UNITED STATES PATENT AND TRADEMARK OFFICE
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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
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`Patent No. 6,943,166
`Issued: September 13, 2005
`Filed: April 26, 2000
`Inventors: Pullman and Whitaker
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`Title: COMPOSITIONS COMPRISING PHOSPHODIESTERASE INHIBITORS
`FOR THE TREATMENT OF SEXUAL DYSFUNCTION
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`Inter Partes Review No. - not yet assigned
`_______________
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`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 6,943,166
`UNDER 35 U.S.C. §§ 311-319 AND 37 C.F.R. §§ 42.1-.80, 42.100-.1
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`Petition for Inter Partes Review of USPN 6,943,166
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`TABLE OF CONTENTS
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`I.
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`INTRODUCTION ............................................................................................. 1
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`II. OVERVIEW ...................................................................................................... 1
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`III. STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFOR (37 C.F.R. § 42.104(B) ............................................. 4
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`A. Person of ordinary skill in the art .......................................................... 4
`B. State of the art before April 30, 1999 .................................................... 5
`1. Sexual dysfunction was a well-known disorder.............................. 5
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`2. Selectively inhibiting PDE5 was a known effective treatment for
`sexual dysfunction ........................................................................... 5
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`3. Tadalafil was a known, potent, highly selective PDE5 inhibitor
`useful for treating sexual dysfunction ............................................. 9
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`4. Identifying a drug's optimal dose range for therapeutic efficacy
`was routine practice in the art .......................................................11
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`C. The '166 patent ....................................................................................14
`D. Claim Construction..............................................................................15
`1. "Compound having the structure" .................................................15
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`2. "Female arousal disorder" .............................................................16
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`3. "Free drug" ....................................................................................17
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`E. Identification of the challenge (37 C.F.R. § 42.104(b)) ......................17
`1. Ground 1: Claims 1-12 would have been obvious over Daugan
`'675 ................................................................................................20
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`2. Ground 2: Claims 1-12 would have been obvious over Daugan
`'675 and the SNDA .......................................................................38
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`Petition for Inter Partes Review of USPN 6,943,166
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`F. Objective indicia of non-obviousness .................................................47
`1. Patent Owner's allegations of objective indicia are insufficient to
`show non-obviousness ..................................................................47
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`a. Patent Owner cannot show unexpectedly superior results .....48
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`b. Patent Owner's alleged evidence of unexpected results is not
`commensurate in scope with the claims .................................52
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`2. There is no evidence that the art taught away from the claimed
`invention ........................................................................................56
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`3. There was no long-felt need satisfied by the claimed invention ..56
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`4. There is no evidence of commercial success that supports
`patentability ...................................................................................57
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`5. There is no other evidence of objective indicia of non-obviousness
` .......................................................................................................58
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`IV. CONCLUSION ...............................................................................................58
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`V. STANDING (37 C.F.R. § 42.104(A)) AND PROCEDURAL STATEMENTS
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` .............................................................................................................59
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`VI. MANDATORY NOTICES (37 C.F.R. § 42.8(A)(1)) ....................................59
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`Petition for Inter Partes Review of USPN 6,943,166
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`I.
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`INTRODUCTION
`INTELGENX CORP. (Petitioner) petitions for inter partes review, seeking
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`cancellation of claims 1-12 of U.S. Patent No. 6,943,166 ("the '166 patent")
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`(INX1001), as unpatentable for obviousness. According to USPTO records, the
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`'166 patent is assigned to ICOS CORP. On information and belief, ICOS CORP. is
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`owned by ELI LILLY AND CO. (collectively, "Patent Owner").
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`II. OVERVIEW
`The '166 patent claims would have been obvious over the prior art—
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`Daugan '675 (INX1002). Like every claim of the ’166 patent, Daugan '675 is
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`directed toward treating sexual dysfunction with a potent, highly-selective
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`phosphodiesterase type 5 (PDE5) inhibitor known as tadalafil. INX1002, 1-5.
