UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_______________
`
`MONOSOL RX, LLC
`Petitioner
`
`v.
`
`ICOS CORPORATION
`Patent Owner
`_______________
`
`Case: IPR2017-00412
`
`Patent 6,943,166
`_______________
`
`
`EXPERT DECLARATION OF ROGER WILLIAMS, M.D.
`REGARDING U.S. PATENT NO. 6,943,166
`
`
`
`
`
` 
`
`MonoSol 1010-0001
`
`MonoSol v. ICOS
`IPR2017-00412
`
`

`
` 
`
`Table of Contents
`
`
`INTRODUCTION AND SCOPE OF WORK ........................................................ 3 
`I. 
`PROFESSIONAL BACKGROUND ........................................................................... 4 
`II. 
`III.  BASIS FOR OPINION ....................................................................................................... 6 
`IV.  THE FIELD OF PDE5 INHIBITORS FOR TREATING SEXUAL
`DYSFUNCTION .................................................................................................................... 7 
`THE LAW OF ANTICIPATION AND OBVIOUSNESS .............................. 11 
`V. 
`VI.  THE ’166 PATENT ............................................................................................................ 15 
`A. 
`Specification and Admitted State of the Art .......................................................... 16 
`B. 
`Prosecution History ............................................................................................................ 18 
`VII.  INTERPRETATION OF THE ’166 CLAIMS AT ISSUE ............................ 28 
`A.  About 1 to about 20 mg..................................................................................................... 28 
`B. 
`Up to a maximum total dose of 20 mg per day ..................................................... 29 
`C.  Compound having the structure .................................................................................. 32 
`VIII.  LEVEL OF ORDINARY SKILL IN THE ART ................................................. 33 
`IX.  THE SCOPE AND CONTENT OF THE PRIOR ART .................................. 33 
`A.  U.S. Patent 5,859,006 (“Daugan ‘006”) .................................................................... 33 
`B. 
`PCT Application Daugan '675 ...................................................................................... 34 
`C.  U.S. Patent No. 6,140,329 (“Daugan ‘329”) ............................................................ 35 
`D. 
`Petition to Add Information ........................................................................................... 37 
`E.  Known Adverse Effects of PDE5 Inhibitors .......................................................... 37 
`F.  Market Need for Effective Drug at Lower Doses ................................................ 38 
`G.  Routine Optimization ........................................................................................................ 39 
`X.  ANALYSIS OF THE PRIOR ART ............................................................................ 42 
`A.  Claims 1-12 Are Obvious § 103(a) Over At Least Daugan ‘675 .................. 42 
`B.  Obvious to Try the Claimed Range ............................................................................ 63 
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`1
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`MonoSol 1010-0002
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`C.  Motivation to Use the Lower the Dose ...................................................................... 66 
`D.  Reasonable Expectation of Success for the Lower Dose ................................. 71 
`E. 
`No “Unexpected” Results ................................................................................................ 72 
`XI.  CONCLUSION ..................................................................................................................... 77 
`
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`2
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`MonoSol 1010-0003
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`I, Roger Williams, M.D., hereby declare and state as follows:
`I.
`
`INTRODUCTION AND SCOPE OF WORK
`
`1. My name is Roger Williams, M.D. I have been asked to provide my
`
`opinions by Petitioner MonoSol RX, LLC in this Inter Partes Review (“IPR”) as
`
`an expert in the relevant art.
`
`2.
`
`I have been asked to provide my opinions and views on the materials I
`
`have reviewed in this IPR related to U.S. Patent No. 6,943,166 (the “‘166 patent”)
`
`(Ex. 1001), and the scientific and technical knowledge regarding the same subject
`
`matter. I have been asked to consider what one of ordinary skill in the art would
`
`have understood from the ‘166 patent. I have also considered whether certain
`
`references disclose or suggest the features recited in the claims of the ‘166 patent.
`
`My opinions are set forth below.
