Trials@uspto.gov
`571.272.7822
`
`
`
`
`
` Paper No. 35
` Entered: June 5, 2019
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`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`FLATWING PHARMACEUTICALS, LLC and
`MYLAN PHARMACEUTICALS INC.,
`Petitioners,
`
`v.
`
`ANACOR PHARMACEUTICALS, INC.,
`Patent Owner.
`____________
`
`Case IPR2018-001691
`Patent 9,566,289 B2
`____________
`
`
`Before GRACE KARAFFA OBERMANN, TINA E. HULSE, and
`JACQUELINE T. HARLOW, Administrative Patent Judges.
`
`HULSE, Administrative Patent Judge.
`
`
`
`
`
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
`
`1 Case No. IPR2018-01359 has been joined with this proceeding.
`
`
`
`
`571.272.7822
`
`
`
`
`
` Paper No. 35
` Entered: June 5, 2019
`
`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`FLATWING PHARMACEUTICALS, LLC and
`MYLAN PHARMACEUTICALS INC.,
`Petitioners,
`
`v.
`
`ANACOR PHARMACEUTICALS, INC.,
`Patent Owner.
`____________
`
`Case IPR2018-001691
`Patent 9,566,289 B2
`____________
`
`
`Before GRACE KARAFFA OBERMANN, TINA E. HULSE, and
`JACQUELINE T. HARLOW, Administrative Patent Judges.
`
`HULSE, Administrative Patent Judge.
`
`
`
`
`
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
`
`1 Case No. IPR2018-01359 has been joined with this proceeding.
`
`
`
`
`
`IPR2018-00169
`Patent 9,566,289 B2
`
`
` INTRODUCTION
`FlatWing Pharmaceuticals, LLC (“FlatWing”) filed a Petition
`requesting an inter partes review of claims 1–15 of U.S. Patent
`No. 9,566,289 B2 (Ex. 1001, “the ’289 patent”). Paper 1 (“Pet.”). Anacor
`Pharmaceuticals, Inc. (“Patent Owner”) did not file a Preliminary Response
`to the Petition. On June 8, 2018, we instituted an inter partes review of
`claims 1–15 of the ’289 patent. Paper 9 (“Dec. Inst.”), 16. On October 11,
`2018, we granted Mylan Pharmaceuticals, Inc.’s (collectively with
`FlatWing, “Petitioners”) Motion for Joinder (IPR2018-01359, Paper 3), and
`joined Case IPR2018-01359 with this proceeding. Paper 16.
`Patent Owner filed a Response to the Petition. Paper 13 (“PO
`Resp.”). Petitioners filed a Reply. Paper 19 (“Pet. Reply”). With our
`authorization, Patent Owner filed a Surreply. Paper 24 (“PO Surreply”).
`The parties also filed Motions to Exclude certain evidence. Paper 23
`(Patent Owner’s Motion); Paper 27 (Petitioners’ Motion). The parties filed
`responsive papers to those motions. Paper 30 (Petitioners’ Opposition to
`Patent Owner’s Motion); Paper 33 (Patent Owner’s Amended Reply to
`Petitioners’ Opposition); Paper 29 (Patent Owner’s Opposition to
`Petitioners’ Motion); Paper 31 (Petitioners’ Reply to Patent Owner’s
`Opposition).
`An oral hearing was held on March 1, 2019, a transcript of which has
`been entered in the record. Paper 34 (“Tr.”).
`We have authority under 35 U.S.C. § 6. This Final Written Decision
`is issued pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73.
`
`1
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`
`
`IPR2018-00169
`Patent 9,566,289 B2
`For the reasons that follow, we determine Petitioners have shown by a
`preponderance of the evidence that claims 1–15 of the ’289 patent are
`unpatentable as obvious.
`Related Proceedings
`A.
`Petitioners filed three other petitions for inter partes review of related
`patents: U.S. Patent No. 9,549,938 (IPR2018-00168), U.S. Patent No.
`9,566,290 (IPR2018-00170), and U.S. Patent No. 9,572,823 (IPR2018-
`00171). Paper 4, 2.
