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
`__________________
`
`DECLARATION OF PAUL J. REIDER, PH.D.
`IN SUPPORT OF PATENT OWNER’S RESPONSE
`
`
`
`
`
`
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`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
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`TABLE OF CONTENTS
`
`INTRODUCTION ........................................................................................... 1
`
`ACADEMIC AND PROFESSIONAL QUALIFICATIONS ......................... 2
`
`
`I.
`
`II.
`
`III. THE ’938 PATENT ......................................................................................... 4
`
`IV. TECHNICAL BACKGROUND ..................................................................... 7
`
`A.
`
`B.
`
`Boron Chemistry ................................................................................... 7
`
`Boron Compounds as Pharmaceutical Drugs ...................................... 12
`
`C. Molecular Structure of Keratin ........................................................... 14
`
`V.
`
`THE CITED REFERENCES......................................................................... 17
`
`A. Austin .................................................................................................. 17
`
`B.
`
`C.
`
`D.
`
`Brehove................................................................................................ 18
`
`Freeman ............................................................................................... 20
`
`Samour ................................................................................................. 21
`
`VI. RESPONSE TO PETITIONER’S GROUNDS ............................................. 22
`
`A. A POSA in 2005 Would Have Expected Tavaborole to Have
`High Keratin-Binding Affinity ............................................................ 22
`
`1.
`
`2.
`
`Boron-Containing Compounds Form Complexes with
`Electron-Rich Atomic Species and Functional Groups to
`Satisfy Boron’s Electron Deficiency ........................................ 23
`
`Keratin’s Molecular Structure Presents an Electron-Rich
`“Gauntlet” for Boron-Containing Compounds ......................... 26
`
`B.
`
`Brehove’s Dioxaborinane Compounds Undergo Hydrolysis and
`Do Not Penetrate the Nail Plate .......................................................... 28
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`A POSA Would Not Have Arrived at the Claimed Amount of
`Tavaborole Through Routine Experimentation .................................. 29
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`Case No. IPR2018-00168
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`
`C.
`
`VII. CONCLUSION .............................................................................................. 33
`
`
`
`ii
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`I, Paul J. Reider, Ph.D., hereby state and declare as follows:
`
`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
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`
`I.
`
`INTRODUCTION
`
`
`
`I have been asked by Patent Owner Anacor Pharmaceuticals, Inc.
`
`(“Anacor”) to offer my expert opinions regarding the petition for inter partes re-
`
`view of U.S. Patent No. 9,549,938 (“the ’938 patent”) filed by FlatWing Pharma-
`
`ceuticals, LLC (“FlatWing”). This declaration contains my opinions related to the
`
`validity of claims 3, 5, and 6 of the ’938 patent.
`
`
`
`I am being compensated at my customary hourly rate, and my com-
`
`pensation is not dependent upon the outcome of, or the content of my testimony in,
`
`the present inter partes review proceeding or any litigation proceedings.
`
`
`
`I have reviewed FlatWing’s petition for inter partes review (“Pet.”) of
`
`the ’938 patent, including the declarations filed in support of the petition submitted
`
`by Dr. Stephen B. Kahl (“Kahl Decl.,” Ex. 1003) and Dr. S. Narasimha Murthy
`
`(“Murthy Decl.,” Ex. 1005). I have further reviewed the exhibits and articles cited
`
`in these documents, as well as the articles and documents cited in this declaration.
`
`
`
`I have additionally reviewed the declaration of Dr. Majella E. Lane
`
`(“Lane Decl.,” Ex. 2014) filed in support Anacor’s response to FlatWing’s petition.
`
`I am also aware of knowledge generally available to and relied upon by persons of
`
`ordinary skill in the art (“POSA”) at the time of the invention.
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`This declaration is based on information currently available to me. I
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`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
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`
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`reserve the right to continue my investigation and analysis, which may include a
`
`review of documents and information not yet provided. I further reserve the right
`
`to expand or otherwise modify my opinions and conclusions as my investigation
`
`and study continues, and to supplement my opinions and conclusions in response
`
`to any additional information that becomes available to me.
`
`II. ACADEMIC AND PROFESSIONAL QUALIFICATIONS
`
`
`
`I am a Lecturer at the rank of Professor of Chemistry at Princeton
`
`University. A copy of my curriculum vitae is attached as Exhibit 2044. My educa-
`
`tional background and my professional experience are summarized below.