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`Daugan '675 explicitly describes that tadalafil can be administered through a
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`variety of dosage forms, across a range of doses, once or more a day to treat both
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`male and female sexual dysfunction. INX1002, 1-5; 12-17. The only purported
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`difference between Daugan '675 and the '166 patent claims is that Daugan '675
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`discloses a dosing range of 0.2–400 mg whereas the '166 patent more narrowly
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`claims 1–20 mg. When "there is a range disclosed in the prior art, and the claimed
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`invention falls within that range, there is a presumption of obviousness." Iron
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`Grip Barbell Co., Inc. v. USA Sports, Inc., 392 F.3d 1317, 1322 (Fed. Cir. 2004).
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`Patent Owner argued during prosecution that the range claimed by the '166
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`patent is non-obvious due to the "unexpected result" that administering a lower
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`dose of tadalafil resulted in lower side effects without a loss of efficacy.
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`INX1024, 536-538, 612-614. But Patent Owner’s argument should be rejected for
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`several reasons. First, there is no evidence of record that a person skilled in the
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`art ("POSA") would have been surprised to discover that a lower dose of tadalafil
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`would be associated with reduced side effects. To the contrary, these are merely
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`differences in degree of results (rather than differences in kind), which would be
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`very much expected by a pharmacologist or similar skilled artisan. INX1007, ¶47.
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`Indeed, the Examiner rejected this argument for the same reasons. INX1024, 628.
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`Second, identifying the optimum dosing regimen for a drug such as tadalafil
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`would have required only routine experimentation and optimization. INX1007,
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`¶¶16–17, 27–33; INX1005, ¶¶60, 84–89. Indeed, before 1999 and even today, it
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`is commonplace when seeking approval for a new drug to conduct a dose-ranging
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`study to establish a safe and effective dosing regimen. A POSA following the
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`teachings of Daugan '675 and accepted industry practices would have quickly and
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`easily arrived at the range of 1–20 mg as set forth in Ground 1. INX1007, ¶47.
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`Third, even if Patent Owner’s evidence of alleged unexpected results is given any
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`weight, the evidence is not commensurate with the full scope of the claims.
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`INX1007, ¶¶51-53; INX1005, ¶¶ 156-158. The broadest claim of the '166 patent
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`covers doses as low as one twentieth of the 20 mg dose, covers administration
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`Petition for Inter Partes Review of USPN 6,943,166
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`multiple times per day, and covers male sexual dysfunctions additional to erectile
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`dysfunction (ED) as well as female sexual dysfunction. But Patent Owner offered
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`only evidence of comparable efficacy between 20 mg and 50 mg when
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`administered to males once per day for treating only ED. INX1005, ¶¶156-157;
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`INX1007, ¶¶51-52. This single reference point falls far short of the required
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`showing of comparable efficacy across this broad scope.
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`If Daugan '675 coupled with a skilled artisan's general knowledge leaves
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`any room for doubt, then Daugan '675 together with the Sildenafil (VIAGRA®)
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`Approval Package confirms the obviousness of the '166 patent claims. INX1005,
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`¶¶ 20, 114-137; INX1003. VIAGRA® contains sildenafil, which is a prior art
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`PDE5 inhibitor used for treating male sexual dysfunction. VIAGRA® received
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`marketing approval from FDA on March 27, 1998, and, as of that date, the FDA
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`Approval Package for VIAGRA® would have been available to the public.
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`INX1003, 1. The VIAGRA® Approval Package discloses that sildenafil is safe and
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`therapeutically effective over placebo in some patients receiving doses as low as
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`5 to 10 mg. Because tadalafil showed greater potency than sildenafil under
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`industry-accepted in vitro studies, a POSA would have been motivated to use a
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`similar dosing regimen for tadalafil as had already been shown to be effective
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`with sildenafil. INX1005, ¶ 75-79.
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`Petition for Inter Partes Review of USPN 6,943,166
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`III. STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFOR (37 C.F.R. § 42.104(B)
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`Petitioner requests IPR under 35 U.S.C. §§ 311-319 and 37 C.F.R. §§ 42.1-
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`.80 and 42.100-42.123, and cancellation of claims 1-12 of the '166 patent as
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`unpatentable under 35 U.S.C. § 103.
