Trials@uspto.gov
`Tel: 571-272-7822
`
`
`Paper 7
`Entered: August 4, 2015
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
`ACTELION PHARMACEUTICALS LTD,
`Petitioner,
`
`v.
`
`ICOS CORPORATION,
`Patent Owner.
`____________
`
`Case IPR2015-00562
`Patent 6,821,975
`_______________
`
`
`
`Before SHERIDAN K. SNEDDEN, SUSAN L. C. MITCHELL, and
`ZHENYU YANG, Administrative Patent Judges.
`
`SNEDDEN, Administrative Patent Judge.
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
`
`1
`
`EX 1022
`IPR of U.S. Pat. No. 7,829,595
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`

`
`IPR2015-00562
`Patent 6,821,975
`
`
`I.
`
`INTRODUCTION
`
`Actelion Pharmaceuticals Ltd (“Petitioner”) filed a Petition (Paper 1;
`
`“Pet.”) to institute an inter partes review of claims 111 of US 6,821,975 B2
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`(Ex. 1001; “the ’975 patent”). ICOS Corporation (“Patent Owner”) filed a
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`Patent Owner Preliminary Response. Paper 6 (“Prelim. Resp.”).
`
`Upon consideration of the above-mentioned Petition and Preliminary
`
`Response, we conclude that Petitioner has established a reasonable
`
`likelihood that it would prevail in showing the unpatentability of at least one
`
`challenged claim. 35 U.S.C. § 314(a). We authorize institution of an inter
`
`partes review as to claims 111.
`
`A. Related Proceedings
`
`The parties inform us of no related litigation between them. Pet. 1;
`
`Paper 4. Concurrent with the present inter partes review, Petitioner also
`
`requested review of claims in U.S. Patent No. 7,182,958 (“the’958 patent”)
`
`(Case IPR2015-00561). Id.
`
`B. The ’975 patent (Ex. 1001)
`
`The ’975 patent discloses particulate preparations of a free drug form
`
`of a β-carboline compound having the following formula:
`
`
`
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`IPR2015-00562
`Patent 6,821,975
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`and pharmaceutically acceptable salts and solvates thereof. The compound
`
`of the above formula, referred to as “compound (I)” in the ’975 patent, is
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`alternatively known as:
`
`1) tadalafil;
`
`2) (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; or
`
`3) (6R, 12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylene-
`
`dioxyphenyl)pyrazino[2′,1′:6.1]pyrido[3,4-b]indole-1,4-dione.
`
`Prelim. Resp. 1415; Ex. 1006, 3:2425.
`
`
`
`“The term ‘free drug’ refers to solid particles of compound (I) not
`
`intimately embedded in a polymeric coprecipitate.” Ex. 1001, 4:56. The
`
`free drug may be crystalline. Id. at 5:8.
`
`
`
`The ’975 patent discloses compound (I) as a free drug in particulate
`
`form, wherein at least 90% of the particles have a particle size of less than
`
`about 40 microns. Id. at 4:615:7. Particles less than 10 microns in size are
`
`also disclosed. Id. The particulate form of the free drug may be achieved
`
`using a milling process. Id. at 5:1220, 10:617.
`
`The ’975 patent discloses that “the use of compound (I) and
`
`pharmaceutical compositions for treatment of sexual dysfunction, e.g., male
`
`erectile dysfunction and female sexual arousal disorder.” Id. at 2:5053.
`
`The ’975 patent discloses pharmaceutical compositions comprising
`
`particulate compound (I) and one or more pharmaceutically acceptable
`
`excipients, diluents, or carriers. Id. at 3:142, 7:955.
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`IPR2015-00562
`Patent 6,821,975
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`C. Challenged Claims
`
`Claims 1, 6, 9, and 11 are the independent claims among the
`
`challenged claims, and are reproduced below: 1
`
`1. A free drug particulate form of a compound having a
`formula
`
`
`or pharmaceutically acceptable salts and solvates thereof,
`comprising particles of the compound wherein at least 90% of
`the particles have a particle size of less than about 40 microns.