`
`
`
`I obtained A.B. degrees in psychology and chemistry from the Wash-
`
`ington Square College at New York University in 1972. I obtained my Ph.D. in
`
`organic chemistry from the University of Vermont in 1978. My Ph.D. thesis con-
`
`cerned the total synthesis of the natural product ibogamine.
`
`
`
`After two years of post-doctoral work at Colorado State University
`
`from 1978–1980, I joined Merck Research Labs as a Senior Research Chemist in
`
`process research. For the next twenty-two years, I remained at Merck, eventually
`
`rising to the rank of Vice President. During that time, I participated in the discov-
`
`ery and development of more than a dozen FDA-approved drugs, including CAN-
`
`CIDAS®, an intravenous antifungal medication.
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`I left Merck in 2002 and joined Amgen as Vice President, Chemistry
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`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
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`
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`Research & Discovery, where I was responsible for chemistry and small molecule
`
`drug discovery, including medicinal chemistry, analytical chemistry, sample col-
`
`lection and compound procurement, computational chemistry, molecular modeling,
`
`protein chemistry, automation and robotics, crystallography, process chemistry,
`
`peptide chemistry, and high-throughput screening.
`
`
`
`In 2008, I left the pharmaceutical industry to join the faculty of
`
`Princeton. I currently serve as a Lecturer at the Rank of Professor in the Princeton
`
`University Department of Chemistry. In this position, I teach organic chemistry,
`
`medicinal chemistry, and pharmaceutical sciences to Princeton undergraduates and
`
`graduate students based on my experiences at Merck and Amgen. My research at
`
`Princeton focuses on treatment for neglected diseases, such as tuberculosis, malar-
`
`ia, dengue fever and Human African Trypanosomiasis (sleeping sickness).
`
` Over the course of my career, I have had extensive experience with
`
`boron-containing catalysts and reactants in the synthesis of potential drug candi-
`
`dates. Although I have never developed boron-containing compounds for use as
`
`drug candidates themselves, my experience with boron compounds as well as my
`
`knowledge of boron chemistry and medicinal chemistry are sufficient for me to of-
`
`fer opinions on boron-containing pharmaceuticals drugs and compositions.
`
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`I have presented numerous invited lectures and am an inventor on
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`over 35 patents. I am the author or co-author of over 180 peer-reviewed scientific
`
`articles, including an article titled “Semisynthesis of an Antifungal Lipopeptide
`
`Echinocandin,” 64 J. Org. Chem. 2411 (1999).
`
`
`
`I have won numerous awards for my research, including the 2000 Prix
`
`Galien Award, the 1998 Merck Scientific Director’s Award, and the 2011 National
`
`Academy of Sciences Award for Chemistry in Service to Society. In 2018, I was
`
`honored by Pomona College as the 56th annual Robbins Lecturer.
`
`
`
`I sat on the Scientific Advisory Boards of the TB Alliance in New
`
`York and the Medicines for Malaria Venture in Geneva between 2011 and 2017. I
`
`currently serve as an advisor to both organizations, as well as the Melinda & Bill
`
`Gates Foundation regarding neglected diseases.
`
`III. THE ’938 PATENT
`
` The inventors of the ’938 patent recognized a “need in the art for
`
`compounds which can effectively penetrate the nail” as well as “compounds which
`
`can effectively treat ungual and/or periungual infections” such as onychomycosis.
`
`’938 patent (Ex. 1001) at 3:1–6. In particular, the inventors recognized that “poor
`
`penetration of the active agent through the . . . nail plate and/or excessive binding
`
`to keratin (the major protein in nails and hair) are the reasons for the poor efficacy”
`
`of existing topical treatments for these infections. Id. at 132:9–12.
`
`4
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` As the inventors of the ’938 patent further explained:
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`Case No. IPR2018-00168
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`In mild cases of onychomycosis, the pathogenic fungi re-
`side in the nail plate only. In moderate to severe cases
`the pathogenic fungi establish a presence in the nail plate
`and in the nail bed. If the infection is cleared from the
`nail plate but not from the nail bed, the fungal pathogen
`can re-infect the nail plate. Therefore, to effectively treat
`onychomycosis, the infection must be eliminated from
`the nail plate and the nail bed. To do this, the active
`agent must penetrate and disseminate substantially
`throughout the nail plate and nail bed.”
