UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`FLATWING PHARMACEUTICALS, LLC,
`Petitioner,
`
`v.
`
`ANACOR PHAMACEUTICALS, INC.,
`Patent Owner
`__________________
`
`Case No. IPR2018-00168
`Patent No. 9,549,938
`__________________
`
`PATENT OWNER’S RESPONSE
`
`
`
`
`
`
`
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`FLATWING PHARMACEUTICALS, LLC,
`Petitioner,
`
`v.
`
`ANACOR PHAMACEUTICALS, INC.,
`Patent Owner
`__________________
`
`Case No. IPR2018-00168
`Patent No. 9,549,938
`__________________
`
`PATENT OWNER’S RESPONSE
`
`
`
`
`
`
`
`
`
`I.
`
`II.
`
`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`
`TABLE OF CONTENTS
`
`PATENT OWNER’S RESPONSE .................................................................. 8
`
`BACKGROUND OF THE INVENTION ....................................................... 8
`
`A.
`
`B.
`
`Boron-Containing Pharmaceutical Drugs ............................................. 8
`
`Onychomycosis and Nail Penetration ................................................. 14
`
`1.
`
`The Challenge of Transungual Drug Delivery ......................... 17
`
`2. Molecular Weight and Nail Permeability ................................. 23
`
`III. RESPONSE TO ASSERTED GROUNDS OF UNPATENTABILITY ....... 26
`
`A.
`
`The Cited Art Teaches Away from 5% Tavaborole ........................... 28
`
`B.
`
`C.
`
`1.
`
`2.
`
`Samour’s Examples Teach Away from 5% .............................. 29
`
`The Broad Ranges of Austin, Brehove, and Freeman
`Would Not Have Led a POSA to 5% ....................................... 35
`
`A POSA Would Not Have Arrived at the Claimed Invention
`Through Simple Substitution or Routine Experimentation ................ 37
`
`A POSA in 2005 Would Have Used More Than 5% Tavaborole
`in a Topical Formulation to Treat Onychomycosis ............................ 41
`
`1.
`
`2.
`
`The Challenge of Achieving Transungual Penetration and
`Fick’s Law of Diffusion Would Have Led a POSA to
`Maximize the Concentration of Tavaborole ............................. 41
`
`A POSA Would Have Used More Than 5% Tavaborole
`to Compensate for Predicted High Keratin-Binding
`Affinity Based on Tavaborole’s Chemical Structure ................ 42
`
`IV. CONCLUSION .............................................................................................. 46
`
`
`
`i
`
`
`
`
`Anacor Pharm. Inc. v. Iancu, 889 F.3d 1372 (Fed. Cir. 2018) .................................. 6
`
`TABLE OF AUTHORITIES
`
`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`
`DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314
`(Fed. Cir. 2009) ............................................................................................. 34, 37
`
`In re Gurley, 27 F.3d 551 (Fed. Cir. 1994) ........................................................ 34, 37
`
`Millennium Pharm., Inc. v. Sandoz, Inc. 862 F.3d 1356 (Fed. Cir.
`2017) ................................................................................................... 4, 12, 13, 38
`
`Panduit Corp. v. Dennison Mfg. Co., 810 F.2d 1561 (Fed. Cir. 1987) ................... 35
`
`Coalition for Affordable Drugs X LLC v. Anacor Pharm., Inc.,
`IPR2015-01776, Paper No. 70 (P.T.A.B. Feb. 23, 2017) ..................................... 5
`
`Coalition for Affordable Drugs X LLC v. Anacor Pharm., Inc.,
`IPR2015-01780, Paper No. 70 (P.T.A.B. Feb. 23, 2017) ..................................... 5
`
`Coalition for Affordable Drugs X LLC v. Anacor Pharm., Inc.,
`IPR2015-01785, Paper No. 70 (P.T.A.B. Feb. 23, 2017) ..................................... 5
`
`
`
`ii
`
`
`
`At the 2005 priority date of U.S. Patent No. 9,549,938 (“the ’938 patent,”
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`Case No. IPR2018-00168
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`Ex. 1001), scientists attempting to develop topical treatments for onychomycosis, a
`
`fungal infection of the human nail, faced a daunting problem—the nail presented a
`
`barrier that was very difficult for drugs to cross. If a drug could not penetrate
`
`through the nail, referred to as “transungual delivery” of the drug, it could not treat
`
`the infection in the nail or its source in the nail bed and related tissue.
