`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`FLATWING PHARMACEUTICALS, LLC,
`Petitioner,
`
`v.
`
`ANACOR PHAMACEUTICALS, INC.,
`Patent Owner
`__________________
`
`Case No. IPR2018-00169
`Patent No. 9,566,289
`__________________
`
`DECLARATION OF MAJELLA E. LANE, PH.D.
`IN SUPPORT OF PATENT OWNER’S RESPONSE
`
`
`
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`TABLE OF CONTENTS
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`INTRODUCTION ........................................................................................... 1
`
`ACADEMIC AND PROFESSIONAL QUALIFICATIONS ......................... 2
`
`
`I.
`
`II.
`
`III. THE ’289 PATENT ......................................................................................... 4
`
`IV. TECHNICAL BACKGROUND ..................................................................... 8
`
`A.
`
`B.
`
`C.
`
`Structure of the Nail Plate ..................................................................... 8
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`Role of Keratin ...................................................................................... 9
`
`Factors Affecting Nail Permeability ................................................... 10
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`1. Molecular Weight ..................................................................... 11
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`2.
`
`3.
`
`Keratin-Binding Affinity .......................................................... 17
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`Other Factors ............................................................................. 20
`
`D.
`
`The Challenge of Transungual Drug Delivery .................................... 22
`
`V.
`
`THE CITED REFERENCES......................................................................... 26
`
`A. Austin .................................................................................................. 26
`
`B.
`
`C.
`
`D.
`
`Brehove................................................................................................ 27
`
`Freeman ............................................................................................... 28
`
`Samour ................................................................................................. 29
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`VI. RESPONSE TO PETITIONER’S GROUNDS ............................................. 30
`
`A.
`
`B.
`
`The Cited Art Teaches Away from 5% Tavaborole ........................... 30
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`A POSA Would Have Used More than 5% Tavaborole to
`Overcome Tavaborole’s Expected High Keratin-Binding
`Affinity ................................................................................................ 36
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`VII. CONCLUSION .............................................................................................. 41
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`I, Majella E. Lane, Ph.D., hereby state and declare as follows:
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`Case No. IPR2018-00169
`U.S. Patent No. 9,566,289
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`I.
`
`INTRODUCTION
`
`1.
`
`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. 9,566,289 (“the ’289 patent”) filed by Petitioner FlatWing
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`Pharmaceuticals, LLC (“FlatWing”). This declaration contains my opinions relat-
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`ed to the validity of claims 10 and 12–15 of the ’289 patent.
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`2.
`
`I am being compensated at my customary hourly rate, and my com-
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`pensation is not dependent upon the outcome of, or the content of my testimony in,
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`the present inter partes review proceeding or any litigation proceedings.
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`3.
`
`I have reviewed FlatWing’s petition for inter partes review (“Pet.”) of
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`the ’289 patent, including the declarations filed in support of the petition submitted
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`by Dr. Stephen B. Kahl (Ex. 1003) and Dr. S. Narasimha Murthy (Ex. 1005). I
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`have further reviewed the exhibits and articles cited in these documents, as well as
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`the articles and documents cited in this declaration.
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`4.
`
`I have additionally reviewed the declaration of Dr. Paul J. Reider
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`(“Reider Decl.,” Ex. 2013) filed in support of Anacor’s response to FlatWing’s pe-
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`tition. I am also aware of knowledge generally available to and relied upon by per-
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`sons 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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`5.
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`reserve the right to continue my investigation and analysis, which may include a
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`review of documents and information not yet provided. I further reserve the right
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`to expand or otherwise modify my opinions and conclusions as my investigation
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`and study continues, and to supplement my opinions and conclusions in response
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`to any additional information that becomes available to me.
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`II. ACADEMIC AND PROFESSIONAL QUALIFICATIONS
`
`6.
`
`I received a Ph.D. in 1997 from Trinity College, Dublin, where my re-
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`search focused on drug transport across biological membranes (in particular skin
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`and mucosa), topical and transdermal formulations, mathematical modeling of top-
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`ical and transdermal drug delivery, and prediction of percutaneous drug penetra-
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`tion. I received a B.S. in pharmacy from Trinity College in 1992.
