UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_______________
`
`AQUESTIVE THERAPEUTICS, INC.
`Petitioner
`
`v.
`
`ICOS CORP.
`Patent Owner
`_______________
`
`Case: IPR2018-01183
`
`Patent 6,943,166
`_______________
`
`
`EXPERT DECLARATION OF ROGER WILLIAMS, M.D.
`REGARDING U.S. PATENT NO. 6,943,166
`
`
`
`
`
` 
`
`ATI 1010-0001
`
`ATI v. ICOS
`IPR2018-01183
`
`

`

` 
`
`E. 
`F. 
`G. 
`H. 
`I. 
`J. 
`X. 
`A. 
`
`D. 
`E. 
`XI. 
`
`
` 
`
`Table of Contents
`INTRODUCTION AND SCOPE OF WORK ............................................................................ 2 
`I. 
`PROFESSIONAL BACKGROUND ............................................................................................ 3 
`II. 
`BASIS FOR OPINION ................................................................................................................. 5 
`III. 
`THE FIELD OF PDE5 INHIBITORS FOR TREATING SEXUAL DYSFUNCTION ....... 6 
`IV. 
`THE LAW OF ANTICIPATION AND OBVIOUSNESS ....................................................... 12 
`V. 
`THE ’166 PATENT ..................................................................................................................... 16 
`VI. 
`Specification and Admitted State of the Art ............................................................................... 17 
`A. 
`Prosecution History ..................................................................................................................... 18 
`B. 
`INTERPRETATION OF THE ’166 CLAIMS AT ISSUE ....................................................... 28 
`VII. 
`Up to a maximum total dose ....................................................................................................... 28 
`A. 
`Free drug ....................................................................................................................................... 29 
`B. 
`VIII.  LEVEL OF ORDINARY SKILL IN THE ART ....................................................................... 30 
`IX. 
`THE SCOPE AND CONTENT OF THE PRIOR ART ......................................................... 30 
`A. 
`U.S. Patent 5,859,006 (“Daugan ‘006”) ....................................................................................... 30 
`B. 
`PCT Application Daugan '675 ..................................................................................................... 31 
`C. 
`U.S. Patent No. 6,140,329 (“Daugan ‘329”) ................................................................................ 33 
`D. 
`
`Sildenafil Citrate (VIAGRA®) Approval Package for New Drug Application No. 020895
`(“SNDA”) ...................................................................................................................................... 34 
`Dose-Response Information to Support Drug Registration (“FDA Guideline”) .................... 39 
`Cutler Article ................................................................................................................................. 40 
`Ruberg Article ............................................................................................................................... 41 
`Known Adverse Effects of PDE5 Inhibitors ............................................................................... 42 
`Market Need for Effective Drug at Lower Doses ...................................................................... 43 
`Maximum Tolerated Dose ........................................................................................................... 43 
`ANALYSIS OF THE PRIOR ART ............................................................................................ 47 
`
`Ground 1: Claims 1-12 Are Obvious § 103(a) Over At Least Daugan ‘675, SNDA, and FDA
`Guideline ....................................................................................................................................... 47 
`Motivation to Use the Maximum Total Dose Of 20 Mg Per Day ............................................. 74 
`No “Unexpected” Results ........................................................................................................... 78 
`CONCLUSION ............................................................................................................................ 84 
`
`1
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`ATI 1010-0002
`
`

`

` 
`
`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 Aquestive Therapeutics, Inc., 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”)
`
`(EX1001), 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 features to
`
` 
`
`2
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`ATI 1010-0003
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`

`

` 
`
`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. I have authored and reviewed
`
`articles and literature on response relationships for both efficacy and toxicity, the drug
`
`development and regulatory processes and reviewing doses, including maximum
`
`tolerated doses, based on in vitro potency.
`
`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.
`3
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` 
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`ATI 1010-0004
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`

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`8. With respect to the subject matter at issue in this IPR, I have extensive
`
`experience. I have coordinated more than 100 clinical and related investigations
`
`during my time as a clinical investigator at the University of California, San Francisco.
`
`While at FDA, I worked with many internal 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 USP, I engaged in a similar broad variety of topics, adding also experience
`
`in adverse event and other reporting programs, dietary supplements, dietary
`
`supplement verification programs, compounded medicines, and general standards
`
`setting for chemical and biological medicines. My special expertise is in 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 (PTAB) denied
`
`institution of the IPR. I am also informed that Eli Lilly has filed suit based on the
`4
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` 
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`ATI 1010-0005
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`