`
`’938 patent (Ex. 1001) at 132:14–23.
`
` To this end, the ’938 patent “provides novel boron compounds” and
`
`“a method of delivering a compound from the dorsal layer of the nail plate to the
`
`nail bed” using such compounds. Id. at 20:30, 134:27–29. Tavaborole (1,3-
`
`dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole) is one the compounds disclosed.
`
`See id. at 187:32–189:57–194:48 (Examples 16–20).
`
`
`
`I understand that claims 3, 5, and 6 of the ’938 patent depend directly
`
`or indirectly on independent claim 1 and therefore incorporate all limitations of the
`
`claim(s) from which they depend.
`
`5
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` Claim 1 of the ’938 patent recites:
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`U.S. Patent No. 9,549,938
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`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.
`
` Claim 3 of the ’938 patent recites:
`
`3. The method of claim 1, wherein the pharmaceuti-
`cal composition is in the form of a solution comprising
`5% w/w of [tavaborole].
`
` Claim 5 of the ’938 patent recites:
`
`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].
`
` Claim 6 of the ’938 patent recites:
`
`6. The method of claim 5, wherein the pharmaceuti-
`cal composition further comprises ethanol and propylene
`glycol.
`
`
`
`I further understand that the ’938 patent claims priority to a provision-
`
`al patent application filed on February 16, 2005. I therefore interpret the meaning
`
`6
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`of the ’938 patent claims in accordance with the knowledge and understanding of a
`
`person of ordinary skill in the art during the 2005 time period.
`
`IV. TECHNICAL BACKGROUND
`
`A. Boron Chemistry
`
` The chemistry of boron differs from the chemistry of atoms typically
`
`found in organic compounds, namely carbon, hydrogen, oxygen, nitrogen, phos-
`
`phorus, sulfur, as well silicon, fluorine, and chlorine. This difference is apparent
`
`simply by looking at the periodic table, which shows boron at the top of the Group
`
`13 column of elements. Notably, none of the elements in Group 13 are common in
`
`organic molecules, so there are few, if any, elements that demonstrate similar
`
`chemical behavior as boron.
`
` Boron’s unusual chemistry is due to its unusual electronic arrange-
`
`ment. Specifically, boron features an empty p-orbital, which renders it inherently
`
`electron deficient. In other words, boron is “hungry” for electrons. This electron
`
`deficiency causes boron to interact not only with the atoms it is covalently bound
`
`to, but also with nearby electron-rich atoms and functional groups. This results in
`
`the tendency of boron-containing compounds to “interact promiscuously” with
`
`other compounds, as boron binds non-selectively with oxygen, nitrogen, and sulfur
`
`atoms found widely in other biomolecules. See, e.g., Dennis G. Hall, Structure,
`
`Properties, and Preparation of Boronic Acid Derivatives: Overview of Their Reac-
`
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`tions and Applications, in Boronic Acids: Preparation and Applications in Organic
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`U.S. Patent No. 9,549,938
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`Synthesis, Medicine and Materials, Second Edition 1, at 9 (Dennis G. Hall ed.
`
`2011) (Ex. 2016); Brown et al., Boron in Plant Biology, Plant Biol. vol. 4, pp. 205–
`
`23, at 206 (2002) (Ex. 2021) (“The ubiquitous nature of potential B binding sites
`
`has often confounded the interpretation of experimental results and has resulted in
`
`the many purported functions of B that have been published . . . .”).
`
` Boron’s unusual electronic arrangement generally allows it form three
`
`covalent bonds with other atoms. In a covalent bond, each atom in the bonding
`
`pair donates an electron to be shared with the other. However, boron is also able to
`
`form coordinative or dative bonds with electron-rich atomic species or functional
`
`groups. In a dative bond, both electrons constituting the bond are donated from the
`
`same atom and are coordinated to the (receiving) electron-deficient atom. To make
`
`this interaction energetically favorable, the receiving atom must be sufficiently
`
`electron deficient, which is not a problem for boron due to its empty p-orbital.