`
`
`6. A method of treating sexual dysfunction in a patient in
`need thereof, which comprises administering to the patient a
`therapeutically effective amount of a solid composition
`comprising the free drug particulate form as in any one of
`claims 1-4 and one or more pharmaceutically-acceptable
`carriers, diluents, or excipients.
`
`
`9. A method of manufacturing the free drug particulate
`form of claim 1 comprising:
`(a) providing a solid, free form of the compound, and
`(b) comminuting the solid free form of the compound to
`provide particles of the compound wherein at least 90% of the
`particles have a particle size of less than about 40 microns.
`
`
`
`1 We consider claims 6 and 9 as independent claims as these claims are
`directed to a different statutory class of invention, methods, rather than
`compositions of matter recited in claim 1.
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`IPR2015-00562
`Patent 6,821,975
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`11. A pharmaceutical solid composition prepared by
`admixing particles of a compound having a formula
`
`
`or a pharmaceutically acceptable salt or solvate thereof, with
`one or more pharmaceutically acceptable carrier, diluent, or
`excipient, wherein the particles of the compound have a d90=40
`or less.
`
`Claims 25 depend from claim 1, either directly or indirectly. Claims
`
`7 and 8 depend from claim 6. Claim 10 depends from claim 9.
`
`D. Prior Art and Supporting Evidence
`
`Petitioner relies on the following prior art:
`
`Daugan et al., WO 97/03675, published Feb. 6, 1997. Ex. 1006
`(“Daugan”).
`
`Butler et al., WO 96/38131, published Dec. 5, 1996. Ex. 1008
`(“Butler”).
`
`U.S. Patent No. 4,344,934, issued Aug. 17, 1982. Ex. 1010
`(“Martin”).
`
`Seth et al., U.S. Patent No. 4,721,709, issued Jan. 26, 1988. Ex. 1011
`(“Seth”).
`
`Deodatt A. Wadke, Abu T. M. Serajuddin, and Harold Jacobson,
`Preformulation Testing in PHARMACEUTICAL DOSAGE FORMS:
`TABLETS, VOL. 1, Chpt. 1, pp. 1-73, Marcel Decker (Herbert A.
`Lieberman, Leon Lachman and Joseph B. Schwartz, Eds., 2nd ed.,
`
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`IPR2015-00562
`Patent 6,821,975
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`rev. and expanded 1989). Ex. 1014 (“Wadke”).
`
`Petitioner further relies on the Declaration of Harry Brittain, Ph.D.,
`
`FRSC (“Brittain Decl.”) (Ex. 1002).
`
`E. Asserted Grounds
`
`Petitioner challenges claims 1–11 of the ’975 patent on the following
`
`grounds. Pet. 12–57.
`
`Reference[s]
`
`Basis
`
`Claims challenged
`
`Daugan ‘675, Butler ‘131, Seth,
`and Wadke
`Daugan ‘675, Butler ‘131, Seth,
`Wadke, and Martin
`
`§ 103(a)
`
`111
`
`§ 103(a)
`
`5, 10, 11
`
`II. ANALYSIS
`
`A. Claim Interpretation
`
`We interpret claims using the “broadest reasonable construction in
`
`light of the specification of the patent in which [they] appear[].” 37 C.F.R.
`
`§ 42.100(b); see also Office Patent Trial Practice Guide, 77 Fed. Reg.
`
`48756, 48766 (Aug. 14, 2012); In re Cuozzo Speed Techs., LLC, No. 2014-
`
`1301, 2015 WL 4097949, at *5–8 (Fed. Cir. July 8, 2015) (“Congress
`
`implicitly approved the broadest reasonable interpretation standard in
`
`enacting the AIA,” 2 and “the standard was properly adopted by PTO
`
`regulation.”). Under the broadest reasonable construction standard, claim
`
`terms are given their ordinary and customary meaning, as would be
`
`understood by one of ordinary skill in the art at the time of the invention. In
`
`
`2 The Leahy-Smith America Invents Act, Pub. L. No. 11229, 125 Stat. 284
`(2011) (“AIA”).
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`IPR2015-00562
`Patent 6,821,975
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`re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007). “Absent
`
`claim language carrying a narrow meaning, the PTO should only limit the
`
`claim based on the specification . . . when [it] expressly disclaim[s] the
`
`broader definition.” In re Bigio, 381 F.3d 1320, 1325 (Fed Cir. 2004).