`

` 
`
`’166 patent 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. I am also informed that Mylan Pharmaceuticals filed Case
`
`IPR2017-00323 against ICOS Corp. on November 22, 2016. The PTAB granted
`
`institution of the IPR. IPR2017-00323, Paper 12.
`
`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 (EX1002), U.S. Patent 6,140,329 (EX1003), U.S. Patent
`
`6,087,362 (EX1004), WO 9703675 (EX1005), certain FDA correspondence, and peer-
`
`reviewed journals. I have also reviewed the petition filed in IPR2017-00412, and the
`5
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` 
`
`ATI 1010-0006
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`

`

` 
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`PTAB decisions denying IPR (IPR2017-00412, Paper 11). I have also reviewed
`
`Mylan’s petition and the decision granting Mylan’s IPR (IPR2017-00323, Paper 12). I
`
`have also reviewed the other documents mentioned below.
`
`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., EX1001 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. The biological mechanism governing penile rigidity and its role in sexual
`
`dysfunctions such as erectile dysfunction was well known and well established in the
`
`art. For example, Boolell teaches that production of cyclic guanosine monophosphate
`
`(cGMP) causes relaxation of smooth muscle cells, which in turn results in penile
`
`rigidity. EX1023, Boolell, M., et al., Sildenafil: an orally active type 5 cyclic GMP-
`
`specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction, 8
`
` 
`
`6
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`ATI 1010-0007
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`

` 
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`INT. J. IMPOT. RES., (1996) 47-52 (“Boolell”). A group of enzymes known as cyclic
`
`nucleotide phosphodiesterase (PDE) isozymes were known to be present in the
`
`corpus cavernosum tissues present in the penis, and were known to hydrolyze cGMP.
`
`Id. at 47. Thus, those in the art recognized that “a pharmacological agent which
`
`inhibits the cGMP-specific phosphodiesterase isozyme, should enhance the action of
`
`nitric oxide/cGMP on penile erectile activity and have the potential to enhance penile
`
`erections during sexual stimulation.” Id.
`
`17. One particular isozyme, PDE5, was identified as “the predominant
`
`cGMP [for its] hydrolyzing activity,” and oral “inhibitors of type 5 PDE [which]
`
`improve erection” were known to serve as pharmaceutical agents in the treatment of
`
`sexual dysfunctions. Terrett, N. K., et al., Sildenafil (ViagraTM), a Potent and Selective
`
`Inhibitor of Type 5 cGMP Phosphodiesterase with Utility for the Treatment of Male Erectile
`
`Dysfunction, 6 BIOORG. MED. CHEM. Lett. (1996) 1819-1824 (“Terrett,” EX1024).
`
`Sildenafil citrate (Viagra®), was identified as a PDE5 inhibitor and as an “orally active
`
`treatment for male erectile dysfunction” prior to 1999. EX1024 at 1819. Those in the
`
`art noted sildenafil exhibited dose-dependent efficacy in the treatment of erectile
`
`dysfunction, showing effectiveness over placebo at doses at least as low as 5-10 mg.
`
`Licht, M.R., Sildenafil (Viagra) for treating male erectile dysfunction, 65 65 CLEVE. CLIN. J.
`
`MED., (1998) 301-304 (“Licht,” EX1025) at 302-03; EX1026, Gingell, C. J. C., et al.,
`
`UK-92,480: A New Oral Treatment for Erectile Dysfunction: A Double-Blind, Placebo-
`
`Controlled, Once Daily Dose Response Study, 155 Suppl 5 J. UROL. (1996) Abstract No. 738
`7
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` 
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`ATI 1010-0008
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`