`
` The inventors of the ’938 patent understood that boron’s propensity to
`
`interact with other electron-rich atomic species to form dative bonds would be true
`
`of the compounds disclosed in the patent, including tavaborole.
`
` As the ’938 patent explains:
`
`Boron is able to form dative bonds with oxygen, sulfur or
`nitrogen under some circumstances in this invention. Da-
`
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`tive bonds are usually weaker than covalent bonds. In
`situations where a boron is covalently bonded to at least
`one oxygen, sulfur or nitrogen, and is at the same time
`datively bonded to an oxygen, sulfur or nitrogen, respec-
`tively, the dative bond and covalent bond between the
`boron and the two identical heteroatoms can interconvert
`or be in the form of a resonance hybrid.
`
`’938 patent (Ex. 1001) at 14:38–47.
`
` The ’938 patent particularly illustrates the formation of a tavaborole-
`
`water complex involving a dative bond with boron and oxygen:
`
`
`
`Id. at 14:53–67. This disclosure thus confirms the understanding of a POSA in
`
`2005 that tavaborole would be able to form dative bonds by virtue of the com-
`
`pound’s boron-containing substituent.
`
` My own experience working with boron demonstrates the practical
`
`implications of boron’s “promiscuous” nature. In attempting to develop an effi-
`
`cient synthesis of an unsymmetrical dithioacetal compound at Merck, we discov-
`
`ered that boron trifluoride etherate (BF3Et2O) proved to be an excellent Lewis acid
`
`capable of catalyzing the reaction without leading to unwanted conjugate addition.
`
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`McNamara et al., Synthesis of Unsymmetrical Dithioacetals: An Efficient Synthesis
`
`of a Novel LTD4 Antagonist, L-660,711, J. Org. Chem., vol. 54, pp. 3718–21, at
`
`3719 (1989) (Ex. 2019). However, because of boron’s tendency to “stick” to elec-
`
`tron-rich functional groups, a higher-than-catalytic amount of BF3Et2O was re-
`
`quired to compensate for a complex formed with a quinoline nitrogen. Id. My
`
`Merck colleagues exploited the same behavior—boron’s tendency to form com-
`
`plexes with nitrogen or amine groups—to activate nitrogen-containing imine func-
`
`tionalities with less reactive diene groups. See Ryan et al., Enhanced Reactivity of
`
`Iminium Ions as Heterodienophiles in Lewis Acid Mediated 4+2 Cycloaddition
`
`Reactions, Tetrahedron Letters, vol. 28, pp. 2103–06, at 2104 (1987) (Ex. 2020).
`
` Boron compounds are generally classified based on their substitution
`
`pattern around the boron atom. Boranes, for instance, are inorganic boron com-
`
`pounds consisting of boron and hydrogen. The simplest commercially available
`
`borane, diborane (B2H6), is a highly reactive reductant that ignites spontaneously
`
`in air. More complex boranes (e.g., decaborane B10H14) are less reactive.
`
` Organoboranes contain carbon and/or hydrogen arranged around a bo-
`
`ron atom. For example, trialkylboranes (BR3) are a specific class of organoborane
`
`compounds that are often highly reactive. As Dr. Kahl points out in his declara-
`
`tion, some of these compounds, such as triethylborane (Et3B), spontaneously ignite
`
`in air. Ex. 1003 ¶ 32. The reactivity of trialkylboranes is modulated by large R
`
`10
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`groups, however, and sufficiently large R groups can prevent trialkylboranes from
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`spontaneously igniting.
`
` Borinic acids are compounds having a boron atom bound to two car-
`
`bons and one oxygen having general formula R2B(OH). These compounds are
`
`frequently unstable in air due to oxidation. See Steiner et al., Diphenylborinic Acid
`
`Is a Strong Inhibitor of Serine Proteases, Bioorg. & Med. Chem. Lett., vol. 4, pp.
`
`2417–20, at 2417 (1994) (Ex. 2024).
`
` Boronic (or boronate) acids are compounds having a boron atom
`
`bound to one carbon and two oxygens having general formula RB(OH)2. Closely
`
`related to boronic acids are the boronic (or boronate) esters, in which the oxygen
`
`atoms of a boronic acid are further substituted by carbon (e.g., an alkyl or aryl
`
`group). Boronic esters have the general formula RB(OR)2.