`
`3. My opinions are guided by my appreciation of how a person of
`
`ordinary skill in the art would have understood the claims of the ‘166 patent at the
`
`time of the alleged invention, which I have been asked to initially assume is April
`
`30, 1999, the earliest filing date potentially attributable to the ‘166 patent.
`
`4.
`
`Based on my experience and expertise it is my opinion that certain
`
`references as discussed in detail below alone or in combination disclose or suggest
`
`all the features recited in the claims of the ‘166 patent, that any differences from
`
`these prior references are obvious, and that these claims combine well known
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` 
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`MonoSol 1010-0004
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`features to provide predictable results. Attached as Appendix A to this report is a
`
`detailed chart showing where each claim limitation is disclosed in the prior art.
`
`II.
`
`PROFESSIONAL BACKGROUND
`
`5.
`
`I earned a B.A. in Chemistry and Zoology from Oberlin College, and
`
`an M.D. from the University of Chicago School of Medicine 1967. I was Board
`
`Certified
`
`in Internal Medicine
`
`in 1972 and Board Certified
`
`in Clinical
`
`Pharmacology in 1991. From 2000 to 2014, I was the CEO and Chair, Council of
`
`Experts of the United States Pharmacopeial Convention (USP). From 1995 to
`
`2000, I was the Deputy Center Director for the Office of Pharmaceutical Science
`
`(CDER) at the United States Food and Drug Administration (FDA). I am
`
`currently an expert consultant and partner at NDA Partners, LLC.
`
`6.
`
`I have
`
`taught
`
`courses
`
`in
`
`Introductory Pharmacokinetics,
`
`Pharmacokinetics
`
`for Pharmaceutical Students, Pharmacology, Clinical
`
`Pharmacology and Therapeutics, and Clinical Drug Investigations.
`
`7.
`
`I am or have been a member of the American Medical Association,
`
`the American Society of Clinical Pharmacology and Therapeutics, American
`
`Association of Pharmaceutical Scientists, the American Association for the
`
`Advancement of Science, and the International Pharmaceutical Federation.
`
`8. With respect to the subject matter at issue in this IPR, I have extensive
`
`experience. I have coordinated and participated more than 100 clinical and related
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` 
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`MonoSol 1010-0005
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`investigations during my time as a clinical investigator at the University of
`
`California, San Francisco. I worked with many FDA and external topic experts to
`
`advance regulatory policy represented in guidances that covered clinical, clinical
`
`pharmacology, biopharmaceutics, microbiology, and chemistry, manufacturing and
`
`controls. During my time at FDA I helped set standards and otherwise engaged in
`
`a similar broad variety of topics, adding also experience in adverse event and other
`
`reporting programs, dietary supplements, verification programs akin to GMPs,
`
`compounded medicines, and general standards setting for chemical and biological
`
`medicines. My special expertise is understanding equivalence questions for drugs
`
`and biologics, which include a broad and detailed understanding of new drug
`
`development in Phases 1, 2, 3 and 4, with specific understanding of how to
`
`generate dose/response information for a new drug or biologic medicine. I have
`
`worked extensively in the International Council for Harmonization and the World
`
`Health Organization.
`
`9.
`
`The opinions set forth in this declaration are my own and I have no
`
`financial ties to the litigation.
`
`10.
`
`I am informed by counsel that the ’166 patent has been challenged in
`
`a related IPR proceeding brought by IntelGenx Corp. against ICOS Corp., Case
`
`IPR2016-00678, and that the Patent Trial and Appeal Board denied institution of
`
`the IPR. I am also informed that Eli Lilly has filed suit based on the ’166 patent
`
` 
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`5
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`MonoSol 1010-0006
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`against the following entities: Cipla USA, Inc., et al., Case No. 16-cv-1208,
`
`Aurobindo Pharma Ltd., et al., Case No. 16-cv-1121, Alembic Pharma., Ltd., et al.,
`
`Case No. 16-cv-1120, Mylan Pharma., Inc., 16-cv-1122, Actavis Laboratories UT,
`
`Inc., Case No. 16-cv-1119, Sun Pharmaceuticals Industries, Ltd., et al., Case No.