`A fourth proceeding, Case IPR2015-01776, was filed by a different
`petitioner and is an inter partes review of U.S. Patent No. 7,582,621 (“the
`’621 patent”), which, according to Patent Owner, “asserts substantially the
`same claim of priority as U.S. Patent No. 9,566,289.” Id. The Board there
`determined each of the claims of the ’621 patent was unpatentable over the
`prior art. Coalition for Affordable Drugs X LLC v. Anacor Pharms., Inc.,
`Case IPR2015-01776, slip op. at 42 (PTAB Feb. 23, 2017) (Paper 70). The
`Federal Circuit affirmed the Board’s final written decision as to claim 6 of
`the ’621 patent (the only claim on appeal) in Anacor Pharmaceuticals, Inc.
`v. Iancu, 889 F.3d 1372, 1385 (Fed. Cir. 2018).
`The parties also identify U.S. Patent Application Nos. 15/355,393 and
`15/355,813 as administrative matters that may be affected by this
`proceeding. Pet. x; Paper 4, 2.
`The ’289 Patent
`B.
`The ’289 patent relates to boron-containing compounds useful for the
`topical treatment of onychomycosis and/or cutaneous fungal infections.
`Ex. 1001, Abstract. The claimed invention is directed to compounds that are
`active against fungi and have physiochemical properties that facilitate
`penetration of the nail plate. Id. According to the Specification, current
`
`2
`
`
`
`IPR2018-00169
`Patent 9,566,289 B2
`treatment for ungual and/or periungual infections generally falls into three
`categories: systemic administration of medicine; surgical removal of the
`nail or hoof followed by topical treatment of the exposed tissue; or topical
`application of medicine with bandages to keep the medication in place on
`the nail or hoof. Id. at 1:47–53.
`Each of those approaches has major drawbacks. Id. at 1:53–54.
`Systemic administration of medicine typically requires long-term, high-dose
`therapy, which can have significant adverse effects on, for example, the liver
`and testosterone levels, which further negatively affects patient compliance.
`Id. at 1:58–2:8. Surgical treatment is painful and undesirable cosmetically
`(or not realistic for animals such as horses). Id. at 2:10–16. And topical
`dosage forms cannot keep the drug in contact with the infected area for
`therapeutically effective periods of time and, because of the composition of
`the nail, topical therapy for fungal infections have generally been
`ineffective. Id. at 2:17–41. Accordingly, the Specification states that “there
`is a need in the art for compounds which can effectively penetrate the nail.
`There is also need in the art for compounds which can effectively treat
`ungual and/or periungual infections.” Id. at 2:66–3:2.
`Dermatophytes are the most common cause of onychomycosis. Id.
`at 131:29–31. Onychomycosis caused by a dermatophyte is called Tinea
`unguium. Id. at 131:31–32. The most frequently isolated dermatophyte in
`Tinea unguium is Trichophyton rubrum (T. rubrum) followed by
`Trichophyton mentagrophytes (T. mentagrophytes). Id. at 131:32–33.
`
`3
`
`
`
`IPR2018-00169
`Patent 9,566,289 B2
`The ’289 patent claims a pharmaceutical formulation comprising 1,3-
`dihydro-5-fluoro-l-hydroxy-2, 1-benzoxaborole, which is referred to as
`compound 1 (see id. at 137:52–61) or compound C10 (see id. at 180:21) in
`the Specification, and has the chemical structure shown below.
`
`
`
`
`
`Illustrative Claim
`C.
`Petitioners challenge claims 1–15 of the ’289 patent, of which
`claims 1, 4, and 12 are independent claims. As explained further
`below, Patent Owner concedes that claims 1–9 and 11 are
`unpatentable, and contests only claims 10 and 12–15. Of the
`remaining claims, claim 12 is illustrative and is reproduced below:
`12. A pharmaceutical formulation, comprising:
`about 5% w/w 1,3-dihydro-5-fluoro-l-hydroxy-2,1-
`benzoxaborole, or a pharmaceutically acceptable salt
`thereof;
`propylene glycol;
`ethanol; and
`ethylene diamine tetraacetic acid (EDTA) or a
`pharmaceutically acceptable salt thereof.
`Ex. 1001, 324:12–19.
`Claim 10 depends from claim 4 and further requires a 5% w/w
`concentration of 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole
`(referred to by the parties as “tavaborole” (Dec. Inst. 7)). Id. at
`
`4
`
`
`
`IPR2018-00169
`Patent 9,566,289 B2
`324:3–6. Claim 13 depends from claim 12 and claim 15 depends
`from claim 14, and further requires that the formulation be suitable for
`the treatment of onychomycosis due to T. rubrum or T.