`
`“Although an inventor is indeed free to define the specific terms used to
`
`describe his or her invention, this must be done with reasonable clarity,
`
`deliberateness, and precision.” In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir.
`
`1994).
`
`We interpret the following terms of the challenged claims as part of
`
`our analysis. The Petition does not require explicit construction of any other
`
`claim term at this time. See, e.g., Wellman, Inc. v. Eastman Chem. Co., 642
`
`F.3d 1355, 1361 (Fed. Cir. 2011) (“[C]laim terms need only be construed ‘to
`
`the extent necessary to resolve the controversy.’”) (quoting Vivid Techs.,
`
`Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999)).
`
`As Petitioner notes, however, the claim terms “free drug” and “d90”
`
`are expressly defined in the ’975 patent. Pet. 2223. According to the ‘975
`
`patent, “[t]he term ‘free drug’ refers to solid particles of Compound (I) not
`
`intimately embedded in a polymeric coprecipitate.” Ex. 1001, 4:56.
`
`The meaning of the term “d90” is explained in the following passage:
`
`The nomenclature describing the particle size of compound (I)
`is commonly referred to, and is herein, as the “d90.” For
`example, a d90 of 40 (or d90=40) means that at least 90% of
`the particles have a particle size of less than 40 microns.
`
`Id. at 4:2529.
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`IPR2015-00562
`Patent 6,821,975
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`Patent Owner agrees with the Specification’s definitions and does not
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`oppose the adoption of the ’975 patent specification’s definitions at this
`
`stage. Prelim. Resp. 10.
`
`B. Principles of Law
`
`An inter partes review may be instituted only if “the information
`
`presented in the [Petition and Preliminary Response] shows that there is a
`
`reasonable likelihood that the petitioner would prevail with respect to at
`
`least 1 of the claims challenged in the petition.” 35 U.S.C. § 314(a). To
`
`prevail in its challenges to the patentability of the claims, a petitioner must
`
`establish facts supporting its challenges by a preponderance of the evidence.
`
`35 U.S.C. § 316(e); 37 C.F.R. § 42.1(d).
`
`A claim is unpatentable under 35 U.S.C. § 103(a) if the differences
`
`between the subject matter sought to be patented and the prior art are such
`
`that the subject matter as a whole would have been obvious at the time the
`
`invention was made to a person having ordinary skill in the art to which said
`
`subject matter pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
`
`(2007). The question of obviousness is resolved on the basis of underlying
`
`factual determinations, including: (1) the scope and content of the prior art;
`
`(2) any differences between the claimed subject matter and the prior art;
`
`(3) the level of skill in the art; and (4) objective evidence of nonobviousness,
`
`i.e., secondary considerations. See Graham v. John Deere Co., 383 U.S. 1,
`
`17–18 (1966).
`
`As to secondary considerations, we note that factual inquiries for an
`
`obviousness determination include secondary considerations based on
`
`evaluation and crediting of objective evidence of nonobviousness. Graham
`
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`IPR2015-00562
`Patent 6,821,975
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`v. John Deere Co., 383 U.S. 1, 17 (1966). Notwithstanding what the
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`teachings of the prior art would have suggested to one with ordinary skill in
`
`the art at the time of the invention, the totality of the evidence submitted,
`
`including objective evidence of nonobviousness, may lead to a conclusion
`
`that the claimed invention would not have been obvious to one with ordinary
`
`skill in the art. In re Piasecki, 745 F.2d 1468, 1471–1472 (Fed. Cir. 1984).
`
`Such a conclusion, however, requires the finding of a nexus to
`
`establish that the evidence relied upon traces its basis to a novel element in
`
`the claim and not to something in the prior art. Institut Pasteur & Universite
`
`Pierre Et Marie Curie v. Focarino, 738 F.3d 1337, 1347 (Fed. Cir. 2013).