`
`Both before and after the priority date, the scientific literature bemoaned
`
`problems with transungual delivery:
`
`• “For the topical therapy to be successful, the drug is re-
`quired to penetrate across the nail plate and distribute in
`the nail stratums at therapeutically effective amounts
`(>MIC). Unfortunately, there are at least two factors that
`could limit the accumulation and activity of drugs in the
`nail on topical application. First the physicochemical
`properties of the drug need to be favorable for absorption
`through [the] nail matrix. The nail matrix is reported to
`be relativity more permeable to polar compounds than
`nonpolar compounds. Second, binding of the drug to
`keratin reduces the availability of the free drug. Antifun-
`gal drugs are reported to possess high-binding affinity to
`keratin . . . This, most likely, is one of the reasons for
`prolonged durations of treatment of nail disorders.
`Moreover, the bound form of the drug does not contrib-
`
`1
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`ute to the concentration gradient due to the lack of ther-
`modynamic activity. This decreases the amount of drug
`penetrating into the deeper nail layers.”1
`
`• “[C]haracteristics of the nail make it a formidable barrier
`to drug permeation and the challenge to improve topical
`delivery of drugs into and through the nail remains for-
`midable as well.”2
`
`• “Currently, topical formulations are available as nail lac-
`quers, creams, ointments, gels, solutions and lotions.
`However, the efficiency of these formulations is limited
`due to their inability to deliver a therapeutically effective
`amount of drug into and across the impermeable nail
`plate. Therefore, this therapy is limited for the treatment
`of superficial and minor subungual onychomycosis.”3
`
`
`1 Murthy et al., Iontophoretic Drug Delivery across Human Nail, J. Pharm. Sci.,
`
`vol. 96, pp. 305–11, at 305–06 (2007) (Ex. 2008).
`
`2 Nair et al., Alteration of the diffusional barrier property of the nail leads to
`
`greater terbinafine drug loading and permeation, Int’l J. Pharm., vol. 375, pp. 22–
`
`27, at 22 (2009) (“Nair et al. 2009a,” Ex. 2004).
`
`3 Nair et al., A study on the effect of inorganic salts in transungual drug delivery of
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`terbinafine, J. Pharm. Pharmacol., vol. 61, pp. 431–37, at 431 (2009) (“Nair et al.
`
`2
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`• “[T]opical therapy based on nail lacquers circumvents
`most of the limitations of oral administration. But be-
`cause of poor drug diffusion into the highly keratinized
`nail plate and the long duration of treatment, the topical
`monotherapy has been currently recommended only in
`the early stages of the disease or when the systemic ther-
`apy is contradicted.”4
`
`• “The absorption of drugs into the nail unit, following top-
`ical application to the nail plate, is highly desirable to
`treat nail disorders, such as onychomycosis (fungal infec-
`tions of the nail). Nail permeability is however quite low
`and limits topical therapy to early/mild disease states.”5
`
`Scientists tried many approaches to achieve transungual drug delivery in
`
`amounts sufficient to treat onychomycosis. They tried chemical penetration en-
`
`hancers to help the drug penetrate through the keratin matrix forming the nail plate.
`
`2009b,” Ex. 2005); see also Transcript of Aug. 20, 2018 Deposition of S. Nara-
`
`simha Murthy, Ph.D. (“Murthy Dep.,” Ex. 2008) at 46:19–47:1.
`
`4 Shivakumar et al., Bilayered Nail Lacquer of Terbinafine Hydrochloride for
`
`Treatment of Onychomycosis, J. Pharm. Sci., vol. 99, pp. 4267–76, at 4276 (2010)
`
`(Ex. 2006); see also Murthy Dep. (Ex. 2008) at 51:11–52:7.
`
`5 Sudaxshina Murdan, Drug delivery to the nail following topical application, Int’l
`
`J. Pharm., vol. 236, pp. 1–26, at 1 (2002) (Ex. 1020).
`
`3
`
`
`
`See, e.g., Nair et al. 2009a (Ex. 2004) at 431. They tried using electrical fields to
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`drive the drug through the nail. See, e.g., Murthy et al. 2007 (Ex. 2008) at 305.
`
`They tried combination therapy using topical treatments together with oral, system-
`
`ic drugs. See, e.g., Shivakumar et al. 2010 (Ex. 2006) at 4267. But the goal was
`
`always to deliver the most drug into and through the nail.