`
`16-cv-518, Teva Pharmaceuticals, USA, Inc., Case No. 16-cv-519, Zydus Pharma.
`
`(USA), Inc., Case No. 16-cv-520, Sun Pharma. Industries, Case No. 16-cv-1168,
`
`Teva Pharma. USA, Inc., Case No. 16-cv-1169, and Zydus Pharma. (USA) Inc.,
`
`Case No. 16-cv-1170 in the Eastern District of Virginia.
`
`11. Attached hereto as Appendix B is a copy of my curriculum vitae.
`
`III. BASIS FOR OPINION
`
`12. My opinions set forth in this declaration are based on my education,
`
`training, and experience as described above as well as the information pertaining to
`
`the ‘166 patent and other references described below.
`
`13.
`
`In preparing this declaration, I have reviewed the ‘166 patent,
`
`including its specification, figures, claims, and the relevant portions of the file
`
`history cited below. I have also reviewed several prior art patents and other
`
`publications. These include U.S. Patent 5,859,006 (Ex. 1002), U.S. Patent
`
`6,140,329 (Ex. 1003), U.S. Patent 6,087,362 (Ex. 1004), WO 9703675 (Ex. 1005),
`
`certain FDA correspondence, and peer-reviewed journals. I have also reviewed the
`
`other documents mentioned below.
`
` 
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`14. Attached hereto as Appendix C is a list of documents I reviewed.
`
`IV. THE FIELD OF PDE5 INHIBITORS FOR TREATING SEXUAL
`DYSFUNCTION
`
`15. The methods claimed in the ’166 patent were well-known in the art
`
`prior to its priority filing date of April 30, 1999 (also known as the critical date).
`
`The ’166 patent relates generally to a method of treating sexual dysfunction with
`
`tadalafil, a highly selective phosphodiesterase (PDE) enzyme inhibitors, in a
`
`specific dose. See, e.g., Ex. 1001 at Abstract.
`
`16. Erectile dysfunction was a well-known condition prior to the critical
`
`date. As of April 30, 1999, it was well known that a phosphodiesterase type 5
`
`(PDE5) inhibitor is a drug used to block the degradative action of cGMP-specific
`
`PDE5 on cyclic GMP in the smooth muscle cells lining the blood vessels supplying
`
`the corpus cavernosum.
`
`17. As of the critical date, it was well known that when incorporated into
`
`a pharmaceutical product, a PDE5 inhibitor is useful for the treatment of sexual
`
`dysfunction. The inhibition of PDE5 enhances erectile function by increasing the
`
`amount of cGMP in the smooth muscle cells.
`
`18. An example of a pharmaceutical product which provides a PDE5
`
`inhibitor is Viagra®. The active ingredient in Viagra® is sildenafil. The product is
`
`sold is 25, 50, and 100 mg tablets of sildenafil. Ex. 1006, Viagra® label.
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`19. Another example of a pharmaceutical product that contains a PDE5
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`inhibitor is Cialis®. The active ingredient in Cialis® is tadalafil. Cialis® tablets
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`are sold in tadalafil strengths of 5mg, 10mg, 20mg. Ex. 1007, Cialis® label.
`
`20. Sildenafil and tadalafil (Cialis®) each share a common mechanism of
`
`action and are only pharmacologically active when cGMP synthesis is activated.
`
`They also share similar side effects. See Ex. 1008, D. Eros, et al., Structure-
`
`Activity Relationships of PDE5 Inhibitors, Current Medicinal Chemistry, 2008
`
`(15), 1570-1585. Sildenafil is known to have the desired pharmacologic effect for
`
`about 4-8 hours; tadalafil is known to have the desired pharmacologic effect for up
`
`to 36 hours. Id. at 1572.