`
`7.
`
`I am currently the Director of the Skin Research Group and a Senior
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`Lecturer in Pharmaceutics at the School of Pharmacy at the University College of
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`London (“UCL”). I have held those positions since 2010 and 2008, respectively.
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`From 2005 to 2008, I was a Lecturer in Pharmaceutics at UCL. Prior to that, I was
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`the director of the Master’s program in Pharmaceutical Technology at Trinity Col-
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`lege, Dublin from 1998 to 2005, after having first worked there as a Lecturer in
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`Pharmaceutical Chemistry starting in 1995, and a Lecturer in Pharmaceutics start-
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`ing in 1997. A copy of my curriculum vitae is attached as Exhibit 2045.
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`8. My areas of expertise include ungual drug absorption, transdermal
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`drug delivery, topical drug delivery, membrane transport, and biophysical ap-
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`proaches towards the elucidation of drug-drug, drug-excipient and drug-membrane
`
`interactions. My research focus includes the development of optimal drug formu-
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`lations for effective delivery of therapeutics, in particular through skin, nail, and
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`mucous membranes. Through my work at the Skin Research Group at UCL, I
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`have conducted or participated in more than 100 studies using a range of biophysi-
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`cal techniques to probe and study the mechanisms of skin and nail penetration and
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`modulation. Another research focus is determining the action of penetration
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`modulating agents, specifically penetration enhancers and retarders.
`
`9.
`
`I currently serve as the Chair of Skin Forum, and am an Advisory
`
`Board Member of the Academy of Pharmaceutical Sciences of Great Britain, Stra-
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`tum Corneum, and the Technical Advisory Group of Skin Health in the Developing
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`World. I am also the Topical Expert of the Chemistry, Pharmacy, and Standards
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`Expert Advisory Group for the Commission on Human Medicines. I am currently
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`a member of a number of pharmaceutical societies, including the Royal Pharma-
`
`ceutical Society of Great Britain, the Pharmaceutical Society of Ireland, the Amer-
`
`ican Association of Pharmaceutical Scientists, the Controlled Release Society, and
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`the Bioactives Committee of the Society of the Chemistry Industry. I am currently
`
`serving as the expert on topical and transdermal medicines for the Chemistry,
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`Pharmacy, and Standards Committee of the U.K. Medicines and Health Regulatory
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`Agency, which is the British equivalent of the Food and Drug Administration
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`(“FDA”) in the United States.
`
`10.
`
`I am currently a member of the editorial board of a number of peer-
`
`reviewed biomedical journals, including the American Journal of Pharmaceutical
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`Sciences, Cosmetics, Current Drug Delivery, Drug Delivery Letters, the Interna-
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`tional Journal of Nanomaterials, Nanotechnology and Nanomedicines, the Journal
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`of Biophysical Chemistry, the Journal of Drug Targeting, the Journal of Pharma-
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`ceutical Science, and the International Journal of Pharmaceutics.
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`11.
`
`I have published more than 130 peer-reviewed articles addressing var-
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`ious aspects of overcoming the barrier properties of skin and nail.
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`12. Based on my qualifications and experience, I consider myself quali-
`
`fied to provide opinions on the understanding of a person of ordinary skill in the
`
`relevant art in 2005 as it pertains to parameters relating to transungual penetration
`
`and the identification of potential drug candidates for transungual penetration.
`
`III. THE ’289 PATENT
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`13. The inventors of the ’289 patent recognized a “need in the art for
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`compounds which can effectively penetrate the nail” as well as “compounds which
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`can effectively treat ungual and/or periungual infections” such as onychomycosis.
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`’289 patent (Ex. 1001) at 2:66–3:2. In particular, the inventors recognized that
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`“poor penetration of the active agent through the . . . nail plate and/or excessive
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`binding to keratin (the major protein in nails and hair) are the reasons for the poor
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`efficacy” of existing topical treatments for these infections. Id. at 133:64–67.