`mentagrophytes by topical application. Id. at 324:20–33. Claim 14
`depends from claim 12 and further recites that a specific concentration
`range of EDTA. Id. at 324:25–28.
`
`The Instituted Grounds of Unpatentability
`D.
`We instituted trial on the following grounds:
`References
`Basis
`Claims challenged
`Austin2 and Brehove3
`§ 103
`1 and 2
`
`Austin, Brehove, and Samour4
`
`§ 103
`
`4–7, 10, and 11
`
`Austin, Brehove, Samour, and
`the Excipients Handbook5
`Austin and Freeman6
`
`§ 103
`
`§ 103
`
`3, 8, 9, and 12–15
`
`1 and 2
`
`Austin, Freeman, and Samour
`
`§ 103
`
`4–7, 10, and 11
`
`
`2 Austin et al., WO 95/33754, published Dec. 14, 1995 (“Austin,” Ex. 1007).
`3 Brehove, US 2002/0165121 A1, published Nov. 7, 2002 (“Brehove,”
`Ex. 1008).
`4 Samour et al., US 6,224,887 B1, issued May 1, 2001 (“Samour,”
`Ex. 1010).
`5 PJ Weller, Handbook of Pharmaceutical Excipients 191–94 (Arthur H.
`Kibbe, ed., 3d ed. 2000) (“Excipients Handbook,” Ex. 1011)
`6 Freeman et al., WO 03/009689 A1, published Feb. 6, 2003 (“Freeman,”
`Ex. 1009).
`
`5
`
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`IPR2018-00169
`Patent 9,566,289 B2
`References
`Austin, Freeman, Samour, and
`the Excipients Handbook
`
`Dec. Inst. 16.
`
`Basis
`§ 103
`
`Claims challenged
`3, 8, 9, and 12–15
`
`Procedural History of Related Cases
`E.
`We previously found unpatentable all claims of related U.S. Patent
`Nos. 7,582,621 B2 (“the ’621 patent”) and 7,767,657 B2 (“the ’657 patent”)
`in three prior inter partes review proceedings over the same or similar prior
`art raised in this proceeding. Coalition for Affordable Drugs X LLC v.
`Anacor Pharms., Inc., Case IPR2015-01776 (PTAB Feb. 23, 2017) (Paper
`No. 70) (finding claims of the ’621 patent unpatentable as obvious over the
`combinations of (1) Austin and Brehove and (2) Austin and Freeman)
`(“-1776 IPR”); Coalition for Affordable Drugs X LLC v. Anacor Pharms.,
`Inc., Case IPR2015-01780 (PTAB Feb. 23, 2017) (Paper No. 70) (finding
`claims of the ’657 patent unpatentable as obvious over various combinations
`of references, including (1) Austin and Brehove and (2) Austin, Brehove,
`and Samour) (“-1780 IPR”); Coalition for Affordable Drugs X LLC v.
`Anacor Pharms., Inc., Case IPR2015-01785 (PTAB Feb. 23, 2017) (Paper
`No. 70) (finding claims of the ’657 patent unpatentable as obvious over
`various combinations of references, including (1) Austin and Freeman and
`(2) Austin, Freeman, and Samour) (“-1785 IPR”).
`In the Final Written Decision of the -1776 IPR, we found the
`combination of Austin and Brehove teaches each limitation of independent
`claims 1, 11, and 12 of the ’621 patent. In particular, we found Brehove
`teaches a method of treating onychomycosis by topically administering to a
`toenail a therapeutic amount of a pharmaceutical composition. Ex. 1014, 15.
`
`6
`
`
`
`IPR2018-00169
`Patent 9,566,289 B2
`We also found Austin teaches that tavaborole is effective against Candida
`albicans. Id. We found a person of ordinary skill in the art would have
`selected tavaborole from among the numerous compounds disclosed by
`Austin because Austin describes tavaborole as a preferred fungicide and as
`having the lowest Minimum Inhibitory Concentration7 (“MIC”) against
`several pathogens, including C. albicans. Id. at 15–16. We also found that a
`person of ordinary skill in the art would have had a reason to combine
`Austin and Brehove in light of the structural similarities and the similar
`fungicidal activity against C. albicans. Id. at 21. Moreover, although
`factors such as lipophilicity, keratin binding, and potency of the compound
`may influence transungual drug delivery, we were persuaded that low
`molecular weight is the most important factor in predicting whether a
`molecule will penetrate the nail plate, and that the remaining factors
`described by Patent Owner’s declarant, Dr. Lane, are of less importance,
`“particularly with a low molecular weight and low MIC molecule such as
`tavaborole.” Id. at 23–24. Accordingly, we determined that a person of
`ordinary skill in the art would have had a reasonable expectation that
`tavaborole administered topically would penetrate the nail. Id. at 24.