`
`In 2005, it was also true that scientists were just beginning to recognize the
`
`possibility of boron-containing compounds as potential drug therapies. But be-
`
`cause boron has unique chemistry and reactivity, formulating boron-containing
`
`compounds was challenging and unpredictable. VELCADE®, for instance, spent
`
`years in development to resolve stability issues with its boron-containing active
`
`pharmaceutical ingredient, bortezomib. See Millennium Pharm., Inc. v. Sandoz,
`
`Inc. 862 F.3d 1356, 1361 (Fed. Cir. 2017).6
`
`
`6 See Baker et al., Therapeutic potential of boron-containing compounds, Future
`
`Med. Chem., vol. 1, pp. 1275–88, at 1275 (2009) (Ex. 2015); Michael P. Groziak,
`
`Boron Therapeutics on the Horizon, Am. J. Therapeutics, vol. 8, pp. 321–28, at
`
`321 (2001) (Ex. 1032) (reporting that as of 2001, “[n]o pharmaceutical based on
`
`boron has yet made it to market”); see also Dennis G. Hall, Structure, Properties,
`
`and Preparation of Boronic Acid Derivatives: Overview of Their Reactions and
`
`Applications, in Boronic Acids: Preparation and Applications in Organic Synthesis,
`
`4
`
`
`
`Both of these challenges—the challenge of transungual drug delivery and
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`U.S. Patent No. 9,549,938
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`the difficulty of formulating boron-containing compounds as pharmaceutical
`
`drugs—are critical to the question presented here: whether a person of ordinary
`
`skill in the art (“POSA”) would have arrived at the specific formulation of the bo-
`
`ron-containing compound claimed in claims 3, 5, and 6 of the ’938 patent. Flat-
`
`Wing largely ignores this question and its perfunctory discussion relies on conclu-
`
`sory assertions that do not meet its burden of proof.
`
`Instead, FlatWing’s petition against the ’938 patent emphasizes the Board’s
`
`invalidation of related U.S. Patent Nos. 7,582,621 and 7,767,657. See Final Writ-
`
`ten Decision, Coalition for Affordable Drugs X LLC v. Anacor Pharm., Inc.,
`
`IPR2015-01776, Paper No. 70 (P.T.A.B. Feb. 23, 2017); Final Written Decision,
`
`Coalition for Affordable Drugs X LLC v. Anacor Pharm., Inc., IPR2015-01780,
`
`Paper No. 70 (P.T.A.B. Feb. 23, 2017); Final Written Decision, Coalition for Af-
`
`fordable Drugs X LLC v. Anacor Pharm., Inc., IPR2015-01785, Paper No. 70
`
`(P.T.A.B. Feb. 23, 2017). Its petition is essentially a “me-too” relying on the
`
`same art previously cited by the Coalition for Affordable Drugs (“CFAD”) and on
`
`the same experts—Dr. S. Narasimha Murthy and Dr. Stephen B. Kahl—to provide
`
`
`Medicine and Materials, Second Edition 1, at 105 (Dennis G. Hall ed. 2011) (Ex.
`
`2016).
`
`5
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`similar opinions. Anacor acknowledges the Board’s rulings in these prior cases, as
`
`well the affirmance of the Board’s final written decision in IPR2015-01776, see
`
`Anacor Pharm. Inc. v. Iancu, 889 F.3d 1372 (Fed. Cir. 2018), and does not chal-
`
`lenge here limitations that were found to have been obvious in those proceedings.
`
`But claims 3, 5, and 6 of the ’938 patent recite a specific formulation that
`
`was not at issue previously. Claims 3, 5, and 6 of the ’938 patent claim a method
`
`of treating a Tinea unguium infection by topically administering a pharmaceutical
`
`composition in the form of a solution comprising a boron-containing antifungal
`
`agent called tavaborole at a 5% w/w concentration.7 This formulation has not been
`
`
`7 Claims 1, 3, 5, and 6 of the ’938 patent recite:
`
`1. A method of treating a Tinea unguium infection of
`a toenail of a human, the method comprising:
`topically administering to the toenail of the human a
`pharmaceutical composition [tavaborole] or a
`pharmaceutically acceptable salt thereof in an
`amount sufficient to treat the infection.
`
`3. The method of claim 1, wherein the pharmaceuti-
`cal composition is in the form of a solution comprising
`5% w/w of [tavaborole].