`
`All types of objective evidence of nonobviousness must be shown to have
`
`nexus. In re GPAC Inc., 57 F.3d 1573, 1580 (Fed. Cir. 1995) (nexus
`
`generally); In re Kao, 639 F.3d 1057, 1069 (Fed. Cir. 2011) (unexpected
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`results); In re Huang, 100 F.3d 135, 140 (Fed. Cir. 1996) (commercial
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`success); Rambus Inc. v. Rea, 731 F.3d 1248, 1256 (Fed. Cir. 2013) (long-
`
`felt need).
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`Objective evidence of nonobviousness also must be reasonably
`
`commensurate in scope with the claim. In re Kao, 639 F.3d at 1068. This
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`does not mean that the proffered evidence must reach every embodiment
`
`within the scope of the claim, so long as an “adequate basis to support the
`
`conclusion that other embodiments falling within the claim will behave in
`
`the same manner.” Id.
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`We analyze the instituted grounds of unpatentability in accordance
`
`with the above-stated principles.
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`IPR2015-00562
`Patent 6,821,975
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`C. Asserted Grounds of Unpatentability
`
`1. Scope and Content of the Prior Art
`
`a. Summary of Daugan (Ex. 1006)
`
`Daugan discloses a class of β-carboline compounds defined by a
`
`structural formula (I). Ex. 1006, 2. Daugan specifically identifies tadalafil
`
`as a compound of the invention, disclosed as (6R,12aR)-2,3,6,7,12,12a-
`
`hexahydro-2-methyl-6-(3,4-methylene-dioxyphenyl)pyrazino[2’,1’:6.1]
`
`pyrido[3,4-b]indole-1,4-dione. Id. at 3:24–25; Prelim. Resp. 1415.
`
`Daugan discloses that the compounds of the invention may be used
`
`for treating male or female sexual dysfunction. Id. at 4:2528.
`
`Daugan discloses formulating the compounds together with excipients
`
`or a pharmaceutically acceptable diluent or carrier. Id. at 5:1521, 3236.
`
`b. Summary of Butler (Ex. 1008)
`
`Butler “relates to the field of solid dispersions of poorly water soluble
`
`drugs, to processes for their preparation and their use in pharmaceutical
`
`compositions,” and identifies co-precipitation as “a recognised technique for
`
`increasing the dissolution of poorly water soluble drugs.” Ex. 1008, 1:35,
`
`1516.
`
`Butler formulates tadalafil (referred to as “Compound A”) as a
`
`polymeric co-precipitate. Id. at 4:1521, 5:129, 14:1315:16, 16:117:4.
`
`Butler discloses tadalafil as a poorly water soluble drug. Id. at 5:47.
`
`c. Summary of Seth (Ex. 1011)
`
`Seth discloses pharmaceutical compositions of hydrophobic drugs
`
`adsorbed onto carriers such as starch and/or microcrystalline cellulose.
`
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`IPR2015-00562
`Patent 6,821,975
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`Ex. 1011, Abstract. Seth describes the problem to be solved in the
`
`following:
`
`It is a common observation that when poorly soluble,
`hydrophobic drug substances are employed in the preparation
`of solid dosage forms such as tablets or capsules, their rate of
`dissolution is rather slow. As a result, their absorption from the
`gastrointestinal tract into systemic blood of the body is slow.
`However, if such drugs are to be administered in oral dosage
`forms and to be used for clinical indications where a rapid onset
`of therapeutic activity is desirable, the slow rate of dissolution
`and slow rate of absorption can put very great limitations on
`their therapeutic utility.
`
`A frequently used method to overcome such problems is
`to finely grind or ‘micronise’ drug substances so as to reduce
`their particle size. For example high speed running pin mills or
`air-jet mills are used to reduce the particle-size to a range of 5-
`10 microns. A major disadvantage of such grinding methods is
`the resulting tendency of the milled particles to agglomerate
`and the formation of an electrostatic charge on their surfaces
`which leads to poor flow and wetting of the particles. These
`disadvantages may even negative the very purpose of obtaining
`a faster rate of dissolution by the particle-size reduction.