`
`21. A chart comparing key attributes of sildenafil and tadalafil is provided
`
`below:
`
`
`Pharmaceutical
`Form
`Structural
`formula
`
`Cialis® (tadalafil)
`Viagra® (sildenafil)
`25mg, 50mg, 100mg tablets 5mg, 10mg, 20mg tablets
`
`Recommended
`dose
`
`50 mg, may be increased to
`100 mg or decreased to 25
`mg
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`10 mg, may be increased to
`20 mg or decreased to 5 mg
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`
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`Effective for
`4-6 hours
`Typical side
`facial flushing, headache,
`effects
`indigestion
`Contraindications Nitrates cause significant
`vasodilation and reduction
`of blood pressure
`
`Up to 36 hours
`headache, indigestion
`
`Nitrates cause significant
`vasodilation and reduction of
`blood pressure
`
`
`Source: Viagra® (sildenafil) label; Cialis® (tadalafil) label; D. Eros, et al.,
`Structure-Activity Relationships of PDE5 Inhibitors, Current Medicinal
`Chemistry, 2008 (15), 1570-1585.
`
`
`
`22. Before the critical date of April 30, 1999, sildenafil was known to be a
`
`potent and selective PDE5 inhibitor. Potency is commonly expressed as IC50, or
`
`the drug concentration required to reduce the activity of the tested PDE by 50%.
`
`Typically, the lower the value of the IC50, the higher the potency of the inhibitory
`
`agent. Sildenafil was known to have an IC50 between 3.5–3.9 nM. See Ex. 1003,
`
`Excerpt from Viagra Approval Pkg., Table 1. Tadalafil, was known to have an
`
`IC50 of 2 nM. See Daugan ‘675 at 17. Prior to the critical date, sildenafil was also
`
`known in the field to be effective at treating erectile dysfunction, and that it was
`
`administered orally. Ex. 1006. The same is true for tadalafil. See, e.g., Ex. 1002,
`
`U.S. Patent 5,859,006 at col. 2, lines 12-20.
`
`23.
`
`Indeed, it was known that sildenafil provides dose-dependent
`
`therapeutic efficacy over placebo in doses ranging from 5 mg to 100 mg. Viagra®
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`Label, at p. 2. Tadalafil was also known to provide dose-dependent therapeutic
`9
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`MonoSol 1010-0010
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`efficacy over placebo in doses ranging from 0.2-400 mg. See, e.g., U.S. Patent
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`5,859,006 at col. 2, lines 12-20 (describing its oral dosage forms of tadalafil of 0.2-
`
`400 mg).
`
`24. As acknowledged in the ‘166 patent, sildenafil was known to be
`
`commercially successful, but significant adverse side effects have limited the use
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`of sildenafil in patients suffering from vision abnormalities, hypertension, and,
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`most significantly, by individuals who use organic nitrates (citing Welds et al.,
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`Amer. J. of Cardiology, 83(5A), pp. 21(C)-28(C) (1999)).” Ex. 1001, col. 1, lines
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`58- 65.
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`25.
`
`It was widely known, prior to the critical date of April 30, 1999, that
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`use of sildenafil in patients taking organic nitrates caused “a clinically significant
`
`drop in blood pressure which could place the patient in danger.” Ex. 1001, col. 1,
`
`lines 66- col. 2, line 1.
`
`26. General side effects for sildenafil and tadalafil include vasodilation,
`
`vision related disturbance, increased heart rate, inhibition of platelet aggregation,
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`nasal congestion, headache, flushing, and dyspepsia. See Ex. 1008, D. Eros, et al.,
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`Structure-Activity Relationships of PDE5 Inhibitors, Current Medicinal Chemistry,
`
`2008 (15), 1570-1585.
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`27. Coadministration of PDE5 inhibitors with nitrates or NO generating
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`molecules is contraindicated because the coadministration causes significant
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`vasodilatation and reduction of blood pressure. Id.
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`V. THE LAW OF ANTICIPATION AND OBVIOUSNESS
`
`28.
`
`I have been informed by counsel, and I understand, that a patent claim
`
`can be invalid for any one of several reasons. Here, I will mention two of them,
`
`anticipation and obviousness. Both of these relate to “prior art,” which involves
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`information that existed at some time before the filing date of a patent application.