`
`6
`
`
`
`considered by either the Board or the Federal Circuit and is not obvious over the
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`art cited by FlatWing
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`As explained herein, given the state of the art at the 2005 priority date,
`
`FlatWing’s references would not have led a person of ordinary skill in the art
`
`(“POSA”) to the claimed 5% w/w limitation, and the lack of data and experience in
`
`the art of formulating boron-containing compounds precludes finding that a POSA
`
`would have arrived at this amount by through routine experimentation or simple
`
`substitution. Moreover, the broader understanding of the relevant scientific fields
`
`of endeavor would have led a POSA to use a higher amount of tavaborole to com-
`
`pensate for the compound’s high predicted binding affinity to the nail’s keratin ma-
`
`trix. Based on its chemical structure, tavaborole’s high predicted keratin-binding
`
`affinity would have been expected to compromise its ability to effectively pene-
`
`trate the nail plate. Although keratin-binding was widely understood in 2005 to
`
`
`5. The method of claim 1, wherein the Tinea unguium
`infection is due to Trichophyton rubrum or Trichophyton
`mentagrophytes, and wherein the pharmaceutical compo-
`sition is in the form of a solution comprising 5% w/w of
`[tavaborole].
`
`6. The method of claim 5, wherein the pharmaceuti-
`cal composition further comprises ethanol and propylene
`glycol.
`
`7
`
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`pose a major obstacle to transungual drug delivery, FlatWing and its experts ignore
`
`it altogether. Accordingly, the grounds asserted by FlatWing fail to establish that
`
`claims 3, 5, and 6 of the ’938 patent would have been obvious over the cited art.
`
`I.
`
`PATENT OWNER’S RESPONSE
`
`Pursuant to 37 C.F.R. § 42.120, Patent Owner Anacor Pharmaceuticals, Inc.
`
`(“Anacor”) provides this Patent Owner’s response to the petition (“Pet.”) filed by
`
`Petitioner FlatWing Pharmaceuticals, LLC (“FlatWing”) requesting inter partes
`
`review of claims 1–6 of the ’938 patent. For the reasons set forth below and the
`
`accompanying declarations of Majella E. Lane, Ph.D. (“Lane Decl.,” Ex. 2014)
`
`and Paul J. Reider, Ph.D. (“Reider Decl.,” Ex. 2013) in support of this response,
`
`the Board should confirm the patentability of claims 3, 5, and 6 of the ’938 patent.
`
`II. BACKGROUND OF THE INVENTION
`
`A. Boron-Containing Pharmaceutical Drugs
`
`Boron is a “unique” element, as Flatwing’s expert acknowledges. See Dec-
`
`laration of Stephen Kahl, Ph.D. (“Kahl Decl.,” Ex. 1003) ¶ 31. Indeed, boron-
`
`containing compounds have generated significant interest among pharmaceutical
`
`researchers due to boron’s unique properties. Despite this interest, however, only a
`
`few boron-containing pharmaceutical drugs have been approved by the FDA, and
`
`as of the priority date of the ’938 patent, only one boron-containing compound,
`
`bortezomib (marketed as VELCADE®), had reached the market. See Hall 2011
`
`8
`
`
`
`(Ex. 2016) at 105 (stating in 2011 that VELCADE® was “the first boronic acid
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`drug on the market”); Baker et al. 2009 (Ex. 2015) at 1275 (describing
`
`VELCADE®
`
` as “the only boron-based therapeutic currently on the market”);
`
`Groziak 2001 (Ex. 1032) at 21 (reporting that as of 2001, “[n]o pharmaceutical
`
`based on boron has yet made it to market”); Reider Decl. (Ex. 2013) ¶ 38.
`
`Boron’s unique properties arise from the unusual arrangement of its elec-
`
`trons, which renders it inherently electron deficient. Transcript of Aug. 23, 2018
`
`Deposition of Stephen B. Kahl, Ph.D. (“Kahl Dep.,” Ex. 2017) at 31:18–21; Reider
`
`Decl. (Ex. 2013) ¶ 25. Although boron typically forms three covalent bonds with
`
`other atoms, the electrons shared from other atoms through these bonds are not suf-
`
`ficient to resolve boron’s inherent electron deficiency. See Kahl Dep. (Ex. 2017)
`
`at 30:3–32:10; Reider Decl. (Ex. 2013) ¶ 26.