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`Person of ordinary skill in the art
`
`A.
`A POSA is a hypothetical person who is presumed to be aware of all
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`pertinent art, thinks along conventional wisdom in the art, and is a person of
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`ordinary creativity. With respect to the subject matter of the '166 patent, a POSA
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`would have had (i) an M.D. specializing in urology including sexual dysfunction
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`or a Ph.D. in chemistry, pharmacology, or a related field in the biological or
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`chemical sciences, and at least about 2 years of experience in clinical
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`pharmacology; or (ii) a Master's degree in chemistry, pharmacology, or a related
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`field in the biological or chemical sciences, and at least about 5 years of
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`experience in clinical pharmacology. INX1005, ¶28; INX1007, ¶21.
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`Also, 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 with experience in treating sexual dysfunction may have
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`been part of the team. INX1005, ¶29; INX1007, ¶22. As of April 30, 1999, the
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`state of the art included the teachings provided by the references discussed in
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`Petition for Inter Partes Review of USPN 6,943,166
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`each of the unpatentability grounds set forth below. Additionally, a POSA would
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`have been aware of other important information and references relating to PDE5
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`inhibitors and treatment of sexual dysfunction.
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`B.
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`State of the art before April 30, 1999
`1.
`Before April 30, 1999, a POSA would have known that sexual dysfunction
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`Sexual dysfunction was a well-known disorder
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`is a common disorder affecting men and women. See INX1009, 47; INX1010,
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`822; INX1002, 1; INX1011, 537; INX1005, ¶40. The prior art taught that sexual
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`dysfunction negatively affects quality of life due to increased anxiety, decreased
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`self-esteem, decreased self-confidence, tension, and difficulties in interpersonal
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`relationships. INX1009, 47; INX1010, 822; INX1005, ¶40. A POSA would have
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`known that ED is a form of sexual dysfunction in men, "described as an important
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`public health problem by a National Institutes of Health Consensus Panel."
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`INX1011, 537; INX1005 ¶42. And a POSA would have known that female
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`arousal disorder is a form of sexual dysfunction in women, affecting anywhere
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`from 25% to 63% of women. INX1012, 52; INX1011, 537. Thus, before April 30,
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`1999, a skilled artisan would have had significant interest in developing
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`treatments for sexual dysfunction. INX1005, ¶¶40-42.
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`2.
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`Selectively inhibiting PDE5 was a known effective treatment for
`sexual dysfunction
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`Before April 30, 1999, a POSA would have known the physiology behind
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`penile erections. INX1009, 47; INX1013, 1397; INX1005, ¶43. A POSA would
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`have known that sexual stimulation causes endothelial cells and nerve endings in
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`the penis to release nitric oxide (NO), which stimulates formation of cyclic
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`guanosine monophosphate (cGMP). INX1009, 47; INX1013, 1397; INX1005,
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`¶43. A POSA would have known that formation of cGMP causes a relaxation of
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`smooth muscle cells in the corpus cavernosum (sponge-like tissues) in the penis,
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`which allows increased arterial blood flow into the sponge-like tissues, ultimately
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`resulting in penile rigidity. INX1009, 47; INX1005, ¶43. A POSA also would
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`have known that cGMP-specific PDE5 is the predominant cGMP-metabolizing
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`enzyme in the corpus cavernosum. INX1013, 1397; INX1005, ¶44. And, as Dr.
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`Hellstrom explains, the prior art taught that selectively inhibiting PDE5 restores
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`the natural erectile response to sexual stimulation. INX1013, 1397-1398;
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`INX1005, ¶45. Thus, before April 30, 1999, there was significant interest in
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`developing selective PDE5 inhibitors for treating sexual dysfunction, such as ED.
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`INX1005, ¶45; INX1013, 1397; INX1009, 47; INX1026, 633–636, 638;
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`INX1002, 1-2; INX1014, 1819; INX1021, 1; INX1020, 1; INX1022, 2.