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`(“Gingell,” EX1026) (describing 65% of men reporting improved erections at a 10 mg
`
`dosage level of sildenafil). In addition, Boolell identified sildenafil as having an IC50 of
`
`3.9 nM for PDE5, and noted that sildenafil is at least “70-fold [more] selective for
`
`PDE5 relative to isozymes from PDE families 1-4.” EX1023 at 50.
`
`18. The administration of sildenafil was associated with mild adverse events,
`
`such as headache, flushing, dyspepsia, rhinitis, and visual disturbances, especially at
`
`higher dosage levels. Goldstein, I., et al., Oral Sildenafil in the Treatment of Erectile
`
`Dysfunction, 338 N. Engl. J. Med., (1998) 1397-1404 (“Goldstein,”) (EX1027) at 1403;
`
`Morales, A., et al., Clinical safety of oral sildenafil citrate (VIAGRA TM) in the
`
`treatment of erectile dysfunction, 10 Int. J. Impot. Res., (1998) 69-74 (“Morales,”)
`
`(EX1028); de Mey, C., Opportunities for the Treatment of Erectile Dysfunction by
`
`Modulation of the NO Axis-Alternatives to Sildenafil Citrate, 14 Curr. Med. Res.
`
`Opin., (1998) 187-202 (“de Mey,”) (EX1029) at 188. In addition, those in the art
`
`noted that “[t]he adverse events of sildenafil reflect its pharmacological activity of
`
`inhibition of PDE5 in various tissues[.]”Cheitlin, M.D., et al, Use of Sildenafil (Viagra)
`
`in Patients with Cardiovascular Disease, 33 J. Am. Coll. Cardiol. (1999) 273-282
`
`(“Cheitlin,”) (EX1030) at 273. Thus, some adverse events, like headache, were known
`
`to be on-target effects, and thus stem directly from the inhibition of PDE5.
`
`19. 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
`
` 
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`8
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`ATI 1010-0009
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`

`

` 
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`dysfunction. The inhibition of PDE5 enhances erectile function by increasing the
`
`amount of cGMP in the smooth muscle cells.
`
`20. 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. EX1006, Viagra® label.
`
`21. Another example of a pharmaceutical product that contains a PDE5
`
`inhibitor is Cialis®. The active ingredient in Cialis® is tadalafil. Cialis® tablets are
`
`sold in tadalafil strengths of 5, 10, and 20 mg. EX1007, Cialis® label.
`
`22.
`
`Prior to 1999, those skilled in the art knew that a drug’s potency can
`
`largely determine the administered dose of the chosen drug. (E.g., EX1033). Sildenafil
`
`and
`
`tadalafil each share a common mechanism of action and are only
`
`pharmacologically active when cGMP synthesis is activated. They also share similar
`
`side effects. See EX1008, 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.
`
`23. A chart comparing key attributes of sildenafil and tadalafil is provided
`
`below:
`
`
`
`
`
` 
`
`9
`
`ATI 1010-0010
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`

`

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`
`
`Pharmaceutical
`Form
`Structural formula
`
`Viagra® (sildenafil)
`25, 50, 100 mg tablets
`
`Cialis® (tadalafil)
`5, 10, 20 mg tablets
`
`Recommended
`dose
`
`50 mg, may be increased to
`100 mg or decreased to 25
`mg
`4-6 hours
`Effective for
`Facial flushing, headache,
`Typical side
`indigestion
`effects
`Contraindications Nitrates cause significant
`vasodilation and reduction of
`blood pressure
`
`
`
`10 mg, may be increased to 20
`mg or decreased to 5 mg
`
`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 (EX1008).
`
`
`24. 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. IC50 values therefore allow for the direct comparison of different
`
`pharmaceuticals with common targets in order to understand relative potencies and
`
`also to determine appropriate comparative dosage values. Sildenafil was known to
`
`have an IC50 between 3.5–3.9 nM. See EX1011, SNDA., Table 1. Tadalafil, was
`
` 
`
`10
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`ATI 1010-0011
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`