`
`Thus, a hallmark of boron chemistry is boron’s propensity to form additional
`
`(fourth, and potentially even fifth and sixth) bonds—sometimes referred to as “co-
`
`ordinate” or “dative” bonds—by accepting lone pairs of electrons from other elec-
`
`tron-rich atoms and functional groups, particularly those containing oxygen, nitro-
`
`gen, and sulfur. See Kahl Dep. (Ex. 2017) at 73:20–74:3 (oxygen), 89:9–21 (nitro-
`
`gen), 75:20–76:1 (sulfur); Reider Decl. (Ex. 2013) ¶¶ 25–26. This propensity to
`
`form additional bonds distinguishes boron from other elements commonly found in
`
`organic chemistry and has led at least one commentator to describe boron as a
`
`9
`
`
`
`“promiscuous[]” element. Hall 2011 (Ex. 2016) at 9; see also Kahl Dep. (Ex.
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`2017) at 42:21–43:9; Reider Decl. (Ex. 2013) ¶ 25.
`
`Boron’s electron-deficient nature and propensity to form dative bonds were
`
`understood by a POSA in 2005 to carry real-world consequences. Boron’s ability
`
`to form complexes with other compounds, for instance, was understood to require
`
`higher than catalytic amounts of boron-containing catalysts due their tendency to
`
`“stick” to other reactants. See Reider Decl. (Ex. 2013) ¶ 30.8 In biological set-
`
`tings, it was also widely understood that boron readily forms complexes with bio-
`
`molecules having electron-rich functional groups, including amino acids and car-
`
`bohydrates. See Reider Decl. (Ex. 2013) ¶ 60–61 & n.1.9 As discussed in greater
`
`
`8 McNamara et al., Synthesis of Unsymmetrical Dithioacetals: An Efficient Synthe-
`
`sis of a Novel LTD4 Antagonist, L-660,711, J. Org. Chem., vol. 54, pp. 3718–21, at
`
`3718 (1989) (Ex. 2019); Ryan et al., Enhanced Reactivity of Iminium Ions as Het-
`
`erodienophiles in Lewis Acid Mediated 4+2 Cycloaddition Reactions, Tetrahedron
`
`Letters, vol. 28, pp. 2103–06, at 2104 (1987) (Ex. 2020).
`
`9 See also Hall 2011 (Ex. 2016) at 102, 105; Brown et al., Boron in Plant Biology,
`
`Plant Biol. vol. 4, pp. 205–23, at 206 (2002) (Ex. 2021); J.D. Lloyd, Borates and
`
`their biological applications, 29th Annual meeting of the International Research
`
`Group on Wood Preservation at 6–7 (June 1998) (Ex. 2022); William G. Woods,
`
`10
`
`
`
`detail below, keratin contains a high proportion of electron-rich functional groups
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`as part of its molecular structure, and a POSA would have expected boron-
`
`containing compounds like tavaborole to readily bind to keratin as a result.
`
`Boron-containing compounds were also generally known by a POSA in
`
`2005 to be reactive and particularly susceptible to hydrolysis or oxidation to boric
`
`acid. These reactions are again driven by boron’s inherent electron deficiency as
`
`well as the high thermodynamic stability of the boron-oxygen bond. Boric acid,
`
`having formula B(OH)3, maximizes the number of oxygen bonds normally availa-
`
`ble to boron, making these hydrolysis reactions energetically favorable. See Kahl
`
`Dep. (Ex. 2017) at 69:4–19; Reider Decl. (Ex. 2013) ¶ 37. Thus in the presence of
`
`water, boron compounds were generally known to hydrolyze to form boric acid.
`
`See Kahl Dep. (Ex. 2017) at 94:21–95:8; Reider Decl. (Ex. 2013) ¶¶ 50–52.10
`
`
`Review of Possible Boron Speciation Relating to its Essentiality, J. Trace Elements
`
`in Exp. Med., vol. 9, pp. 153–63, at 57 (1996) (Ex. 2023).
`
`10 See also Hall 2011 (Ex. 2016) at 9 (“T]he ultimate fate of all boronic acids in air
`
`and aqueous media is their slow oxidation into boric acid.”); Steiner et al., Diphe-
`
`nylborinic Acid Is a Strong Inhibitor of Serine Proteases, Bioorg. & Med. Chem.
`
`Lett., vol. 4, pp. 2417–20, at 2417 (1994) (Ex. 2024).