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`For example, the FDA approved VIAGRA® (sildenafil citrate; "sildenafil")
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`for the treatment of ED on March 27, 1998. INX1025, 2. Before VIAGRA®'S
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`approval in 1998, a POSA would have known that sildenafil is a potent, selective
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`PDE5 inhibitor. INX1005, ¶46. In 1996, Boolell described sildenafil as a "potent
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`inhibitor of PDE5 activity" as evinced by a "mean IC50 of 0.0039 µM [i.e., 3.9
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`nM]" and "at lest [sic] 70-fold selective for PDE5 relative to isozymes from PDE
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`families 1-4." INX1009, 50. Similarly, the publicly-available Sildenafil Citrate
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`(VIAGRA®) Approval Package for New Drug Application No. 020895 ("the
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`SNDA") reported that sildenafil is "a potent, complete inhibitor of Type V
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`phosphodiesterase" as evinced by a mean IC50 of 3.5 nM. INX1003, 37. Thus, as
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`Dr. Hellstrom explains, a POSA would have understood that sildenafil has a
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`PDE5 IC50 of 3.5–3.9 nM. INX1005, ¶46. VIAGRA®'S product label from 1998
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`states that the "maximum recommended dosing frequency is once per day."
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`INX1016, 17; INX1003, 50. VIAGRA®'S product label also shows it was approved
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`in tablet form for oral administration in 25, 50, and 100 mg dosages. INX1016, 1.
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`Accordingly, the prior art taught that sildenafil doses of 25, 50, and 100 mg are
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`therapeutically effective for treating ED. INX1009, 51; INX1013, 1339-1340;
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`INX1003, 127-128, 215, 217-219; INX1005, ¶47.
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`The prior art also taught that sildenafil is therapeutically effective for ED in
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`some patients when administered in doses as low as 5 to 10 mg compared with
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`placebo. INX1009, 51; INX1003, 127-128, 215, 217-219; INX1017, 302;
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`INX1005, ¶47. For example, in 1996, Boolell described results from a clinical
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`trial in which patients received oral sildenafil at 10, 25, and 50 mg doses.
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`INX1009, 49-52. According to Boolell, the "duration of rigidity of greater than
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`60% at the base and tip of the penis during [visual sexual stimulation] was
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`significantly higher in each treatment group compared with placebo." INX1009,
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`51 (emphasis added); INX1005, ¶48. Also in 1996, Gingell reported that 65% of
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`men receiving a 10 mg dose of sildenafil (referred to as compound UK-92,480)
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`reported improved erections. INX1018, no. 738. In 1998, Licht described results
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`from a clinical study showing sildenafil doses as low as 5 mg are clinically
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`effective over placebo, stating that "significantly more men at any dose" had
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`improved erections and improved ability to achieve and maintain erections
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`compared with placebo. INX1017, 302-303 (emphasis added); INX1005, ¶47.
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`Indeed, the prior art SNDA shows that oral sildenafil doses of 5, 10, 25, 50, and
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`100 mg all provided at least some therapeutic efficacy compared with placebo.
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`INX1003, 127-128, 215, 217-219; INX1005, ¶48. Thus, before April 30, 1999, a
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`POSA would have known that (i) sildenafil is a potent, selective PDE5 inhibitor
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`with an IC50 between 3.5–3.9 nM; (ii) orally administered sildenafil is effective
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`for treating ED; and (iii) sildenafil provides dose-dependent therapeutic efficacy
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`over placebo in doses ranging from 5 mg to 100 mg. INX1009, 50-51; INX1016,
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`1; INX1003, 127-128, 215, 217-219; INX1017, 302-303; INX1005, ¶¶46–48.
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`After its launch in 1998, VIAGRA® garnered "overwhelming" public
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`acclaim and "outstanding" early sales. INX1019, 188; INX1017, 301; INX1005,
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`¶49. But the prior art taught that sildenafil may have certain side effects, such as
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`headaches, facial flushing, and dyspepsia (indigestion). INX1013, 1403;
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`INX1005, ¶49. And, as de May stated in 1998, "sildenafil citrate has important
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`drawbacks. Safety concerns exclude an important fraction of the affected
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`population - those with cardiovascular diseases and those taking nitrates, in
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`particular." INX1019, 188; see also, INX1017, 304; INX1005, ¶49. Thus, as Dr.