`
` The compounds disclosed by Freeman are boronic acids. See, e.g.,
`
`Ex. 1009 ¶ [0027]. Specifically, compounds disclosed by Freeman include (from
`
`left to right) phenyl boronic acid, 3-nitro-phenyl boronic acid, 3-amino phenyl bo-
`
`ronic acid, and pentafluoro phenyl boronic acid:
`
`F
`
`F
`
`OH
`B
`
`F
`
`OH
`
`
`
`F F
`
`OH
`B
`
`OH
`
`OH
`B
`
`OH
`
`NO2
`
`OH
`B
`
`OH
`
`H2N
`
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` Borate esters and boric acid—corresponding to B(OR)3 and B(OH)3,
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`respectively—are boron compounds having a boron atom covalently bound to
`
`three oxygen atoms. The compounds of Brehove, 2,2’-(1-methyltrimethylene di-
`
`oxy) bis-(4-methyl-1,3,2-dioxaborinane) and 2,2’-oxybis(4,4,6-trimethly-1,3,2-
`
`dioxaborinane), are diborate esters and belong to this class of boron compounds.
`
` As a consequence of boron’s electron-deficient nature, boron-
`
`containing compounds are inherently susceptible to hydrolysis or oxidation to bo-
`
`ric acid. The susceptibility of boronic acids and borate esters has been particularly
`
`noted. See, e.g., Hall 2001 (Ex. 2016) at 9 (“[T]he ultimate fate of all boronic ac-
`
`ids in air and aqueous media is their slow oxidation into boric acid.”). For exam-
`
`ple, the hydrolysis of one of Brehove’s diborate esters is shown below:
`
`OH
`
`O
`B
`
`O
`
`O
`
`6 H2O
`
`2
`
`HO
`
`OH
`
`B
`
`OH
`
`3+
`
`H
`
`O
`
`BO
`
`O
`
`2,2'-(1-methyltrimethylene dioxy)
`bis-(4-methyl-1,3,2-dioxaborinane)
`
`Boric Acid
`
`
`Boron Compounds as Pharmaceutical Drugs
`
`B.
`
` As of 2005, there were few natural products, drugs, or drug candidates
`
`containing boron. See, e.g., Michael P. Groziak, Boron Therapeutics on the Hori-
`
`zon, Am. J. Therapeutics, vol. 8, pp. 321–28, at 321 (2001) (Ex. 1032) (“No phar-
`
`maceutical based on boron has yet made it to market . . . [B]oron is seldom seen as
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`a constituent of a bioactive agent . . . .”). The only boron-containing active phar-
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`maceutical ingredient that had been approved by the FDA for human use by early
`
`2005 was VELCADE®, a formulation of bortezomib, a boronic acid. See Baker et
`
`al., Therapeutic potential of boron-containing compounds, Future Med. Chem.,
`
`vol. 1, pp. 1275–88, at 1275 (2009) (Ex. 2015) see also Hall 2011 (Ex. 2016) at
`
`105. A POSA in 2005 therefore would have had little biological data related to bo-
`
`ron-containing compounds and even less guidance on how to formulate such com-
`
`pounds as active pharmaceutical ingredients.
`
` The development of VELCADE® is illustrative of the challenge and
`
`unpredictability that would have confronted a POSA in 2005 seeking to formulate
`
`a boron-containing active pharmaceutical ingredient. Although bortezomib’s effi-
`
`cacy had been known since 1995, it was not approved by the FDA for a number of
`
`years due to its rapid degradation in liquid formulations. Ultimately, a more stable
`
`formulation was achieved by lyophilizing bortezomib in the presence of mannitol.
`
` Although mannitol was known to be an inert excipient (a bulking
`
`agent), because of boron’s electron-deficient nature and its tendency to associate
`
`with other electron-rich functional groups and atomic species, lyophilizing borte-
`
`zomib in the presence of mannitol resulted in the following chemical reaction:
`
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`
`OH
`
`OH
`OH
`
`HO
`
`OH
`
`Mannitol
`
`HO
`
`OH
`
`OH
`B
`
`OH
`
`HN
`
`O
`
`NH
`
`O
`
`NN
`
`Bortezomib
`
`OH
`OH
`
`OH
`
`O
`B
`
`O
`
`HN
`
`O
`
`NH
`
`O
`
`NN
`
`Mannitol Ester of Bortezomib
`
`
`
`C. Molecular Structure of Keratin
`
` The main chemical constituent of the human nail is keratin. See, e.g.,
`
`Sudaxshina Murdan, Drug delivery to the nail following topical application, Int’l J.