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`The printed publication prior art may include, for example, publications, or patents.
`
`29.
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`I understand that the description in a written prior art reference does
`
`not need to be in the same words as the claim, but all of the physical requirements
`
`of the claim must be present either explicitly or inherently. That is, features of the
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`claim must either be stated or implied so that someone of ordinary skill in the
`
`relevant field looking at that reference would be able to understand and use that
`
`information
`
`30.
`
`I understand that a patent claim is invalid as anticipated if all of the
`
`claim limitations exist in a single device that predates the claimed invention, or if
`
`all the claim limitations have been described in a single previous publication or
`
`patent that predates the claimed invention.
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`31.
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`I understand that a patent claim is invalid as obvious if the claimed
`
`invention would have been obvious to a person of ordinary skill in the art at the
`
`time the invention was made, which in the absence of earlier proof, is presumed to
`
`be the date the patent application was filed. I further understand that this means
`
`that even if all the requirements of the claim cannot be found in a single prior art
`
`reference, a person of ordinary skill in the art who knew or who had access to all of
`
`the relevant prior art could have arrived at the claimed invention by, for example,
`
`applying common sense to combine or rearrange the features of that prior art.
`
`32.
`
`I understand that as part of evaluating whether a patent claim would
`
`have been obvious, one must analyze the scope and content of the prior art, the
`
`differences between the prior art and what has been claimed in the patent, and the
`
`level of skill in the art. I further understand that when combining multiple prior art
`
`references to arrive at the claimed invention, one must determine whether there
`
`would have been a reason to combine those references. I understand that the
`
`reason may come from a variety of sources, including the prior art references
`
`themselves, design incentives, and problems that were known in the particular
`
`field.
`
`33.
`
`I further understand that in evaluating whether a claim would have
`
`been obvious, one must put himself or herself in the position of a person of
`
`ordinary skill in the art, i.e., the technical field of the invention. The person of
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`ordinary skill is a hypothetical concept, and while he is not considered an expert,
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`he is understood to think along the lines of conventional wisdom. At the same
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`time, I understand that a person of ordinary skill is also a person of ordinary
`
`creativity, not an automaton.
`
`34.
`
`I also understand that objective evidence relevant to the issue of
`
`obviousness must be evaluated. Such evidence, sometimes referred to as
`
`“secondary considerations,” may include evidence of commercial success, long-
`
`felt but unsolved needs, failure of others, and unexpected results. This evidence
`
`may be included in the specification as filed, accompany the application, or be
`
`provided in a timely manner at some other point during the prosecution.
`
`35.
`
`I understand
`
`that
`
`the current
`
`legal standard for determining
`
`obviousness is set forth in KSR International Co. v. Teleflex, Inc., a Supreme Court
`
`case decided on April 30, 2007. KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398
`
`(2007).
`
`36.
`
`I understand that before April 30, 2007, the legal standard for
`
`obviousness was more difficult to meet, meaning the obviousness standard for
`
`patentability was lower than it is after KSR. Specifically, a patent claim could only
`
`be proven obvious if the prior art revealed some teaching, motivation or suggestion
`
`to combine the prior art teachings. This was also known as the teaching,
`
`suggestion or motivation test (or the TSM test). Under that earlier standard, a
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`patent claim could not be proven obvious mere by showing that the combination of
`
`elements was “obvious to try.”
`
`37. However, the Supreme Court changed the standard for determining
`
`obviousness in April 30, 2007 in KSR. The obviousness analysis “cannot be
`
`confined by a formalistic conception of the words teaching, suggestion, and
`
`motivation, or by overemphasis on the importance of published articles and the
`
`explicit content of issued patents.” Id. at 418.
`
`38. Specifically, the Supreme Court held that:
`
`When there is a design need or market pressure to solve a problem and
`there are a finite number of identified, predictable solutions, a person of
`ordinary skill has good reason to pursue the known options within his or her
`technical grasp. If this leads to the anticipated success, it is likely the product
`not of innovation but of ordinary skill and common sense. In that instance
`the fact that a combination was obvious to try might show that it was
`obvious under § 103.”