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`Hellstrom explains, artisans were actively developing other PDE5 inhibitors as an
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`alternative to sildenafil before April 30, 1999. INX1005, ¶49; INX1021, 1;
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`INX1020, 1; INX1022, 2. For example, Edelhart reported in 1998 that the PDE5
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`inhibitor IC351 is a more selective PDE5 inhibitor compared to sildenafil.
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`INX1022, 2; INX1005, ¶49. Artisans at the time understood that a drug with
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`greater selectivity for PDE5 compared to sildenafil would "eliminate some of the
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`side effects associated with Viagra…." INX1021, 1; INX1005, ¶49.
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`3.
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`Tadalafil was a known, potent, highly selective PDE5 inhibitor
`useful for treating sexual dysfunction
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`Before April 30, 1999, tadalafil (also referred to by its chemical name,
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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) was a
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`known, potent, "highly selective" PDE5 inhibitor. INX1015, 62 (Ex. 95), 75-76,
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`Table 1; INX1002, 16-17, Table 1; INX1005, ¶¶50–51 . For example, in 1995,
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`International Application Publication No. WO 95/19978 ("Daugan '978";
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`INX1015) published methods of preparing certain tetracyclic compounds,
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`including tadalafil, for use as selective PDE5 inhibitors. INX1015, 1, 62 (Ex. 95).
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`Daugan '978 teaches that tadalafil (the compound of Example 95 in the
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`publication) is a potent PDE5 inhibitor with an IC50 value of 2 nM. INX1015, 76,
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`Table 1. Daugan '978 also teaches methods of formulating tadalafil for oral
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`administration, such as tablets and capsules. INX1015, 71-74; INX1005, ¶50.
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`In 1997, International Application Publication No. WO 97/03675 ("Daugan
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`'675"; INX1002) described using tadalafil for treating male and female sexual
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`dysfunction, including ED in men and clitoral disturbances in women. INX1002,
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`1-6. Daugan '675 describes tadalafil as a potent, "highly selective" PDE5 inhibitor
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`with an IC50 value of 2 nM. INX1002, 16-17, Table 1; INX1005, ¶51. As Dr.
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`Hellstrom explains, a POSA would have understood that tadalafil is a more potent
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`PDE5 inhibitor than sildenafil because Daugan '675 teaches that the PDE5 IC50
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`value for tadalafil is 2 nM, which is lower than sildenafil's reported PDE5 IC50
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`value of 3.5–3.9 nM. INX1005, ¶51; INX1002, 17, Table 1; INX1009, 50; Table
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`2; INX1003, 37. Daugan '675 teaches a range of effective oral tadalafil doses for
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`treating sexual dysfunction (0.2 to 400 mg), examples of 50 mg dosage forms for
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`oral administration, and expressly states that "other doses may be prepared."
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`INX1002, 5, 12-16. Daugan '675 also teaches that dosing regimens "vary with the
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`age, weight and response of the particular patient," and that the "physician will
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`determine the actual dosing regimen which will be most suitable for an individual
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`patient." INX1002, 5; INX1005, ¶52. And Daugan '675 states that "there can be
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`individual instances in which higher or lower dosage ranges may be merited."
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`INX1002, 5. Daugan '675 also teaches that tadalafil can be administered once per
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`day or on-demand. INX1002, 5; INX1005, ¶52. Thus, before April 30, 1999, a
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`POSA would have known that (i) tadalafil is a potent, highly selective PDE5
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`inhibitor; (ii) tadalafil is a more potent PDE5 inhibitor than sildenafil; and (iii)
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`tadalafil is useful for treating sexual dysfunction, including ED and female sexual
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`dysfunction, in doses of 0.2 to 400 mg. INX1015, 1, 62 (Ex. 95) 71-76, Table 1;
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`INX1002, 1-6, 12-17, Table 1; INX1005, ¶53.
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`4.