`
`Id. at 2:913. Seth further discloses the following:
`
`The problem is solved by providing a dry powder
`pharmaceutical composition containing a hydrophobic, poorly
`soluble drug that is adsorbed on to a pharmaceutical carrier
`preferably an organic pharmaceutical carrier such as starch or
`cellulose and is characterised in that the drug is present in
`particulate form and that the drug particles have a mean particle
`size of less than 10 microns and a particle size distribution such
`that at least 95% of particles are smaller than 15 microns.
`
`Id. at 4:4452 (emphasis added).
`
`Seth discloses that “[t]he drug particles have a mean size of less than
`
`10 microns the size distribution of particles being such that at least 95% of
`
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`particles are smaller than 15 microns.” Id. Seth further discloses that “high
`
`speed running pin mills or air-jet mills are used to reduce the particle-size to
`
`a range of 5-10 microns.” Id. 2:913; Ex. 1002, ¶¶ 34, 47 and 53.
`
`
`
`Seth discloses that the particle size distribution is preferably “at least
`
`95% of the particles are less than 9 microns.” Id. at 6:2122. The
`
`compositions may be compressed into tablets for oral administration. Id. at
`
`8:1718; Ex. 1002, ¶ 35.
`
`d. Summary of Wadke (Ex. 1014)
`
`Wadke discloses the following:
`
`It is now generally recognized that poorly soluble drugs
`showing a dissolution rate-limiting step in the absorption
`process will be more readily bioavailable when administered in
`a finely subdivided state than as a coarse material. Very fine
`materials are difficult to handle; but many difficulties can be
`overcome by creating solid solution of a material of interest in a
`carrier, such as a water-soluble polymer.
`
`Ex. 1014, 5 (internal citation omitted).
`
`Wadke discloses that grinding poorly water-soluble materials
`
`increases dissolution rate and that “[g]rinding should reduce coarse material
`
`to, preferably, the 10- to 40- μm range.” Id. at 56; Ex. 1002, ¶¶ 34, 87-97.
`
`e. Summary of Martin (Ex. 1010)
`
`Martin discloses “compositions of poorly soluble or water insoluble
`
`drugs which provide higher dissolution rates in vitro and increased
`
`bioavailability of said drugs in vivo.” Ex. 1010, 3:1417, 4:2430. The
`
`formulations of Martin “comprises a mixture or solution of the drug with a
`
`nontoxic, pharmacologically acceptable water soluble polymer wherein said
`
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`mixture or solution has been treated with a minor amount of a wetting agent
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`selected from anionic and cationic surfactants.” Id. at 3:1722.
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`The mixture may be “milled, screened or ground prior to formulating
`
`into suitable dosage forms with pharmaceutically acceptable excipients.”
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`Id., 6:9-12. The mixture may be compressed to form solid dosage forms. Id.
`
`at 15:130.
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`2. Obviousness of Claims 111 Over the Combination of Daugan,
`Butler, Seth, and Wadke
`
`a. Claims 18
`
`Claims 14 are directed to a free drug particulate form of tadalafil,
`
`wherein at least 90% of the drug particles are less than about 40 microns to
`
`less than about 10 microns. Ex 1001, 13:4114:10. Claim 5 is directed to
`
`“[a] pharmaceutical solid composition comprising the free drug particulate
`
`form as in any one of claims 14 and one or more pharmaceutically-
`
`acceptable carriers, diluents, or excipients.” Id. at 14:1114. Claims 68
`
`relate to a method of treating sexual dysfunction by administering “a solid
`
`composition comprising the free drug particulate form as in any one of
`
`claims 14 and one or more pharmaceutically-acceptable carriers, diluents,
`
`or excipients.” Id. at 14: 1525.
`
`Petitioner contends that claims 1–8 would have been obvious over the
`
`combination of Daugan, Butler, Seth, and Wadke. In support of its assertion
`
`that the combination of Daugan, Butler, Seth, and Wadke renders claims 1–8
`
`obvious, Petitioner sets forth the foregoing teachings of Daugan, Butler,
`
`Seth, and Wadke and provides a detailed claim chart explaining how each
`
`claim limitation is disclosed in the combination of references. Pet. 2539.
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`Specifically, Petitioner contends that tadalafil is a known drug (id., citing
`
`Ex. 1006) and known to be characterized by poor solubility (id., citing Ex.
