`Inter Partes Review of USPN 6,943,166
`Declaration of Douglas Reid Patterson, D.V.M., Ph.D. (INX1007)
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`and the accompanying likelihood of side effects. See INX1030, 68-69, Figure 4-3;
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`INX1032, 396, 404 and 406; INX1033, 25; INX1023, 52.
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`33.
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` Accordingly, a POSA would have routinely utilized a dose-
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`escalation study and generated dose-response curves to identify the therapeutic
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`ratio and to determine the lowest dose of a drug that provides maximum
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`therapeutic efficacy while minimizing toxicity or side effects. See INX1040, 2, 5,
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`13.
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`34. When identifying the optimal dose range for therapeutic efficacy, a
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`POSA also would have considered a drug's in vitro potency, i.e., the drug's EC50
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`or IC50 values. INX1034, 27; INX1030, 67; INX1009, 50. A POSA would have
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`understood that potency is the amount of drug required to produce a specified
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`level of effect. INX1034, 27; INX1023, 54. The prior art taught that it was
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`standard practice to measure potency using in vitro IC50 (the concentration of
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`drug required for 50% inhibition of the target function) and EC50 (the
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`concentration of drug required to produce 50% of the maximal effect) values.
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`INX1034, 27; INX1009, 50; INX1002, 17. For example, Boolell tested several
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`doses of sildenafil for therapeutic efficacy in treating erectile dysfunction because
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`it was "a potent inhibitor of PDE5" having an IC50 value of 3.9 nM. INX1009, 50.
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`Also, Daugan '675 described tadalafil as a "potent" PDE5 inhibitor with an IC50 of
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`- 18 -
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`2 nM. INX1002, 1, 4, 17. As Katzung stated in 1994, "potency can largely
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`Inter Partes Review of USPN 6,943,166
`Declaration of Douglas Reid Patterson, D.V.M., Ph.D. (INX1007)
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`determine the administered dose of the chosen drug." INX1034, 27. Though a
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`drug's potency is not necessarily indicative of its in vivo therapeutic benefits, a
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`POSA would have understood that (i) "potency obviously affects drug dosage,"
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`and (ii) a drug's in vitro IC50 value is a useful measure of potency. INX1030, 67.
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`VIII. The Daugan '675 application
`35. PCT Application Publication No. WO 97/03675 to Daugan ("Daugan
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`'675") (INX1002) published on February 6, 1997, and is entitled "Use of cGMP-
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`Phosphodiesterase Inhibitors to Treat Impotence." I understand that Daugan '675
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`is prior art to the '166 patent.
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`36. Daugan '675 teaches a method of administering tadalafil to treat
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`sexual dysfunction in both men and women. INX1002, 4. According to Daugan
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`'675, tadalafil is a highly selective PDE-5 inhibitor that exhibits an IC50 value of 2
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`nM. INX1002, 17, Table 1. The methods of Daugan '675 utilize between 0.2-400
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`mg of tadalafil in different forms, such as a free drug, tablets, capsules, gelcaps,
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`and liquid preparations, that "may be administered orally" in "single or multiple
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`doses, once or several times per day." INX1002, 3, 5, 15. Daugan '675 also states
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`that "[o]ther doses may be prepared by altering the ratio of active ingredient to
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`excipient, the fill weight and if necessary changing the capsule size[]" and that
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`"higher or lower dosage ranges may be merited . . . ." INX1002, 5, 16. Thus, a
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`- 19 -
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`POSA would have understood that Daugan '675 discloses the oral administration
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`Inter Partes Review of USPN 6,943,166
`Declaration of Douglas Reid Patterson, D.V.M., Ph.D. (INX1007)
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`once or several times per day of 0.2-400 mg of tadalafil either alone or formulated
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`with other excipients to treat sexual dysfunction in both men and women. See
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`INX1002, 3-5, 14-16. Therefore, because it teaches every element of the methods
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`claimed in the '166 patent, I understand that Daugan '675 i
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