`The Final Written Decisions in the -1780 IPR and -1785 IPR were
`similar to that of the -1776 IPR. The challenged claims of the ’657 patent, at
`issue in the -1780 IPR and -1785 IPR, recite a pharmaceutical formulation
`comprising tavaborole that is for topical administration to an animal
`suffering from an infection. See, e.g., Ex. 1015, 323:2–8 (claim 1). As in
`the -1776 IPR, we found in the -1780 IPR that a person of ordinary skill in
`
`7 The Minimum Inhibitory Concentration is the lowest concentration at
`which a drug inhibits the growth of a pathogen.
`
`7
`
`
`
`IPR2018-00169
`Patent 9,566,289 B2
`the art would have had a reason to use Austin’s tavaborole in Brehove’s
`pharmaceutical composition for topical treatment of nail infections such as
`onychomycosis. Ex. 1017, 28.
`Patent Owner did not appeal the Final Written Decisions in the
`-1780 IPR or the -1785 IPR. Patent Owner only appealed the Final Written
`Decision as to claim 6 of the ’621 patent in the -1776 IPR,8 and the Federal
`Circuit affirmed our determination of unpatentability over the combination
`of Austin and Brehove.9 Anacor Pharms., 889 F.3d at 1385.
`Given those prior decisions, Patent Owner states that it
`“acknowledges the Board’s rulings in these prior cases, as well [as] the
`affirmance of the Board’s final written decision in IPR2015-01776 . . . , and
`does not challenge here limitations that were found to have been obvious in
`those proceedings.” PO Resp. 6. Patent Owner contends, however, that
`claims 10 and 12–15 of the ’289 patent in this proceeding recite a specific
`formulation of tavaborole that was not at issue in the prior proceedings. Id.
`
`
`8 Claim 6 of the ’621 patent depends from claims 1 and 4, all of which
`recite:
`1. A method of treating an infection in an animal, said method
`comprising administering to the animal a therapeutically effective
`amount of 1,3-dihydro-5-fluoro-l-hydroxy-2,1-benzoxaborole, or a
`pharmaceutically acceptable salt thereof, sufficient to treat said infection.
`4. The method of claim 1, wherein said infection is onychomycosis.
`6. The method of claim 4, wherein said onychomycosis is tinea
`unguium.
`Anacor Pharms., 889 F.3d at 1375.
`9 The Federal Circuit did not address the unpatentability of claim 6 over the
`combination of Austin and Freeman because it affirmed our conclusion that
`claim 6 was obvious over the combination of Austin and Brehove. Id. at
`1376 n.2.
`
`8
`
`
`
`IPR2018-00169
`Patent 9,566,289 B2
`Specifically, Patent Owner contends that tavaborole at a 5% w/w
`concentration was not considered by the Board or the Federal Circuit and is
`not obvious over the cited prior art. Id. at 6–7. For those claims that do not
`recite the 5% w/w concentration limitation, counsel for Patent Owner
`concedes that they are unpatentable. Tr. 33:11–18.10
`Accordingly, we focus this Decision primarily on Petitioners’
`challenges to claims 10 and 12–15 of the ’289 patent.
` ANALYSIS
`Person of Ordinary Skill in the Art
`A.
`Petitioners assert that a person of ordinary skill in the art at the time of
`the invention would have had either a Master’s degree or Ph.D. in chemistry,
`pharmacology, or biochemistry, and at least two years of experience with the
`research, development, or production of pharmaceuticals. Pet. 18 (citing
`Ex. 1005 ¶¶ 19–21; Ex. 1003 ¶ 22). Patent Owner does not address the level
`of ordinary skill in the art in its Patent Owner Response.
`
`
`10 We appreciate the candor of Patent Owner’s counsel during oral
`argument:
`
`JUDGE HULSE: [D]o you concede that the other claims
`[that do not recite the 5% w/w limitation] are invalid per our prior
`decisions and the Federal Circuit decision?