`
`1008). Petitioner contends that “Seth teaches micronization of a
`
`hydrophobic poorly soluble drug to improve its dissolution and
`
`bioavailability.” Id. at 31 (citing 4:4452). Petitioner reasons that “it would
`
`have been routine to grind the drug particles to the 10 to 40 micron range
`
`specified in the ‘975 patent.” Id. at 27 (citing Ex. 1014); see also, Ex. 1002,
`
`¶ 81 (“[T]the best formulation will be the one that yields fine (i.e., very
`
`small) particles of ‘free drug’ in the dissolution medium.”).
`
`Regarding claim 5, Petitioner contends that Daugan discloses that the
`
`compounds disclosed therein may be admixed with pharmaceutical
`
`excipients and administered as tablets or capsules. Pet. 3940 (citing Ex.
`
`1006, 5:1521; Ex. 1002, ¶¶ 6065.
`
`Regarding claims 68, Petitioner contends that Daugan discloses that
`
`compounds disclosed therein may be used for treating male or female sexual
`
`dysfunction. Pet. 38 (citing Ex. 1006, 4:2528).
`
`At this stage of the proceeding, Patent Owner contends that the
`
`Petitioner does not identify a prior art disclosure of the claimed “free drug
`
`particulate form” of tadalafil. Prelim. Resp. 1119. Patent Owner does not
`
`challenge whether the combination of references teaches any other limitation
`
`of claims 1–8, id., and we are persuaded that the asserted combination of
`
`references disclose these additional limitations of claims 1–8. See Pet. 25–
`
`39. We are not persuaded on this record, however, by Patent Owner’s
`
`contention that the claimed “free drug particulate form” is not disclosed.
`
`This argument is unpersuasive as it addresses the individual teachings of the
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`IPR2015-00562
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`references rather than what is taught or suggested by the combination of
`
`references. That is, the fact that Daugan may not disclose tadalafil in free
`
`drug particulate form is not sufficient to establish that one would not
`
`consider the teachings of Seth and Wadke, which disclose the preparation of
`
`drug particulates for poorly water soluble drugs, in combination with
`
`Daugan. Based on the current record, the combination of Seth, Wadke, and
`
`Daugan, taken as a whole, appears to disclose the claimed “free drug
`
`particulate form" to one of skill in the art. See In re Merck & Co. Inc., 800
`
`F.2d 1091, 1097 (Fed. Cir. 1986) (stating that each reference “must be read,
`
`not in isolation, but for what it fairly teaches in combination with the prior
`
`art as a whole.”). Seth, for example, discloses that “a conventional method
`
`for increasing the rate of dissolution of solids is by reduction of their particle
`
`size by micronisation or similar dry grinding methods.” Ex. 1011, 3:6467.
`
`This disclosure alone appears to meet the claim element for a micronized
`
`free drug of claim 1, which only requires drug in particulate form.
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`Patent Owner further contends that the Petition fails to address a
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`motivation to prepare the “free drug particulate form” in view of the art’s
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`contrary teachings in Butler and Seth. Prelim. Resp. 1922. We are not
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`persuaded on this record. As addressed above, the Petition sets forth where
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`each claim limitation is disclosed in the combination of references. In KSR,
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`the Court offered guidance on when a combination might be obvious under §
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`103:
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`When a work is available in one field, design incentives and
`other market forces can prompt variations of it, either in the
`same field or in another. If a person of ordinary skill in the art
`can implement a predictable variation, and would see the
`benefit of doing so, § 103 likely bars its patentability.
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`Moreover, if a technique has been used to improve one device,
`and a person of ordinary skill in the art would recognize that it
`would improve similar devices in the same way, using the
`technique is obvious unless its actual application is beyond that
`person’s skill. A court must ask whether the improvement is
`more than the predictable use of prior art elements according to
`their established functions.
`
`550 U.S. at 401. Here, the Petitioner has set forth its case that tadalafil is a
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`poorly soluble drug and that it was known that grinding poorly water-soluble
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`materials to the 10- to 40- μm range increases dissolution rate of the drug,
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`thereby increasing its bioavailability. Pet. 13, 16, 1921, 2728; Ex. 1011,
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`1:65–2:8; Ex. 1014, 56; Ex. 1002, ¶¶ 34, 4547, 82, 8697.