`
`Id. at 420 (emphasis added).
`
`39. Put another way, I understand that for determining obviousness, one
`
`may also consider whether the invention was merely a predictable result of using
`
`prior art elements according to their known function. One may also consider
`
`whether there was a design need or market pressure to solve a problem, and
`
`whether there are a finite number of solutions a person of ordinary skill would
`
`have pursued based on the knowledge and skill in the art.
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`40. After the KSR holding of April 30, 2007, the obviousness analysis
`
`does not require express teachings, but may be based on the common sense,
`
`inferences, and creative steps expected of a person of ordinary skill in the art. One
`
`may also consider whether the claimed invention would have been obvious to try.
`
`41.
`
`In evaluating obviousness, I understand that a patent owner may also
`
`rely on objective indicia or evidence of commercial success, long-felt and unmet
`
`need, failure/skepticism of others, industry acclaim, unexpected results and
`
`copying in arguing non-obviousness. However, it is not sufficient that a product
`
`or its use merely be within the scope of a claim in order for objective evidence of
`
`nonobviousness tied to that product to be given substantial weight. There must also
`
`be a causal relationship, termed a "nexus," between the evidence and the claimed
`
`invention. Merck & Co., Inc. v. Teva Pharms. USA, Inc., 395 F.3d 1364, 1376[, 73
`
`U.S.P.Q.2d 1641] (Fed. Cir. 2005).
`
`42. Thus, if relying on any of the objective indicia above, the patent
`
`owner must establish (1) the objective evidence was reasonably commensurate in
`
`scope with the challenged claims, (2) the requisite nexus, and (3) whether the
`
`results in fact were unexpected. See, e.g., Phigenix, Inc. v. Immunogen, Inc.,
`
`IPR2014-00676.
`
`VI. THE ’166 PATENT
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`43.
`
`I have reviewed the overview of the ‘166 patent set forth in the
`
`Petition for IPR. The ’166 patent has one independent claim (claim 1), and 11
`
`dependent claims.
`
`44. The ‘166 patent is one of five U.S. patents directed to various aspects
`
`of orally administered tadalafil, under the brand name Cialis®. These patents
`
`include U.S. Patent 5,859,006 (claims a compound of tadalafil); U.S. Patent
`
`6,140,329 (claims a method of treating erectile dysfunction with tadalafil); U.S.
`
`Patent 6,821,975 (claims a free drug form of tadalafil); U.S. Patent 6,943,166 (the
`
`patent at issue); and U.S. Patent 7,182,958 (claims a pharmaceutical formulation of
`
`tadalafil).
`
`45. The ‘166 patent is directed to a method of administering a specific
`
`dose of tadalafil, namely “about 1 to about 20 mg unit dosage forms as needed,
`
`up to a maximum total dose of 20 mg per day”. See, e.g., Ex. 1001, claim 1.
`
`A.
`
`Specification and Admitted State of the Art
`
`46. Put simply, the ’166 patent addresses known problems in the art using
`
`known solutions. The ‘166 patent acknowledges that sexual dysfunction was a
`
`known disorder, and that PDE5 inhibitors were known to treat sexual dysfunction.
`
`Examples of such PDE5 inhibitors were sildenafil (Viagra® and tadalafil (as
`
`taught in U.S. Patent 5,859,006). Ex. 1001, col. 1, lines 58- col. 2, line 21.
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` 
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`47. The ‘166 patent also acknowledges that certain side effects limited
`
`sildenafil’s use in certain individuals. Ex. 1001, col. 1, lines 58- 65.
`
`48. The ‘166 patent further acknowledges that tadalafil was a known
`
`PDE5 inhibitor that did not have apparent “significant side effects” when orally
`
`administered in doses of 0.2-400 mg. Id. col. 2, lines 12-21 (emphasis added).