`
`14. As the inventors further explained:
`
`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.”
`
`’289 patent (Ex. 1001) at 134:2–11.
`
`15. To this end, the ’289 patent “provides novel boron compounds” and
`
`“a method of delivering a compound from the dorsal layer of the nail plate to the
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`nail bed” using such compounds. Id. at 20:32, 136:21–23. Tavaborole (1,3-
`
`dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole) is one of the compounds dis-
`
`closed. See id. at 189:48–197:7 (Examples 16–20)
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`16.
`
`I understand that claim 10 of the ’289 patent depends from independ-
`
`ent claim 4 and therefore incorporates all limitations of independent claim 4.
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`17. Claim 4 of the ’289 patent recites:
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`4. A pharmaceutical formulation, comprising:
`[tavaborole], or a pharmaceutically acceptable salt
`thereof;
`a solvent system and
`a chelating agent.
`
`18. Claim 10 of the ’289 patent recites:
`
`10. The pharmaceutical formulation of claim 4,
`wherein the [tavaborole], or a pharmaceutically accepta-
`ble salt thereof, is present in a concentration of about 5%
`w/w.
`
`19.
`
`I understand that claims 13–15 of the ’289 patent depend directly or
`
`indirectly on independent claim 12 and therefore incorporate all limitations of the
`
`claim(s) from which they depend.
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`20. Claim 12 of the ’289 patent recites:
`
`12. A pharmaceutical formulation, comprising:
`about 5% w/w [tavaborole], or a pharmaceutically ac-
`ceptable salt thereof;
`propylene glycol;
`ethanol; and
`ethylene diamine tetraacetic acid (EDTA) or a phar-
`maceutically acceptable salt thereof.
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`21. Claim 13 of the ’289 patent recites:
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`13. The pharmaceutical formulation of claim 12,
`wherein the formulation is suitable for the treatment of
`onychomycosis of a toenail due to Trichophyton rubrum
`or Trichophyton mentagrophytes by topical application of
`the formulation to the toenail.
`
`22. Claim 14 of the ’289 patent recites:
`
`14. The pharmaceutical formulation of claim 12,
`wherein the ethylene diamine tetraacetic acid (EDTA) or
`a pharmaceutically acceptable salt thereof, is present in a
`concentration of from about 0.005% to about 2.0% w/w.
`
`23. Claim 15 of the ’289 patent recites:
`
`15. The pharmaceutical formulation of claim 14,
`wherein the formulation is suitable for the treatment of
`onychomycosis of a toenail due to Trichophyton rubrum
`or Trichophyton mentagrophytes by topical application of
`the formulation to the toenail.
`
`24.
`
`I understand that the ’289 patent claims priority to a provisional patent
`
`application filed on February 16, 2005. I therefore interpret the meaning of the
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`’289 patent claims in accordance with the knowledge and understanding of a per-
`
`son of ordinary skill in the art during the 2005 time period.
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`IV. TECHNICAL BACKGROUND
`
`A.
`
`Structure of the Nail Plate
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`25. The human nail is composed of densely packed layers of keratinized
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`cells. Walters et al., Physicochemical characterization of the human nail: permea-
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`tion pattern for water and the homologous alcohols and differences with respect to
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`the stratum corneum, J. Pharm. Pharmacol. vol. 35, pp. 28–33, at 29 (1983) (Ex.
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`2031); see also Sudaxshina Murdan, Drug delivery to the nail following topical
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`application, Int’l J. Pharm., vol. 236, pp. 1–26, at 2–3 (2002) (Ex. 1020). Keratin-
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`ized cells, unlike most other human cells, contain no organelles or nuclei and are
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`comprised substantially of keratin fibrils, embedded in a protein matrix. Bo For-
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`slind, Biophysical Studies of the Normal Nail, Acta Derm Venerol, vol. 5, pp. 161–
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`68, at 161–62 (1970) (Ex. 2043). These cells are tightly fused together to form the
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`hard, slightly elastic structure of the nail plate. Id.