`
`Pharmaceutics, vol. 236, pp. 1–26, at 3–4 (2002) (Ex. 1020). Nail also contains a
`
`relatively high level of water content (between 16% and 30%, with 18% being av-
`
`erage) and a small amount of lipid. Id. at 4.
`
` Like all proteins, keratin’s basic primary structure is a polypeptide
`
`chain consisting of a sequence of covalently bound amino acids. As a structural
`
`component of the nail plate, however keratin adopts a hierarchical “coiled coil” su-
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`perstructure in which multiple keratin polypeptide chains coil and bundle together
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`in a regular pattern to form intermediate filaments. See Wang et al., Keratin:
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`Structure, mechanical properties, occurrence in biological organisms, and efforts
`
`at bioinspiration, Prog. Mater. Sci., vol. 76, pp. 229–318, at 235–36 (2016) (Ex.
`
`2028). The formation of this hierarchical structure is driven by intermolecular in-
`
`teractions (hydrogen bonding, peptide bonds, and disulfide linkages) between the
`
`functional groups of keratin’s amino acid sequence. Id.
`
` The intermolecular interactions responsible for keratin’s structure are
`
`a consequence of its amino acid composition, which includes a high proportion of
`
`amino acids bearing functional groups capable of such interactions, such as hy-
`
`droxyl, amine, and thiol groups. Specifically, the amino acid composition of the
`
`keratin present in human nails comprises approximately 9.6% serine (–OH), 11.4%
`
`half cystine (indicative of cysteine or –SH content), 6.1% threonine (–OH), and
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`3.0% lysine (–NH2). Id. at 239 tbl.5.
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` The hierarchical structure of keratin is shown below:
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`
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`Id. at 235 fig.4; see also Murdan 2002 (Ex. 1020) at 15 fig.10.
`
` Keratin in the human nail also undergoes non-enzymatic glycosyla-
`
`tion, a process in which keratin protein molecules become bound to glucose. Alt-
`
`hough this is especially the case for individuals with diabetes having high blood
`
`sugar, it is true of healthy individuals as well. See, e.g., Marova et al., Non-
`
`enzymatic glycation of epidermal proteins of the stratum corneum in diabetic pa-
`
`tients, Acta Diabetologica, vol. 32, pp. 38–43, at 42 (1995) (Ex. 2041); Bakan &
`
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`Bakan, Glycosylation of nail in diabetics: possible marker of long-term hypergly-
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`caemia, Clin. Chim. Acta, vol. 147, pp 1–5, 4 (1985) (Ex. 2042) (“[G]lycosylation
`
`of nail proteins occurs and is increased in diabetics . . . .”).
`
`V. THE CITED REFERENCES
`
`A. Austin
`
` Austin is directed to “the use of oxaboroles and salts thereof as indus-
`
`trial biocides.” Ex. 1007 at 1:1–4. Austin discloses a vast number of compounds;
`
`I estimate that the number of compounds included in Austin’s “preferred” classes
`
`is at least in the tens of thousands. I also estimate that at least tens of thousands of
`
`compounds are included in the class that Austin identifies as “particularly pre-
`
`ferred.” Id. at 5:5–23. Tavaborole is not included in this class.
`
` Austin exemplifies 93 compounds, one of which is tavaborole. Id. at
`
`15–33 (Example 64). Consistent with the disclosure of the ’938 patent, Austin
`
`teaches that tavaborole remains reactive and uses the compound as an intermediate
`
`in a reaction with 8-hydroxyquinoline to obtain the compound of Austin’s Example
`
`80. Id. at 26:8–25; see also id. at 16:11–22.
`
` Austin does not disclose the use of oxaboroles to treat humans, and
`
`contains no in vivo or in vitro data relevant to the permeability of oxaboroles
`
`through the nail. Austin discloses potency of its compounds (including tavaborole)
`
`against Candida albicans, but does not disclose potency against either Tri-
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`chophyton rubrum or Trichophyton mentagrophytes, the principal causes of ony-
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`chomycosis. See id. at 37 tbl.9; see also Boni E. Elewski, Onychomycosis: Patho-
`
`genesis, Diagnosis, and Management, Clin. Microbiology Revs., vol. 11, pp. 415–
`
`29, at 416–17 (1998) (Ex. 2027).