`
`Identifying a drug's optimal dose range for therapeutic efficacy
`was routine practice in the art
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`Before April 30, 1999, artisans in the field of drug development routinely
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`performed dose escalation studies and generated dose-response curves to identify
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`the optimal therapeutic dose range for a particular drug. INX1023, 54; INX1030,
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`66-67; INX1040, 2, 5; INX1005, ¶¶54–61; INX1007, ¶¶27-34. As the Color Atlas
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`of Pharmacology stated in 1993, "[t]he relationship between the concentration of
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`a drug and its effect is determined in order to define the range of active drug
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`concentrations (potency) and the maximum possible effect (efficacy)." INX1023,
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`54. Before April 30, 1999, a POSA would have understood the concept and the
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`significance of a drug's therapeutic index—i.e., the margin between the doses of a
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`drug required to produce a therapeutic effect and doses that cause toxicity.
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`INX1007, ¶28; INX1033, 26-27; INX1032, 404; INX1030, 68-99; see also,
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`INX1005, ¶55. For example, the 1994 ICH Guidelines for Industry, developed by
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`the International Conference on Harmonisation of Technical Requirements for the
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`Registration of Pharmaceuticals for Human Use (ICH)1, states that assessment of
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`dose response "should be an integral component of drug development" and that
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`"the most helpful" aspect in choosing the starting dose of a drug is "knowing the
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`shape and location of the population (group) average dose-response curve for
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`both desirable and undesirable effects." INX1040, 2, 5.
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`Before April 30, 1999, a POSA would have understood that a drug's
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`therapeutic efficacy is dose-dependent. INX1023, 52; INX1030, 68-69; INX1007,
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`¶32. A POSA would have known that increasing the dose of a drug increases the
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`degree of therapeutic efficacy until a maximum therapeutic efficacy is reached
`
`(i.e., the peak of the dose-response curve), at which point the therapeutic efficacy
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`no longer increases with a corresponding dose increase. INX1030, 67-68;
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`INX1023, 54; INX1034, 11-12; INX1007, ¶30. A POSA also would have known
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`that increasing the dosage amount beyond the peak of the therapeutic efficacy
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`curve ceases to provide any additional therapeutic benefit, and instead, begins to
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`produce adverse events (toxicity). INX1007, ¶30; INX1023, 54; INX1030, 68-69;
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`1 The ICH Guidelines were published in the Federal Register on November
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`9, 1994. See 59 FED. REG. 55972 (Nov. 9, 1994); INX1040, 1, 15.
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`INX1034, 11-12; INX1032, 404. Thus, artisans routinely sought to identify the
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`lowest dose of a drug that still provides the maximum therapeutic efficacy.
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`INX1023, 54; INX1007, ¶33. Further, a POSA would have known that drug doses
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`lower than those providing maximum therapeutic efficacy, such as doses on the
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`"shoulder" and along the slope of the dose-response curve, still provide a dose-
`
`dependent degree of therapeutic efficacy. INX1030, 67; INX1032, 404; INX1007,
`
`¶46. Thus, before April 30, 1999, artisans routinely optimized drug doses by
`
`generating dose-response curves to identify the optimal dose range for therapeutic
`
`efficacy. INX1007, ¶33; INX1040, 2, 5.
`
`To determine a drug's therapeutic index, artisans routinely considered
`
`different factors, such as a drug's potency. INX1034, 27; INX1007, ¶34;
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`INX1005, ¶61. As Nies stated in 1990, "potency obviously affects drug dosage."