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`26. More specifically, the nail plate is composed of three very tightly knit,
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`keratinized layers. See Runne & Orfanos, The Human Nail: Structure, Growth and
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`Pathological Changes, Curr. Prob. Derm. vol. 9, pp. 102–49, at 104–06 (1981)
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`(Ex. 2029). The outermost dorsal layer is hard and thin, and only a few cells
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`thick. Id. at 105. The intermediate layer is softer, thicker, more flexible than the
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`dorsal layer, and comprises the majority of the nail’s thickness. Id. The innermost
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`ventral layer is very thin and connects the nail plate to the nail bed. Id.
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`27. The nail plate has been described as a hydrophilic gel membrane, or a
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`hydrogel. See, e.g., Walters et al. 1983 (Ex. 2031) at 31. There is very little lipid
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`in the nail; the total lipid content of the nail plate is not more than 1%. See Murdan
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`2002 (Ex. 1020) at 4. The principal reason for the nail’s elasticity and flexibility is
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`its water content. The nail typically contains 18% water on average, but may con-
`
`tain less than 16% or up to 30% water depending on the relative humidity. See
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`Runne & Orfanos (Ex. 2029) at 106. The water content of the nail is an important
`
`factor in ensuring appropriate integrity and function of this tissue.
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`28. The nail plate overlays the nail bed. The nail bed is a thin, soft, non-
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`keratinized epithelium, which acts as a holder and a slide for the growing nail plate
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`and contributes to its growth. Id. at 104. The nail bed is typically the site of nail
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`infections such as onychomycosis. See Boni E. Elewski, Onychomycosis: Patho-
`
`genesis, Diagnosis, and Management, Clin. Microbiology Revs., vol. 11, pp. 415–
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`29, at 417 (1998) (Ex. 2027) (“[T]he most common form of onychomycosis . . . is
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`characterized by invasion of the nail bed and underside of the nail plate.”).
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`B. Role of Keratin
`
`29. About 80% of the nail is composed of a dense network of keratin fi-
`
`bers, which network is responsible for the nail’s mechanical strength and barrier
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`properties. See Murdan 2002 (Ex. 1020) at 3–4. Keratin is a protein that assem-
`
`bles into a “coiled coil” hierarchical structure where multiple keratin fibers bundle
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`together in a regular pattern to form intermediate filaments. See Wang et al., Kera-
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`tin: Structure, mechanical properties, occurrence in biological organisms, and ef-
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`forts 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
`
`forces: hydrogen bonding, peptide bonds, and disulfide linkages. Id.
`
`30. One technique that has been used to improve drug permeation into the
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`nail plate is the use of chemical agents that break apart the dense keratin network.
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`See Murdan 2002 (Ex. 1020) at 15–16. These keratolytic agents disrupt the higher-
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`order structure formed by keratin fibers. Although these agents can compromise
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`the physical integrity of the nail, they have been shown to improve the transungual
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`penetration of a number of compounds, including high molecular weight antifungal
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`agents. See Shivakumar et al., Approaches to Enhance Ungual and Trans-Ungual
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`Drug Delivery, in Topical Nail Products and Ungual Drug Delivery 87, 93–94
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`(Murthy & Maibach eds., 2013) (Ex. 2030).
`
`C.
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`Factors Affecting Nail Permeability
`
`31. At the time of the invention, the field of transungual drug delivery
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`was (and still is) very small. As a consequence, only a handful of studies have sys-
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`tematically investigated the fundamental factors underlying nail permeability. The
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`conflicting information gathered in these studies demonstrates that in 2005, there
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`were no “ground rules” for formulators seeking to achieve penetration into the nail.
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`32. The limited understanding and conflicting information concerning the
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`state of the art of nail penetration would have precluded a POSA from rationally
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`deciding which drug compounds could be used in transungual formulations, much
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`less reasonably predicting which compounds could penetrate the nail. A POSA in
`
`2005, therefore, would have known that nail penetration is unpredictable.