`MR. MAURER: Correct. We’re not challenging the
`petition on those claims as a result of the prior determinations
`that were made.
`JUDGE HULSE: You’re not challenging it; but do you
`concede that they are unpatentable?
`MR MAURER: Right. We’re not defending those other
`claims. Yes; we concede that they are unpatentable.
`Tr. 33:11–18.
`
`9
`
`
`
`IPR2018-00169
`Patent 9,566,289 B2
`Absent opposition from Patent Owner, we accept and adopt
`Petitioners’ description of the level of ordinary skill in the art because it is
`consistent with the level of skill reflected in the asserted prior art references.
`In that regard, the prior art itself is sufficient to demonstrate the level of skill
`in the art at the time of the invention. See Okajima v. Bourdeau, 261 F.3d
`1350, 1355 (Fed. Cir. 2001) (explaining that specific findings regarding
`ordinary skill level are not required “where the prior art itself reflects an
`appropriate level and a need for testimony is not shown” (quoting Litton
`Indus. Prods., Inc. v. Solid State Sys. Corp., 755 F.2d 158, 163 (Fed. Cir.
`1985))).
`
`Claim Construction
`B.
`In an inter partes review, the Board interprets claim terms in an
`unexpired patent according to the broadest reasonable construction in light
`of the specification of the patent in which they appear. 37 C.F.R.
`§ 42.100(b) (2017);11 Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131,
`2142 (2016) (affirming applicability of broadest reasonable construction
`standard to inter partes review proceedings). Under that standard, and
`absent any special definitions, we generally give claim terms their ordinary
`and customary meaning, as would be understood by one of ordinary skill in
`the art at the time of the invention. See In re Translogic Tech., Inc., 504
`F.3d 1249, 1257 (Fed. Cir. 2007). Any special definitions for claim terms
`
`
`11 A recent amendment to this rule does not apply here, because the Petition
`was filed before November 13, 2018. See “Changes to the Claim
`Construction Standard for Interpreting Claims in Trial Proceedings Before
`the Patent Trial and Appeal Board,” 83 Fed. Reg. 51,340 (Oct. 11, 2018) (to
`be codified at 37 C.F.R. pt. 42).
`
`10
`
`
`
`IPR2018-00169
`Patent 9,566,289 B2
`must be set forth in the specification with reasonable clarity, deliberateness,
`and precision. See In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994).
`In our Decision on Institution, we construed the term “1,3-dihydro-5-
`fluoro-1-hydroxy-2,1-benzoxaborole,” which is recited in each of the
`claims, as equivalent to the compound referred to in Austin as “5-fluoro-
`1,3 dihydro-1-hydroxy-2,1-benzoxaborole” and referred to by the parties
`as “tavaborole.” Dec. Inst. 7. Neither party contests that construction.
`See generally PO Resp.; Reply. Accordingly, we adopt the construction
`and, for convenience, refer to the claimed compound as “tavaborole” in
`this Decision.
`C. Obviousness of Claims 1–9 and 11 over Austin, Brehove,
`Samour, and the Excipients Handbook
`Petitioners assert that claims 1 and 2 of the ’289 patent are
`unpatentable as obvious over the combination of Austin and Brehove.
`Pet. 31–40. Petitioners further rely on Samour to assert that claims 4–7 and
`11 are unpatentable as obvious. Id. at 41–46. And Petitioners further rely
`on the Excipients Handbook to assert that claims 3, 8, and 9 are unpatentable
`as obvious. Id. at 46–48.
`
`Austin (Ex. 1007)
`1.
`Austin relates to the use of oxaboroles as industrial biocides, and
`especially as fungicides for the protection of plastic materials. Ex. 1007, 1
`(Abstract).12 The Abstract further states that “[p]referred compounds are 5-
`and 6-fluoro or bromo-1,3-dihydro-1-hydroxy-2,1-benzoxaborole including
`O-esters thereof.” Id. Austin notes that it has been found that compounds
`
`12 Unless stated otherwise, the cited page numbers in this Decision refer to
`the page numbers provided by the parties pursuant to 37 C.F.R. §
`42.63(d)(2).
`
`11
`
`
`
`IPR2018-00169
`Patent 9,566,289 B2
`containing an oxaborole ring are “particularly effective against micro-
`organisms such as bacteria, algae, yeasts and particularly fungi, especially
`fungi which cause degradation of plastics materials.” Id. at 3:35–38.