`
`49. The ’166 patent therefore attempts to describe tadalafil “in a unit dose
`
`that provides an effective treatment without the side effects associated with the
`
`presently marketed PDE5 inhibitor, sildenafil.” Id. at col. 2, lines 29-33. This
`
`“present invention provides a pharmaceutical unit dosage form of tadalafil with
`
`“instructions to administer one or more about 1 to about 20 mg unit dosage
`
`forms as needed, up to a maximum total dose of 20 mg per day.” Id. col. 4,
`
`lines 15-18 (emphasis added).
`
`50.
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`In short, the ’166 patent sought to address the known problems of
`
`sildenafil: side effects including vision abnormalities, hypotension, and, most
`
`significantly, hypotension in individuals who also use organic nitrates. Ex. 1001 at
`
`col. 2, lines 61-64.
`
`51. To solve these well-known problems, the applicants for the ’166
`
`patent provided a well-known solution: tadalafil, a known compound, known to be
`
`orally administered in doses from 0.2-400 mg in a daily dose, without “significant
`
`adverse side effects.” Id. at col. 2, lines 12-21.
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`17
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`B.
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`Prosecution History
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`52. The ’166 patent was originally filed with two independent claims: one
`
`directed to a composition including about 1 to about 20 mg of tadalafil, and one
`
`directed
`
`to a method of
`
`treating sexual dysfunction comprising orally
`
`administering tadalafil in one or more unit doses containing about 1 to about 20
`
`mg, up to a maximum total dose of 20 mg per day.
`
`53. While prosecuting the application that matured into the ‘166 patent, I
`
`understand that the patent Examiner initially rejected the claims over U.S. Patent
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`6,140,329 (“the ‘329 patent”), which is directed to treating sexual dysfunction with
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`tadalafil. See Ex. 1009, Pros. History, Office Action of 8-30-2002 at 2-3. The
`
`Examiner noted:
`
`“ ‘329 (column 3, lines 48-65, column 5, lines 60-65, claims 16-17) disclose
`the instant compound and a method of using it to treat sexual dysfunction. It
`further discloses oral administration and a dosage within the recited range.
`It also discloses that individual enantiomers may be prepared.”
`
`See Office Action of 8-30-2002 at 2-3
`
`54.
`
` Following that rejection, the Applicant apparently engaged in the
`
`Examiner interview, and the Examiner noted that she “will consider a showing of
`
`unexpected results to overcome the rejection under 35 U.S.C. 103(a). See
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`Examiner Interview Summary of 11-13-2002.
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`55. The applicants did not dispute the teachings of the ‘329 patent, and its
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`applicability to the claims. Rather, the applicant argued in response that “in view
`
`of the unexpected results demonstrated by the claimed compound at the claimed
`
`low dosage… this rejection is in error and should be withdrawn.” See Response of
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`2-10-2003, at 3-4. The applicant further argued that “although the ‘329 patent
`
`teaches a unit dosage for the disclosed compounds of 0.2 to 400 mg, administered
`
`once or several times per day, the ‘329 patent does not teach or suggest the low
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`maximum daily dose for effective treatment of sexual dysfunction.” Id. at 5. In
`
`that same response, the applicants amended the method claim to require “orally”
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`administering the drug.
`
`56. On August 26, 2003, the Applicants and the Examiner again
`
`conducted an interview, during which the Examiner “informed attorney for
`
`applicants that the composition claims are not allowable and that a showing of
`
`unexpected results commensurate in scope with the claims is required to
`
`overcome the prior art for the method claims.” See Examiner Interview
`
`Summary dated 9-17-2003 (referring to Aug. 26, 2003 Interview) (emphasis
`
`added).
`
`57.
`
`In response, the applicants canceled the composition claim and chose
`
`to pursue the method claim alone. See Amendment of 9-9-2003. The applicants
`
`argued that the “present claims recited a method of treating sexual dysfunction in a
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`patient in need thereof by the oral administration of a unit dosage composition
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`containing about 1 to about 20 of a specifically claimed compound, up to a
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`maximum total dose of 20 mg per day.” Id. at 5-6. The applicants explained that
`
`the
`
`“presently claimed invention provides unexpected benefits and is a
`substantial advance in the art. In particular, the presently claimed invention
`(a) effectively treats sexual dysfunction using a low dose of a particular
`PDE5 inhibitor, (b) eliminates or reduces various adverse side effects
`associated with current PDE5 inhibitor therapy used to treat sexual
`dysfunction, i.e., VIAGRA®, and (c) increases the population treatable for
`sexual dysfunction using a PDE5 inhibitor.”