`
`INX1030, 67. And Katzung stated in 1995, "pharmacologic potency can largely
`
`determine the administered dose of the chosen drug." INX1034, 27. A POSA
`
`would have understood that a drug's in vitro IC50 value (the concentration of the
`
`drug required to reduce its target enzyme function by 50%) is a common and
`
`useful measure of potency. INX1005, ¶ 61; INX1007, ¶ 34. Artisans also
`
`routinely performed dose-escalating studies, administering low doses of a drug
`
`and incrementally increasing dosage amounts until the peak of the dose-response
`
`curve is reached and toxicity begins to appear. INX1007, ¶31; INX1009, 49;
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`Petition for Inter Partes Review of USPN 6,943,166
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`INX1035, 339-340. For example, in 1996, Boolell described an "escalating single
`
`oral dose study" of sildenafil doses ranging from 1.25 mg to 90 mg, and then up
`
`to 200 mg in an extension study. INX1009, 49; INX1007, ¶31; see also,
`
`INX1023, 54; INX1030, 69; INX1032, 404; INX1005,¶58. Boolell reported that
`
`"[t]he main adverse events" of headache and facial flushing occurred in "doses of
`
`90 mg and above…." INX1009, 50-51.
`
`C. The '166 patent
`Against this background, the '166 patent issued from U.S. Application No.
`
`10/031,556 ("the '556 application"), which is a national stage application of
`
`PCT/US00/11129 ("the '129 application"), filed April 26, 2000. The '166 patent
`
`asserts its earliest priority claim to provisional application no. 60/132,036, filed
`
`on April 30, 1999. INX1001. The '166 patent is directed to "highly selective
`
`phosphodiesterase (PDE) enzyme inhibitors and their use in pharmaceutical
`
`articles of manufacture." INX1001, Abstract. Independent claim 1 is copied
`
`below:
`
`1. A method of treating sexual dysfunction in a patient
`in need thereof comprising orally administering one or
`more unit dose containing about 1 to about 20 mg, up to
`a maximum total dose of 20 mg per day, of a compound
`having the structure
`
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`Petition for Inter Partes Review of USPN 6,943,166
`
`
`INX1001, claim 1. Dependent claims 2 and 3 require that the sexual dysfunction
`
`is male erectile dysfunction and female arousal disorder, respectively. Dependent
`
`claims 4, 5, 8, and 20 require specific dosage amounts of tadalafil. Dependent
`
`claim 7 requires specific dosage forms of tadalafil. Dependent claims 6, 9, and 10
`
`require that tadalafil is administered once per day. And, dependent claim 11
`
`requires that the tadalafil is administered as a free drug.
`
`D. Claim Construction
`The challenged claims should be given their broadest reasonable
`
`interpretation in light of the specification. 37 C.F.R. § 42.100(b). Claim terms not
`
`discussed below are generally plain on their face and should be given their
`
`ordinary meaning.
`
`"Compound having the structure"
`
`1.
`Claim 1 recites a method of treating sexual dysfunction with a compound
`
`having the following structure:
`
`
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`Petition for Inter Partes Review of USPN 6,943,166
`
`INX1001, claim 1. The specification of the '166 patent states that "[t]he present
`
`invention provides a pharmaceutical dosage form for human pharmaceutical use,
`
`comprising about 1 to about 20 mg of (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-
`
`methyl-6-(3,4-methylenedioxyphenyl)pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-
`
`dione in a unit dosage form suitable for oral administration." INX1001, 2:58-63.
`
`The specification states that this compound is "alternatively named (6R-trans)-6-
`
`(1, 3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methylpyrazino-
`
`[1',2':1,6]pyrido[3,4-b]indole-1,4-dione" and referred to as "Compound I."
`
`INX1001, 2:25-28. A POSA reading the '166 patent specification would have
`
`understood that the compound recited by its chemical name in the specification is
`
`the same compound structure shown in claim 1. INX1005, ¶36; INX1007, ¶24.
`
`That compound is also called tadalafil. INX1029, 11; see also, Actelion Pharms.
`
`Ltd. v. ICOS Corp., IPR2015-00561, Paper 7 at 7 (PTAB August 4, 2015).
`
`"Female arousal disorder"
`
`2.
`Claim 3 recites that "the sexual dysfunction is female arousal disorder."
`
`INX1001, claim 3. The phrase "female arousal disorder" is not explicitly defined
`
`in the '166 patent, but the specification recites "[s]pecific conditions that can be
`
`treated by the present invention include, but are not limited to, male erectile
`
`dysfunction and female sexual dysfunction, particularly female arousal disorder,
`
`also known as female sexual arousal disorder." INX1001, 3:6-10. Thus, a POSA
`
`
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`Petition for Inter Partes Review of USPN 6,943,166
`
`reading the '166 patent would have understood that "female arousal disorder" is a
`
`type of sexual dysfunction, more specifically a type of female sexual dysfunction.