`
`33.
`
`It was also understood in 2005 that a compound’s nail permeability is
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`influenced by several different factors. Among these factors is molecular weight,
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`which provides an indirect measure of a compound’s size and mobility. Another
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`factor is the compound’s keratin-binding affinity, that is, the degree to which the
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`compound “sticks” to the dense keratin network that comprises the overriding ma-
`
`jority of nail’s molecular structure. Other important factors include the com-
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`pound’s hydrophilicity/lipophilicity (“log P”), the nature of the vehicle being used
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`to deliver the compound, and other physicochemical properties such as molecular
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`charge. See Murdan 2002 (Ex. 1020) at 9.
`
`1. Molecular Weight
`
`34. One factor affecting the diffusion or permeability through the nail
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`plate is a compound’s molecular weight. It was generally understood in 2005 that
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`compounds with high molecular weight tend to diffuse more slowly than com-
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`pounds with low molecular weight. However, transport through the nail was
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`known to be complex and nonlinear. Thus, a POSA in 2005 would have under-
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`permeability of compounds, particularly those below 300 Da.
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`35. This understanding of the POSA in 2005 is based on the few studies
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`that have systematically examined the role of molecular weight and nail permeabil-
`
`ity. To start, Walters et al. in 1983 studied the diffusion of a homologous series of
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`n-alkanols through human cadaver nails. By using a homologous series—
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`methanol, ethanol, n-propanol, and so on—Walters et al. sought to develop the
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`“basic concept of the permeability of the human nail plate” by using structurally
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`similar compounds. Walters et al. 1983 (Ex. 2031) at 28–29 & tbl.1. What they
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`discovered was that the trend between molecular weight (roughly proportional to
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`chain length) and permeability was nonlinear, as shown below. Id. at 30 fig.1.
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`36. Walters et al. thus found that the permeability coefficient of n-
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`dodecanol (MW 186.34 Da) in a human nail was comparable to that of methanol
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`(MW 32.04 Da), a compound nearly six-fold smaller in terms of molecular weight.
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`Moreover, the permeability of n-dodecanol was an order of magnitude greater
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`than n-pentanol (88.15 Da), a compound less than half its weight. Id. at 29 tbl.1.
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`These results demonstrate that even as between structurally similar compounds,
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`relative permeability cannot be predicted through molecular weight.
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`37. Walters et al. explained n-dodecanol’s increased permeability by hy-
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`pothesizing the existence of a “lipid pathway” through the nail. Id. at 32. As dis-
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`cussed, the human nail’s lipid content is approximately 1%. See Murdan 2002 (Ex.
`
`1020) at 4. Based on their data, Walters et al. determined that there was “[a] nomi-
`
`nal molecular size sensitivity . . . considering the narrow spread in [effective diffu-
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`sivity] values.” Walters et al. 1983 (Ex. 2031) at 31 (emphasis added). Instead of
`
`relying on molecular weight, Walters et al. concluded that the partition coeffi-
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`cient—a measure of the hydrophilicity or lipophilicity of the compound based on
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`its preferential distribution in water versus a non-polar solvent such as octanol (or
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`log P)—was the principal factor governing nail permeability.
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`38. Subsequent work by Mertin & Lippold in 1997 using a different ho-
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`mologous series disagreed with Walters et al. with respect to the importance of the
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`partition coefficient. See Mertin & Lippold, In-vitro Permeability of the Human
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`ficient Octanol/Water and the Water Solubility of Drugs on their Permeability and
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`Maximum Flux, J. Pharm. Pharmacol., vol. 49, pp. 30–34, at 32 (1997) (“Mertin &
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`Lippold 1997b,” Ex. 2033). Consequently, Mertin & Lippold also disagreed with
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`Walters et al. regarding the existence of a lipid pathway through the nail. Id.
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`39.