`

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`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
`
`when administered orally. EX1006. The same is true for tadalafil. See, e.g., EX1002,
`
`U.S. Patent 5,859,006 at col. 2, lines 12-20.
`
`25.
`
`Indeed,
`
`it was known
`
`that sildenafil provides dose-dependent
`
`therapeutic efficacy over placebo in doses ranging from 5 mg to 100 mg. Viagra®
`
`Label, at p. 2. Tadalafil was also known to provide dose-dependent therapeutic
`
`efficacy over placebo in doses ranging from 0.2-400 mg. See, e.g., U.S. Patent
`
`5,859,006 at col. 2, lines 12-20 (describing its oral dosage forms of tadalafil of 0.2-400
`
`mg).
`
`26. As acknowledged in the ‘166 patent, sildenafil was known to be
`
`commercially successful, but significant adverse side effects have limited the use of
`
`sildenafil in patients suffering from vision abnormalities, hypertension, and, most
`
`significantly, by individuals who use organic nitrates.” EX1001, col. 1, lines 58- 65.
`
`27.
`
`It was widely known, prior to the critical date of April 30, 1999, that use
`
`of sildenafil in patients taking organic nitrates caused “a clinically significant drop in
`
`blood pressure which could place the patient in danger.” EX1001, col. 1, lines 66- col.
`
`2, line 1.
`
`28. General side effects for sildenafil and tadalafil include vasodilation,
`
`vision related disturbance, increased heart rate, inhibition of platelet aggregation, nasal
`
` 
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`11
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`ATI 1010-0012
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`congestion, headache, flushing, and dyspepsia. See EX1008, D. Eros, et al., Structure-
`
`Activity Relationships of PDE5 Inhibitors, Current Medicinal Chemistry, 2008 (15), 1570-
`
`1585.
`
`29. Co-administration of PDE5 inhibitors with nitrates or NO generating
`
`molecules
`
`is contraindicated because the co-administration causes significant
`
`vasodilatation and reduction of blood pressure. Id.
`
`V. THE LAW OF ANTICIPATION AND OBVIOUSNESS
`
`30.
`
`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
`
`information that existed at some time before the filing date of a patent application.
`
`The printed publication prior art may include, for example, publications, or patents.
`
`31.
`
`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 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.
`
`32.
`
`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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`12
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`ATI 1010-0013
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`33.
`
`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.
`
`34.
`
`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.
`
`35.
`
`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 ordinary skill is a
`
`hypothetical concept, and while he or she is not considered an expert, he or she is
`
`understood to think along the lines of conventional wisdom. At the same time, I
`13
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`ATI 1010-0014
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`understand that a person of ordinary skill is also a person of ordinary creativity, not an
`
`automaton.
`
`36.
`
`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.
`
`37.
`
`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).
`
`38.
`
`I understand that before April 30, 2007, the legal standard for
`
`obviousness was more difficult to meet. 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 patent claim could
`
`not be proven obvious mere by showing that the combination of elements was
`
`“obvious to try.”
`
`39. However, I understand that the Supreme Court changed the standard for
`
`determining obviousness in April 30, 2007 in KSR. The obviousness analysis after
`
`this case was easier to meet in the sense that teaching, suggestion or motivation test
`14
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`ATI 1010-0015
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`

`

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`for obviousness “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.
`
`40.
`
`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).
`
`41.
`
`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.
`
`42. After the KSR holding of April 30, 2007, I understand that the
`
`obviousness analysis does not require express teachings, but may also 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.
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`43.
`
`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).
`
`44. Thus, if relying on any of the objective indicia above, I understand that
`
`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
`
`45.
`
`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
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`claims.
`
`46. 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
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`ATI 1010-0017
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`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.
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`Patent 7,182,958 (claims a pharmaceutical formulation of tadalafil).
`
`47. 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., EX1001, claim 1.
`
`A.
`
`48.
`
`Specification and Admitted State of the Art
`
`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). EX1001, col. 1, lines 58- col. 2, line 21.
`
`49. The ‘166 patent also acknowledges that certain side effects limited
`
`sildenafil’s use in certain individuals. EX1001, col. 1, lines 58- 65.
`
`50. 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).
`
`51. 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
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`“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).
`
`52.
`
`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. EX1001 at col.
`
`2, lines 61-64.
`
`53. 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.
`
`B.
`
`Prosecution History
`
`54. 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.
`
`55. While prosecuting the application that matured into the ‘166 patent, I
`
`understand that the patent Examiner initially rejected the claims over U.S. Patent
`
`6,140,329 (“the ‘329 patent”), which is directed to treating sexual dysfunction with
`
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`18
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`ATI 1010-0019
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`tadalafil. See EX1009, 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 [tadalafil] 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 EX1009, Office Action of 8-30-2002 at 2-3
`
`56.
`
` Following that rejection, the Applicant apparently engaged the
`
`Examiner in an 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
`
`Examiner Interview Summary of 11-13-2002.
`
`57. The Applicant did not dispute the teachings of the ‘329 patent, and its
`
`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 2-10-
`
`2003, at 3-4. The Applicant further argued that “although the ‘329 patent teache