`
`11
`
`
`
`In addressing the development of VELCADE® from its active bortezomib
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`ingredient, the Federal Circuit acknowledged the difficulty posed by boron’s unu-
`
`sual reactivity in preparing suitable pharmaceutical formulations. As the Court ex-
`
`plained, bortezomib is a boronic acid and its “properties as a proteasome inhibitor”
`
`were known. Millennium, 862 F.3d at 1361. Despite its known efficacy, the de-
`
`velopment of bortezomib stalled “after years of unsuccessful attempts to solve
`
`formulation and stability problems” associated with the compound. Id. at 1362.
`
`These problems finally were resolved by lyophilizing bortezomib in the presence
`
`of mannitol to produce a new compound—the boronic ester of bortezomib and
`
`mannitol11—that unexpectedly resolved the “previously intractable problems of
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`bortezomib formulation.” Id. at 1364; Reider Decl. (Ex. 2013) at ¶¶ 38–40. This
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`new compound was a “prodrug” of bortezomib “that converts to or releases the ac-
`
`tive pharmaceutical ingredient upon administration to a patient.” Millennium, 862
`
`F.3d at 1362. In other words, despite years of effort, no stable pharmaceutical
`
`
`11 A boronic acid is a boron-containing compound in which the boron is bonded to
`
`two oxygens in hydroxyl groups and one carbon in a carbon-containing group hav-
`
`ing general formula RB(OH)2. A boronic ester is a derivative of a boronic acid in
`
`which the oxygen atoms bound to the boron atom are further bound to a carbon in
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`a carbon-containing group having general formula RB(OR)2.
`
`12
`
`
`
`formulation containing the active boron compound (bortezomib) emerged, and the
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`stable formulation of VELCADE® was achieved only through the discovery of a
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`completely “new chemical compound.” Id.
`
`Tavaborole, the compound recited in claims 3, 5, and 6 the ’938 patent and
`
`depicted below in Figure 1, belongs to a class of boron compounds known as ben-
`
`zoxaboroles, which are generally understood to be boronic acid derivatives. See
`
`note 11, supra; Hall 2011 (Ex. 2016) at 103–04; Kahl Decl. (Ex. 1003) ¶ 31; Kahl
`
`Dep. (Ex. 2017) at 52:16–54:2; Reider Decl. (Ex. 2013) ¶ 59–61.
`
`
`
`FIGURE 1
`
`Based on the scientific literature at the time concerning benzoxaboroles and
`
`boronic acids, a POSA in 2005 would have had no reason to think that tavaborole’s
`
`boron substituent would behave any differently with respect to its reactivity, stabil-
`
`ity, and propensity to form complexes and dative bonds than other boronic acids
`
`and boron-containing compounds. See Kahl Dep. (Ex. 2017) at 54:17–22, 94:11–
`
`13
`
`
`
`15; Reider Decl. (Ex. 2013) ¶ 59–61.12 Moreover, these properties would have
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`been unique to tavaborole as a boron-containing compound, as compared to other
`
`non-boron-containing antifungal agents. See Reider Decl. (Ex. 2013) ¶ 57.
`
`B. Onychomycosis and Nail Penetration
`
`Onychomycosis is a fungal infection of the human nail that is typically
`
`caused by the dermatophytes Trichophyton rubrum and Trichophyton men-
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`tagrophytes. See Lane Decl. (Ex. 2014) ¶ 57. Anatomically, the infection general-
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`ly involves the both the nail plate (what a layperson would consider to be the nail)
`
`and the nail bed from which the nail plate emerges. See id. ¶ 25.13 The nail plate
`
`
`12 See also Hall 2011 (Ex. 2016) at 5; Zhdankin et al, Synthesis and structure of
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`benzoboroxoles: novel organoboron heterocycles, Tetrahedron Letters, vol. 40, pp.
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`6705–08, at 6706–07 & fig.1 (1999) (Ex. 2025); see also Rock et al., An Antifungal
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`Agent Inhibits an Aminoacyl-tRNA Synthetase by Trapping tRNA in the Editing
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`Site, Science, vol. 316, pp. 1759–61, at 60 (2007) (Ex. 1037); Dowlut & Hall, An
`
`Improved Class of Sugar-Binding Boronic Acids, Soluble and Capable of Com-
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`plexing Glycosides in Neutral Water, J. Am. Chem. Soc., vol. 128, pp. 4226–27, at
`
`4226 (2006) (Ex. 2026).