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`Patent Owner contends that “Butler identified a problem, discovered
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`an inventive solution that worked, and disclosed no further problem with
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`tadalafil’s solubility to be solved.” Prelim. Resp. 21. We are not persuaded
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`on the current record that the products disclosed in Butler would have
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`deterred a person of ordinary skill in the art from improving the dissolution
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`rate and bioavailability of tadalafil using the techniques described in, for
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`example, Seth and Wadke. Furthermore, this argument fails to address what
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`Butler, in combination with the prior art as a whole, suggests to a person of
`
`ordinary skill in the art. Here, we note that Butler is relied upon for its
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`disclosure of tadalafil as a poorly water soluble drug. Pet. 3031. Seth and
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`Wadke are relied upon for the teachings of finely grinding drug substances
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`for improved solubility. Id.
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`Patent Owner contends that Wadke discloses “a long list” of problems
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`associated with micronization of drug particles that “undermin[e] the
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`premise of the petition that it would have been obvious to micronize a ‘free
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`drug particulate form’ of tadalafil.” Prelim. Resp. 24 (citing Ex. 1014, ¶ 2–
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`6). Patent Owner further contends that Wadke discloses that co-precipitation
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`methods like that of Butler “represents the ultimate in size reduction,” and
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`explains the many unpredictable problems associated with micronizing
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`generally. We are not persuaded on this record. The passage of Wadke
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`relied upon by Patent Owner discloses as follows:
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`Very fine materials are difficult to handle; but many difficulties
`can be overcome by creating solid solution of a material of
`interest in a carrier, such as a water-soluble polymer. This
`represents the ultimate in size reduction, since in a (solid)
`solution, the dispersed material of interest exists as discrete
`molecules or agglomerated molecular bundles of very small
`dimensions indeed.
`
`Ex. 1014, 5. This passage from Wadke appears to disclose a preference for a
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`mixture of drug and polymer. We note, however, that Petitioner also relies
`
`on Seth for the teaching of a “drug in particulate form.” Pet. 31. Despite the
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`difficulties and disadvantages associated with finely grinding drug
`
`substances disclosed in Wadke, Seth discloses that grinding or milling is “[a]
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`frequently used method to overcome” a slow rate of dissolution and slow
`
`rate of absorption. Ex. 1011, 2:113. Furthermore, Seth discloses a method
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`of preparing a pharmaceutical composition where a “drug is present in
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`particulate form and that the drug particles have a mean particle size of less
`
`than 10 microns and a particle size distribution such that at least 95% of
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`particles are smaller than 15 microns.” Ex. 1011, 4:4452 (emphasis
`
`added). We understand Seth to disclose a process in which a drug is
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`provided in particulate form, which is distinct from the process disclosed, for
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`example, in Butler, which relates to the milling of coprecipitates of a drug
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`and polymer. Ex. 1008, 4:1521, 5:129, 14:1315:16, 16:117:4.
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`Moreover, even if co-precipitation methods like that of Butler
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`“represent[] the ultimate in size reduction,” it does not compel us to ignore
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`evidence of record (Ex. 1011, 3:6467) indicating that micronization of drug
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`substances for the purposes of improving dissolution rate was a conventional
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`method known in the art. In re Mouttet, 686 F.3d 1322, 1334 (Fed. Cir.
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`2012)(“[J]ust because better alternatives exist in the prior art does not mean
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`that an inferior combination is inapt for obviousness purposes.”).
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`Furthermore, we note that there is no evidence on the current record to show
`
`that providing tadalafil in free drug particulate form was uniquely
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`challenging or difficult for one of ordinary skill in the art.
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`On this record, we are persuaded that the combination of Daugan,
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`Butler, Seth, and Wadke suggest tadalafil in free drug particulate form, the
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`claim element that Patent Owner asserts is not taught by the combination.
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`Accordingly, we conclude that Petitioner has presented sufficient
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`information to show a reasonable likelihood that it would prevail in showing
`
`that claims 1–8 of the ’975 patent would have been obvious over the
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`combination of Daugan, Butler, Seth, and Wadke.