`Along with a number of different preferred oxaboroles, Austin
`discloses tavaborole as Example 64, as well as the results of a study showing
`tavaborole has effective antifungal activity against five different fungi:
`Aspergillus niger (AN), Candida albicans (CA), Aureobasidium pullulans
`(AP), Gliocladium roseum (GR), and Penicillium pinophylum (PP). Id. at 39
`(Table 9). Of the preferred compounds tested (i.e., Examples 64, 68, and
`70), tavaborole had the lowest Minimum Inhibitory Concentration (“MIC”)
`value of five parts per million for Candida albicans. Id.; Ex. 1003 ¶ 36.
`According to Austin, “[t]he concentration of the oxaborole in the
`biocide composition is preferably up to a level at which the biocide
`composition is stable under the conditions of storage or transportation and is
`preferably from 1 to 50%, especially from 5 to 30% and more especially
`from 10 to 20% by weight relative to the total weight of the biocide
`composition.” Ex. 1007, 9:5–9.
`Brehove (Ex. 1008)
`2.
`Brehove relates to the topical treatment of nail infections such as
`onychomycosis caused by bacteria, fungi, and other pathogens. Ex. 1008
`¶ 3. Brehove explains that onychomycosis is a nail disease typically caused
`by Candida albicans, Trichophyton mentagrophytes, Trichophyton rubrum,
`or Epidermpophyton floccusum. Id. ¶ 5. Brehove states that Candida
`albicans is the most common pathogen causing onychomycosis. Id. ¶ 18.
`Brehove teaches that to be effective for onychomycosis, the topical
`treatment should exhibit a powerful potency for pathogens, be permeable
`through the nail barrier, and be safe for patient use. Id. ¶ 6. According to
`
`12
`
`
`
`IPR2018-00169
`Patent 9,566,289 B2
`Brehove, “[t]here exists a need in the art for a topical application that
`combines these traits in high degree.” Id.
`Brehove states that the “safety and non-toxicity of organo-boron
`compounds has been questioned.” Id. ¶ 13. On the one hand, Brehove
`describes one reference that states that boron compounds are “very toxic,”
`while on the other hand, Brehove describes references that found the toxicity
`of a certain boron-containing compound to be “very low” and another
`industrial fungicide compound called Biobor® JF to cause only “mild
`irritation.” Id. ¶¶ 14–15.
`Biobor® JF contains a combination of 2,2’-(1-methyltrimethylene
`dioxy) bis-(4-methyl-1, 3, 2-dioxaborinane) (referred to by Brehove as “S1”)
`and 2,2’-oxybis (4, 4, 6-trimethyl-1, 3, 2-dioxaborinane) (referred to by
`Brehove as “S2”). Id. ¶¶ 15, 30. Brehove describes the results of in vitro
`testing of the antifungal activity of S1 and S2 against Candida albicans. Id.
`¶¶ 30–33. Brehove also describes successful examples of in vivo testing of
`S1 and S2 on various patients with onychomycosis of the toenails. Id.
`¶¶ 34–38 (Examples 16–20).
`According to Brehove, the active dioxaborinane ingredient is
`preferably at least about 0.1 wt % of the composition. Id. ¶ 28. “Most
`preferably, dioxaborinane ingredient constitutes between about 0.1 wt % and
`25 wt % of the composition.” Id.
`Samour (Ex. 1010)
`3.
`Samour relates to a nail lacquer formulation effective for treating or
`preventing fungal infections, such as onychomycosis. Ex. 1010, Abstract.
`Samour states that onychomycosis is frequently caused by dermatophytes,
`
`13
`
`
`
`IPR2018-00169
`Patent 9,566,289 B2
`but can also be caused by molds and Candida. Id. at 1:22–24.13 Samour
`states “[t]here is no particular limitation on the antifungal agents used in the
`composition of this invention; any of the agents known to be effective for
`this purpose may be used.” Id. at 11:39–41. Samour also states that
`typically, “the amount of active [antifungal] agent is generally about 1 to
`50%, preferably about 2 to 35%, more preferably, from about 2 to 30%,
`especially preferably from about 5 to 20%, by weight of the composition.”