`
` Austin discloses that its oxaboroles may be formulated with a carrier
`
`to form a biocide composition of the oxaborole in a liquid medium. Id. at 6:11–23.
`
`The concentration of the oxaborole in the biocide composition “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 composition.” Id. at 7:5–9.
`
`B.
`
`Brehove
`
` Brehove reports the use of dioxaborinane active ingredients of the jet
`
`fuel additive Biobor JF as a topical treatment for onychomycosis. Ex. 1008 ¶¶
`
`[0015], [0022]. Brehove provides in vitro experiments using Biobor’s dioxa-
`
`borinanes against C. albicans and five examples applying a mineral oil or petrole-
`
`um jelly formulation of Biobor’s dioxaborinanes to individuals purportedly having
`
`onychomycosis. Id. ¶¶ [0030]–[0038]. In these examples, a mixture of the afore-
`
`mentioned dioxaborinanes comprises 12.5% and 25% by weight of the topical
`
`formulations. Id. Brehove provides no in vivo pharmacokinetic, pharmacodynam-
`
`ic, or nail penetration data, and provides no data regarding controls or diagnoses of
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`onychomycosis. Brehove also discloses the use of penetration enhancers, particu-
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`larly dimethyl sulfoxide and N-methyl-2-pyrrolidone. Id. ¶ [0027].
`
` A POSA in 2005 would have known that Brehove’s dioxaborinanes
`
`were susceptible to hydrolysis in aqueous environments simply because they con-
`
`tain boron. See Yao et al., Borate Esters Used as Lubricant Additives, Lubrication
`
`Science, vol. 14, pp. 415–23, at 417 (2002) (Ex. 2039) (“The susceptibility of bo-
`
`rates to hydrolysis is due to the existence of electron-deficient boron.”).
`
`
`
`Indeed, as discussed above, Brehove’s dioxaborinanes are diborate es-
`
`ters whose “ultimate fate” is “slow oxidation into boric acid.” Hall 2011 (Ex.
`
`2016) at 9. Sales and product literature concerning Biobor JF confirm that Bre-
`
`hove’s dioxaborinanes readily decompose into boric acid by design. See Biobor
`
`Material Safety Data Sheet (Ex. 1022) at 4 (“INCOMPATABILITY WITH OTH-
`
`ER MATERIALS: Water.”); Biobor JF Service Bulletin No. 982 (Ex. 2038) at 10
`
`(“BIOBOR® JF must be kept from direct contact with excessive amounts of water
`
`to prevent hydrolysis of active ingredients into fuel insoluble materials.”); J.D.
`
`Lloyd, Borates and their biological applications, 29th Annual meeting of the In-
`
`ternational Research Group on Wood Preservation (June 1998) (Ex. 2022) at 17
`
`(“The boroesters [of Biobor JF] are particularly suited to this application as they
`
`have a good partition between water and fuel mixtures and boric acid produced as
`
`a result of the ester hydrolysis in water is also effective in controlling the causative
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`organisms, when it is delivered to the aqueous phase by the fuel itself.”); Lee &
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`Wong, Toxic Effects of Some Alcohol and Ethylene Glycol Derivatives on
`
`Cladosporium resinae, Applied & Envtl. Microbiol., vol. 38, pp. 24–28, at 25
`
`(1979) (Ex. 2040) (“It has been observed that Biobor JF at the recommended con-
`
`centration of 270 µL/liter of fuel gives rise to a deposit of boric acid after standing
`
`for some length of time, both in the laboratory and in fuel tanks.”).
`
`C.
`
`Freeman
`
` Freeman discloses the in vitro use of phenyl boronic acid (“PBA”)
`
`and derivatives of PBA to inhibit or kill certain pathogens. Ex. 1009 ¶ [001].
`
`Freeman asserts that PBA and PBA derivatives can be used to treat a wide variety
`
`of microbial infections, including “nail fungal infections.” Id. ¶¶ [0022]. Freeman
`
`also discloses that nail infections are particularly difficult to eradicate with topical
`