`
`b. Claims 9 and 10
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`Claims 9 and 10 are directed to a method of manufacturing the free
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`drug particulate form comprising the step of comminuting the solid free
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`form of the compound to provide particles of the compound wherein at least
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`90% of the particles have a particle size of less than about 40 microns.
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`Patent Owner contends that the Petition’s grounds “do not show or
`
`address the elements of claims 9 and 10, fail to discuss them in combination,
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`and fail to set forth a prima facie case of obviousness of those claims.”
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`Prelim. Resp. 30. We are not persuaded by these arguments on this record.
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`As set forth in the Petition, the comminuting step of claim 9 is met by the
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`grinding or milling step disclosed in the cited references. Pet. 37; Ex. 1011,
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`2:913, 4:4452; Ex. 1002 ¶¶ 37, 5354. The admixing step of claim 10 is
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`met by the disclosure of Daugan related to the formulations of compound
`
`together with excipients or a pharmaceutically acceptable diluent or carrier.
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`Pet. 39 42.
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`Accordingly, we conclude that Petitioner has presented sufficient
`
`information to show a reasonable likelihood that it would prevail in showing
`
`that claims 9 and 10 of the ’975 patent would have been obvious over the
`
`combination of Daugan, Butler, Seth, and Wadke.
`
`c. Claim 11
`
`Patent Owner disclaims claim 11. Prelim. Resp. 9. There is no
`
`evidence of record indicating that a statutory disclaimer under 35 U.S.C.
`
`253(a) in compliance with § 1.321(a) was filed. 37 C.F.R. § 42.107(e). As
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`such, claim 11 is included in this inter partes review until a statutory
`
`disclaimer under 35 U.S.C. 253(a) in compliance with § 1.321(a) is filed.
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`d. Patent Owner’s Evidence of Unexpected results
`
`In its Preliminary Response, Patent Owner relies on the Declaration of
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`Martha A. Kral (Ex. 2012 (“Kral Decl.”)), which is a 37 C.F.R. § 1.132
`
`declaration submitted during the prosecution of the’958 patent. Prelim.
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`Resp. 45, 21, 2728, 37, 4041, 4751. Patent Owner contends that the
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`Kral Declaration contains data “demonstrating, through experiment, a
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`combination of unexpected results such as unexpectedly rapid onset of the
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`therapeutic effect, enhanced bioavailability, uniform potency, and desirable
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`increased stability of those formulations.” Id. at 5. We are not persuaded,
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`based on the current record, for the reasons that follow.
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`Much of the discussion in the Kral Declaration compares the
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`compositions of the’958 patent with the compositions of Daugan. Ex. 2012,
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`¶¶ 913. Seth, however, is relied upon by the Petitioner for the disclosure of
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`micronizing drug substances for the purposes of increasing dissolution rate
`
`and enhancing bioavailability of the drug when administered in oral dosage
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`form. Pet. 31 (citing Ex. 1002, ¶ 37). In this regard, the Kral Declaration
`
`does address the teachings of Seth, and specifically provides as follows:
`
`Seth did not teach nor suggest how to utilize micronised free
`drug to improve bioavailability without adsorbing the drug to
`the carrier. Surprisingly, our invention was able to use
`micronised free drug without adsorbing the drug on to a carrier
`to achieve uniform potency, rapid absorption, and improved
`bioavailability.
`
`Ex. 2012, ¶ 14.
`
`The claims, however, do not recite a pharmaceutical composition
`
`requiring micronized free drug without adsorbing the drug on to a carrier.
`
`Claim 1, for example, requires micronized tadalafil not intimately embedded
`
`in a polymeric coprecipitate. See discussion in Sec. II.A above regarding the
`
`construction of the claim term “free drug.” Claim 5, on the other hand,
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`requires the micronized tadalafil of claim 1 and “one or more
`
`pharmaceutically-acceptable carriers, diluents, or excipients.” Likewise,
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`claim 10 recites a method in which the micronized tadalafil is admixed with
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`“with one or more pharmaceutically-acceptable carriers, diluents, or
`
`excipients.”
`
`Based on the current record, it appears that intimate