`
`INX1005, ¶ 37.
`
`"Free drug"
`
`3.
`Claim 11 recites that the "compound is administered as a free drug." The
`
`'166 patent states that "free drug" means "solid particles of drug not intimately
`
`embedded in a polymeric coprecipitate." INX1001, 4:1-2. Thus, a POSA would
`
`have understood that "free drug" includes solid particles of drug administered
`
`alone. INX1005, ¶38.
`
`Identification of the challenge (37 C.F.R. § 42.104(b))
`
`E.
`Petitioner requests IPR of claim 1-12 of the '166 patent based on the
`
`unpatentability grounds summarized below. Copies of the cited references
`
`accompany the Petition. 37 C.F.R. § 42.6(c). In support of the proposed grounds
`
`for unpatentability, this Petition is accompanied by the Declarations of Dr. Wayne
`
`Hellstrom (INX1005) and Dr. Reid Patterson (INX1007). Dr. Hellstrom is an
`
`expert in the field of urology, including male and female sexual dysfunction.
`
`INX1005, ¶6. Dr. Patterson is an expert in the field of clinical pharmacology and
`
`toxicology, including drug development and clinical trials. INX1007, ¶6.
`
`Ground Basis
`1
`§ 103
`2
`§ 103
`
`Claims
`References
`1-12
`Daugan '675
`Daugan '675 and Sildenafil NDA 1-12
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`Petition for Inter Partes Review of USPN 6,943,166
`
`
`International Application No. PCT/EP96/03024 to Daugan published on
`
`February 6, 1997 as WO 1997/003675 A1 ("Daugan '675"; INX1002). Daugan
`
`'675 qualifies as § 102(b) art to the '166 patent because Daugan '675 published
`
`more than one year before April 30, 1999. During Patent Owner's prosecution of
`
`the '166 patent, the Office rejected the pending claims as obvious over U.S. Patent
`
`No. 6,140,329 to Daugan. INX1024, 527-528, 576, 599-600, 628. The Daugan
`
`'329 patent is a U.S. National Phase entry of the Daugan '675 PCT application.
`
`Daugan '675 is cited on the face of the '166 patent; however, the Office did not
`
`assert Daugan '675 during prosecution of the '166 patent. INX1024, 527-528, 576,
`
`599-600, 628. Further, Daugan '675 contains additional disclosures related to
`
`tadalafil's potency, which are not found in Daugan '329. See, e.g., INX1002, 17;
`
`INX1005, ¶ 65. Thus, the grounds based on Daugan '675 raised in this Petition
`
`are not "the same or substantially the same prior art or arguments
`
`previously…presented to the Office." 35 U.S.C. § 325(d); see e.g., Praxair
`
`Distribution, Inc. v. Ino Therapeutics, LLC, IPR2015-008899, Paper 14 at 9-10
`
`(PTAB Sept. 22, 2015).
`
`The Sildenafil Citrate (VIAGRA®) Approval Package for New Drug
`
`Application No. 020895 ("the SNDA"; INX1003) qualifies as § 102(b) art to the
`
`'166 patent because the SNDA became publicly available on January 22, 1998,
`
`more than one year before April 30, 1999. INX1003, 2. In fact, during
`
`
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`Petition for Inter Partes Review of USPN 6,943,166
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`prosecution, Patent Owner admitted that the SNDA's publication date is January
`
`22, 1998. INX1024, 569-570, 578. Patent Owner's statement during prosecution
`
`"identifying certain matter not the work of the inventor as prior art is an
`
`admission that the matter is prior art." Riverwood Int'l. Corp. v. RA Jones & Co.,
`
`Inc., 324 F.3d 1346, 1354 (Fed. Cir. 2003) (internal quotations omitted). A Patent
`
`Owner admission "can reside in the patent file (made of record during the
`
`prosecution of the patent application) or may be presente