`
`13 See also Boni E. Elewski, Onychomycosis: Pathogenesis, Diagnosis, and Man-
`
`agement, Clin. Microbiology Revs., vol. 11, pp. 415–29, at 417 (1998) (Ex. 2027).
`
`14
`
`
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`is further understood to possess three distinct layers: the dorsal (top) layer, an in-
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`termediate (middle) layer, and a ventral (bottom) layer. See id. ¶ 23.
`
`Approximately 80% of the nail plate is composed of a dense matrix of kera-
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`tin fibers which are responsible for the nail’s mechanical strength and barrier prop-
`
`erties. See id. ¶ 26. At a molecular level, keratin is a protein that assembles into a
`
`“coiled coil” hierarchical superstructure where multiple keratin fibers bundle to-
`
`gether in a regular pattern to form intermediate filaments. Id. The formation of
`
`this superstructure is driven by intermolecular interactions between keratin fi-
`
`bers—namely hydrogen bonding, peptide bonds, and disulfide linkages. Id.14
`
`Keratin contains a high proportion of amino acids having free hydroxyl,
`
`amine, and thiol functional groups that mediate the intermolecular forces responsi-
`
`ble for its structure. See Wang et al. 2016 (Ex. 2028) at 239 tbl.5; Reider Decl.
`
`(Ex. 2013) ¶ 42–43. These functional groups can also interact with topically ap-
`
`plied antifungal compounds transiting through the nail plate. See Murthy Dep.
`
`
`14 See also Wang et al., Keratin: Structure, mechanical properties, occurrence in
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`biological organisms, and efforts at bioinspiration, Prog. Mater. Sci., vol. 76, pp.
`
`229–318, at 235–36 (2016) (Ex. 2028); Murdan 2002 (Ex. 1020) at 3–4; Bo For-
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`slind, Biophysical Studies of the Normal Nail, Acta Derm Venerol, vol. 5, pp. 161–
`
`68, at 161–62 (1970) (Ex. 2043).
`
`15
`
`
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`(Ex. 2018) at 60:23–61:3; Reider Decl. (Ex. 2013) ¶ 63. This interaction with ker-
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`atin—known as the compound’s “keratin-binding affinity”—has serious conse-
`
`quences as only the unbound fraction of an antifungal compound is available to
`
`penetrate through the nail plate and exert a therapeutic effect. See Murthy et al.
`
`2007 (Ex. 2008) at 305–06; Tatsumi et al., Therapeutic Efficacy of Topically Ap-
`
`plied KP-103 against Experimental Tinea Unguium in Guinea Pigs in Comparison
`
`with Amorolfine and Terbinafine, Antimicrobial Agents & Chemotherapy, vol. 46,
`
`pp. 3797–801, at 3799–800 (2002) (Ex. 2037); Lane Decl. (Ex. 2014) ¶¶ 43–46.
`
`The nail is also composed of water, which comprises from about 10% to
`
`30% of the nail depending on the relative humidity, and a small amount (less than
`
`1%) of lipid. See Reider Decl. (Ex 2013) ¶ 40; Lane Decl. (Ex. 2014) ¶ 24.15 The
`
`relatively high water content of the nail plate renders it an aqueous environment,
`
`and POSA in 2005 would have known that the nail plate acts like a hydrophilic gel
`
`membrane or hydrogel. See Lane Decl. (Ex. 2014) ¶ 24.
`
`A POSA in 2005 would have understood that an effective topical treatment
`
`for onychomycosis requires an antifungal agent to penetrate through the three lay-
`
`ers of the nail plate and into the nail bed in order to eradicate the infection. See id.
`
`
`15 See also Runne & Orfanos, The Human Nail: Structure, Growth and Pathologi-
`
`cal Changes, Curr. Prob. Derm. vol. 9, pp. 102–49, at 104–06 (1981) (Ex. 2029).
`
`16
`
`
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`Case No. IPR2018-00168
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`¶¶ 50, 81. In particular, the rate of penetration or flux of the compound through the
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`nail plate is required to be sufficient for the concentration of the agent to achieve or
`
`exceed its minimum inhibitory concentration (“MIC”) against T. rubrum and T.
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`mentag. See id; see also Murthy et al. 2007 (Ex. 2008) at 305–06.
`
`1.