`
`Id. at 5-6.
`
`58. The applicants argued that while the ‘329 patent “discloses” oral
`
`dosage forms over a range of 0.2-400 mg, “provided no teaching or suggestion of a
`
`preferred unit dose, except for the 50 mg dose in the examples. Thus, the lowest
`
`dose of the PDE5 inhibitor of embodied in the ‘329 patent in a unit dose
`
`composition is 50 mg of the active ingredient.” Id. at 6-7.
`
`59. The Examiner did not find the applicants’ arguments persuasive and
`
`maintained the rejections because the ‘329 patent “disclose[s] the instant
`
`compound and a method of using it to treat sexual dysfunction. It further discloses
`
`oral administration and a dosage with the recited range.” Office Action of 9-17-
`
`2003, at 2. The Examiner further explained that the ‘329 patent discloses at col. 3,
`
`lines 50-52, “a dose ranging from 0.5-800 mg, which includes the instant 1-20 mg.
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`20
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`In the absence of a showing of unexpected results comparing the 50 mg dose of
`
`Daugan with the upper dosage range of 20 mg of instant claim 13 [issued claim 1],
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`no unobviousness is seen in the dosage range of the instant claims.” Id. at 3.
`
`There is no dispute that the ‘329 patent also teaches that individual tablets or
`
`capsules can contain from “0.2-400 mg of active compound…for administration in
`
`single or multiple doses.” Col. 3, lines 53-54.
`
`60. On December 10, 2003, the applicants engaged in another Examiner
`
`Interview. The Examiner noted that “Attorneys for applicants will submit a
`
`Declaration under 37 CFR 1.132 which shows unexpected reduction of side effect
`
`at 20 mg when compared to the 50 mg dosage disclosed in Daugan. They will also
`
`submit a Terminal Disclaimer over 6,451,807. Examiner will consider a showing
`
`of unexpected results favorably.” See Examiner Interview Summary dated 12-10-
`
`2003.
`
`61. On January 15, 2004, the applicants submitted an affidavit from
`
`Gregory Sides, M.D., a physician employed by applicants Eli Lilly and Co. See
`
`Affidavit dated 1-15-2004. Dr. Sides described the invention as a “method of
`
`treating sexual dysfunction…which comprises orally administering to a patient in
`
`need thereof one or more unit dose containing about 1 to about 20 mg of
`
`Compound (I), up to a maximum total dose of 20 mg per day.” See Sides Affidavit
`
`at 4.
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`62. Dr. Sides explained that the “present invention is based on detailed
`
`experiments and clinical trials, and the unexpected discovery of a unit dosage form
`
`incorporating about 1 to about 20 mg of Compound (I) that, when orally
`
`administered, effectively treats sexual dysfunction and substantially reduces
`
`various undesirable adverse events.” Id. at 4.
`
`63. Dr. Sides further explained that the “new and surprisingly unexpected
`
`results achieved by the present invention are illustrated in Example 7 of the
`
`specification” and certain “Phase 3 clinical trials.” Id. at 5.
`
`64.
`
`In this Declaration, Dr. Sides refers to an “unexpected decrease in
`
`treatment-emergent adverse events in the table at page 32 of the specification,”
`
`which he notes were “corroborated” by eight Phase 3 studies for “placebo, 5 mg,
`
`10 mg and 20 mg doses.” Id. at 5. He explained that the “Phase 3 studies were
`
`conducted using 20 mg or lower doses because higher doses above 20 mg of
`
`Compound (I) had a sufficient number of adverse events such that the dose
`
`would have reduced tolerability to the genera