`Id. at 12:23–26. Samour’s Examples 6–8 provide examples of lacquer
`formulations containing 5% w/w active antifungal ingredient econazole with
`propylene glycol and ethanol. Id. at 21:41–24:8. Samour’s Example 9
`taught the effect of changing the concentration of econazole “for a single
`dose application,” testing the efficacy of 1%, 2%, 5%, 10%, and 20% w/w
`econazole. Id. at 24:24–25:15.
`The Excipients Handbook (Ex. 1011)
`4.
`The Excipients Handbook is an excerpt from the Handbook of
`Pharmaceutical Excipients relating to edetic acid, which is also known as
`EDTA. Ex. 1011, 1, 3. The Excipients Handbook states that EDTA is used
`in pharmaceutical formulations as chelating agents. Id. at 3. That is, EDTA
`forms “water-soluble complexes (chelates) with alkaline earth and heavy
`metal ions.” Id.
`
`Analysis
`5.
`A patent claim is unpatentable under 35 U.S.C. § 103(a) if the
`differences between the claimed subject matter and the prior art are such that
`the subject matter, as a whole, would have been obvious at the time the
`
`
`13 We cite the column and line numbers of the Samour patent rather than the
`page numbers provided by the parties.
`
`14
`
`
`
`IPR2018-00169
`Patent 9,566,289 B2
`invention was made to a person having ordinary skill in the art to which the
`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.
`Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966).
`“[A] patent composed of several elements is not proved obvious
`merely by demonstrating that each of its elements was, independently,
`known in the prior art.” KSR, 550 U.S. at 418. “[I]t can be important to
`identify a reason that would have prompted a person of ordinary skill in the
`relevant field to combine the elements in the way the claimed new invention
`does.” Id. Moreover, a person of ordinary skill in the art must have had a
`reasonable expectation of success of doing so. PAR Pharm., Inc. v. TWi
`Pharms., Inc., 773 F.3d 1186, 1193 (Fed. Cir. 2014).
`Patent Owner does not challenge Petitioners’ assertions and concedes
`that claims 1–9 and 11 are unpatentable in light of the prior proceedings.
`PO Resp. 6; Tr. 33:11–18. Having considered the arguments and evidence
`presented in the Petition, and, in light of Patent Owner’s concession of
`unpatentability, we find that each limitation of those claims is taught by the
`cited combinations of prior art and that a person of ordinary skill in the art
`would have had a reason to combine the cited references to achieve the
`claimed invention with a reasonable expectation of success for the reasons
`stated in the Petition, as supported by the cited evidence. See Pet. 31–48,
`51–61; Ex. 1005 ¶¶ 101–155, 160–184; see also Anacor Pharms., 889 F.3d
`at 1382–85 (affirming the Board’s finding that a person of ordinary skill in
`the art would have had a reason to combine Austin and Brehove to achieve
`
`15
`
`
`
`IPR2018-00169
`Patent 9,566,289 B2
`the claimed invention with a reasonable expectation of success). We further
`note that Patent Owner has not asserted any objective indicia of
`nonobviousness of the claimed invention. See Graham, 383 U.S. at 17–18.
`Accordingly, having considered the arguments and evidence presented
`at trial, we determine that Petitioners have established by a preponderance of
`the evidence that claims 1–9 and 11 are unpatentable as obvious over the
`cited prior art.
`D. Obviousness of Claims 10 and 12–15 over Austin, Brehove, and
`Samour
`Petitioners assert that claim 10 is unpatentable as obvious over the
`combination of Austin, Brehove, and Samour (Pet. 43–44) and that claims
`12–15 are unpatentable as obvious over the combination of Austin, Brehove,
`Samour, and the Excipients Handbook (id. at 48–50). We incorporate our
`findings above with respect to the teachings of those references.
`Claim 10 of the ’289 patent depends from independent claim 4, and
`claims 13–15 depend from independent claim 12. Ex. 1001, 324:3–6, 12–
`33. Each claim requires a pharmaceutical composition comprising 5% w/w
`of tavaborole.14 Id. Patent Owner contests Petitioners’ challenge only with
`respect to the 5% w/w concentration of tavaborole limitation. PO Resp. 6.
`Accordingly, the parties agree that claims 10 and 12–15, which all include
`the 5% w/w limitation, rise and fall together. Tr. 8:23–9:10; 33:7–10.