`
`The Challenge of Transungual Drug Delivery
`
`The goal of achieving sufficient nail penetration is the central focus of the
`
`field of transungual drug delivery, i.e., the delivery of active pharmaceutical com-
`
`pounds across the nail plate in therapeutic quantities. A POSA in 2005 would have
`
`understood transungual drug delivery to pose a challenging multidimensional prob-
`
`lem marked by numerous failures. See Lane Decl. (Ex. 2014) ¶ 48.
`
`In these proceedings, however, FlatWing has reduced the entire field of
`
`transungual drug delivery to a one-dimensional correlation between a compound’s
`
`molecular weight and its permeability through the nail. See Pet. at 37–39, 41, 48–
`
`49, 54–55, 58, 64. Specifically, FlatWing contends that a compound’s nail perme-
`
`ability can be predicted solely by reference to the compound’s molecular weight,
`
`where “lower molecular weight fungicidal compounds are more effective at pene-
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`trating the nail plate” and vice versa. Id. at 48. Based on this correlation, Flat-
`
`Wing asserts that a POSA would have predicted that tavaborole could more effec-
`
`tively penetrate the nail plate relative to other known antifungal agents based on its
`
`lower molecular weight. See also, e.g., Declaration of Narasimha Murthy, Ph.D.
`
`17
`
`
`
`(“Murthy Decl.,” Ex. 1005) ¶ 99 (asserting that POSA would have known “that
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`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
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`lower molecular weight compounds are more effective at crossing the nail plate
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`following topical administration”).
`
`Flatwing’s molecular-weight-based approach is a gross oversimplification of
`
`the field of transungual drug delivery and would have been contrary to the under-
`
`standing of a POSA at the time of the invention. As an initial matter, and notwith-
`
`standing FlatWing’s hindsight-driven attempt to rewrite history, practitioners in the
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`field uniformly recognized transungual drug delivery to be technically challenging
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`both before and after the priority date. See, e.g., Murdan 2002 (Ex. 1020) at 7 (“It
`
`must be stressed, however, that nail permeability is generally poor and drug flux
`
`through the nail plate is low.”). Indeed, despite his present opinions, Dr. Murthy
`
`has agreed that transungual drug delivery is difficult to achieve by repeatedly stat-
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`ing as much in numerous peer-reviewed articles.
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`In 2009, for example, Dr. Murthy wrote that “the barrier properties . . . of the
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`nail make it a formidable barrier to drug permeation and the challenge to improve
`
`topical delivery of drugs into and through the nail remains formidable as well.”
`
`Nair et al. 2009a (Ex. 2004) at 22. In a review co-authored by Dr. Murthy in 2014,
`
`he again wrote that “topical therapy continues to pose a challenge owing to the
`
`poor permeability of the nail plate to many therapeutic agents.” Shivakumar et al.,
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`Transungual drug delivery: an update, J. Drug Del. Sci. Tech., vol. 24, pp. 301–
`
`18
`
`
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`10, at 301 (2014) (Ex. 2007); Murthy Dep. (Ex. 2018) at 74:6–9. And in prefacing
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`his 2013 book on transungual drug delivery, Dr. Murthy wrote yet again that the
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`“[d]evelopment of topical formulations to deliver effective amounts of drugs into
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`the nail apparatus is highly challenging,” a point which he later admitted under
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`oath was a “fundamental proposition” known to a POSA in 2005. See Topical Nail
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`Products and Ungual Drug Delivery at vii (Murthy & Maibach eds. 2013) (Ex.
`
`2030); Transcript of May 2016 Deposition of S. Narasimha Murthy, Ph.D.
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`(“Murthy 2016 Dep.,” Ex. 2002) at 88:12–89:16; see also Nair et al. 2009b (Ex.
`
`2005) at 431 (“[T]he efficacy of [topical] formulations is limited due to their ina-
`
`bility to deliver a therapeutically effective amount of drug into an across the im-
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`penetrable nail plate.”); Murthy Dep. (Ex. 2018) at 75:6–9 (“Penetrability of drugs
`
`across a nail plate is a challenge. . . . It’s definitely a challenge.”) Dr. Murthy’s
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`testimony under oath and repeated statements in peer-reviewed publications cannot
`
`be squared with the extreme reductive approach that Dr. Murthy now asserts to
`
`have been understanding of a POSA in 2005.
`
`Nor, for that matter, can Dr. Murthy’s testimony and peer-reviewed publica-
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`tions be square
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