`Patent Owner also concedes that the Excipients Handbook reference is not
`relevant to its arguments with respect to the 5% w/w limitation. Id. at
`
`14 Claims 12–15 further recite a pharmaceutical formulation comprising
`propylene glycol, ethanol, and EDTA that is suitable for treating
`onychomycosis due to T. rubrum or T. mentagrophytes. Ex. 1001, 324:12–
`33. These limitations also appear in claims 1–9 and 11, found unpatentable
`above over the same prior art references. See id. at 323:2–324:2, 324:7–11.
`16
`
`
`
`IPR2018-00169
`Patent 9,566,289 B2
`40:20–25. We, therefore, focus our analysis—as the parties do—on the
`limitation requiring 5% w/w of tavaborole.
`Austin teaches a preferred concentration of tavaborole of “especially
`from 5 to 30% . . . by weight relative to the total weight of the biocide
`composition.” Ex. 1007, 9:5–9. Brehove teaches that its active organoboron
`compound “[m]ost preferably . . . constitutes between about 0.1 wt % and
`25 wt % of the composition.” Ex. 1008 ¶ 28. And Samour teaches a
`topically applied pharmaceutical composition with 5% w/w active antifungal
`ingredient, econazole. Ex. 1010, 22:20–24:23. Thus, because the use of 5%
`by weight of an antifungal agent falls within the ranges disclosed in Austin
`and Brehove, and Samour specifically teaches the use of that amount, we
`find that the combination of Austin, Brehove, and Samour teaches the
`topical application of a composition having 5% w/w of tavaborole to treat
`onychomycosis.
`Petitioners assert that a person of ordinary skill in the art would have
`had a reason to use 5% by weight of tavaborole in a pharmaceutical
`composition to treat onychomycosis. Pet. 43–44. We are persuaded that a
`preponderance of the evidence supports Petitioner’s assertion. As explained
`above, the use of 5% by weight of an antifungal agent is within the range of
`preferred concentrations of tavaborole taught by Austin as a fungicide and of
`organoboron as taught by Brehove to treat onychomycosis. Ex. 1007, 9:5–9;
`Ex. 1008 ¶ 28; Ex. 1005 ¶ 165. Moreover, Samour specifically teaches
`topically applying a pharmaceutical composition with 5% w/w active
`antifungal ingredient to treat onychomycosis. Ex. 1010, 22:20–24:23.
`Petitioners’ declarant, Dr. Narasimha Murthy, testifies that “[f]ormulating
`pharmaceutical compositions involves nothing more than routine
`experimentation based on well-known protocols.” Ex. 1005 ¶ 142. Dr.
`
`17
`
`
`
`IPR2018-00169
`Patent 9,566,289 B2
`Murthy also notes that the ’289 patent states that formulating pharmaceutical
`compositions was well known in the art. Id. (citing Ex. 1001, 162:50–60
`(“Those skilled in the art will recognize various synthetic methodologies that
`may be employed to prepare non-toxic pharmaceutical formulations
`incorporating the compounds described herein.”)).
`Petitioners further assert that a person of ordinary skill in the art
`would have had a reasonable expectation of success using 5% by weight of
`tavaborole to treat onychomycosis. Pet. 44–46. According to Petitioners’
`declarant, a person of ordinary skill in the art would have had a reasonable
`expectation of success in light of Samour’s successful use of 5% by weight
`of econazole, which has a molecular weight that is twice that of tavaborole.
`Ex. 1005 ¶¶ 143–144; Ex. 1026, 1 (disclosing molecular weight of econazole
`is 381.68 Daltons); Ex. 1027, 1 (disclosing molecular weight of tavaborole is
`151.93 Daltons). We find the evidence of record supports Petitioners’
`assertion that a person of ordinary skill in the art would have reasonably
`expected that a 5% by weight concentration of the smaller tavaborole would
`more effectively penetrate the nail plate than Samour’s econazole. Ex. 1005
`¶¶ 143–144; see also Ex. 1020, 9 (“As expected, molecular size has an
`inverse relationship with penetration into the nail plate. The larger the
`molecular size, the harder it is for molecules to diffuse through the keratin
`network and [the] lower the drug permeation.”). We also note that
`conclusive proof of efficacy is not required to show obviousness. See
`Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir.
`2014) (“Conclusive proof of efficacy is not necessary to show obviousness.
`All that is required is a reasonable expectation of success.”).
`Patent Owner does not dispute that the combination of Austin,
`Brehove, and Samour teaches concentration ranges that overlap
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