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`In contrast to the findings of Walters et al., Mertin & Lippold found
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`that there was no relationship between nail permeability and the partition coeffi-
`
`cient in a homologous series of nicotinic acid esters. They concluded instead that
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`water solubility was the principal factor relevant to a drug’s maximum flux
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`through the nail. Id. at 32–33 (“It has to be emphasized that the maximum flux of
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`a substance firstly depends on its water solubility . . . .”). To date, the disagree-
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`ment between Walters et al. and Mertin & Lippold has not been resolved. See
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`Murdan 2002 (Ex. 1020) at 11.
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`40. At the same time, Mertin and Lippold also observed a nonlinear rela-
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`tionship between molecular weight and nail permeability in bovine hoof, echoing
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`the earlier results of Walters et al. Specifically, Mertin & Lippold found that octyl
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`nicotinate (MW 235.3 Da) had the same or higher permeability than methyl nico-
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`tinate (MW 13.1 Da). Mertin & Lippold 1997b (Ex. 2033) at 32 fig.1. Thus, Mer-
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`tin & Lippold results demonstrate that the overall trend between molecular weight
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`and permeability does not always obtain.
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`41. Moreover, Mertin & Lippold further explained that the differences be-
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`tween their findings and those of Walters et al. were attributable to their respective
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`homologous series. They therefore agreed that the partition coefficient could pre-
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`dominate “when the affinity of the substance to the nail plate”—its keratin-binding
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`affinity—“decreases faster than its affinity to water with increasing lipophilicity.”
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`Id. at 32. In other words, the chemical structure of a compound and its interaction
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`with the nail’s keratin matrix cannot be ignored when it comes to nail penetration.
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`42. Thus, although I agree that, broadly speaking, higher molecular
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`weight compounds generally display lower nail permeability, a POSA would have
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`understood that this general observation applies only as a statistical matter and
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`cannot be used to predict the relative permeability of particular compounds, even
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`compounds deemed “structurally similar.” Any statistical correlation between mo-
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`lecular weight and nail permeability is a coarse tool backed by conflicting and am-
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`biguous data. This type of statistical correlation would not have been relied upon
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`by a POSA to make precise relative judgments, particularly without first consider-
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`ing the other factors known to influence nail permeability.
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`43.
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`Instead of making predictive judgments concerning permeability
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`based on molecular weight, a POSA would have understood the correlation to
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`mean that “macromolecules” having a mass greater than about 300 Da would have
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`more difficulties penetrating the nail. See, e.g., Shivakumar et al., Transungual
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`drug delivery: an update, J. Drug Del. Sci. Tech., vol. 24, pp. 301–10, at 303
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`(2014) (Ex. 2007) (“Generally, molecules that exceed 300 Daltons in size may face
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`hindrance while permeating the nail plate.”). A POSA would have also understood
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`that the relative permeability of small molecules below this threshold would not be
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`dominated by molecular weight; other factors would play a more significant role.
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`44. Permeability data from a separate study by Mertin & Lippold provide
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`an ample illustration of the logical error of taking the contrary position.
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`45. The table above is reproduced from Mertin & Lippold, In-vitro Per-
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`meability of the Human Nail and of a Keratin Membrane from Bovine Hooves:
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`Prediction of the Penetration Rate of Antimycotics through the Nail Plate and their
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`Efficacy, J. Pharm. Pharmacol., vol. 49, pp. 866–72, at 868 tbl.1 (1997) (“Mertin &
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`Lippold 1997a,” Ex. 1031). The data show that ciclopirox (MW 207.3 Da) has
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`lower permeability in a human nail than a number of higher molecular weight an-
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`timycotics: naftifine (MW 287.4 Da), tolnaftate (MW 307.4 Da), bifonazole (MW
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`310.4 Da), and econazole (MW 381.7 Da).1 Thus, a POSA would not have con-
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`cluded that the relative permeability of any two antimycotic agents could be pre-
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`dicted based on molecular weight alone. Instead, a POSA would view a com-
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`pound’s molecular weight as just one of several factors to be considered, which
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`factors include the compound’s keratin-binding affinity.
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`2. Keratin-Binding Affinity
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`46. The binding of a compound to the nail’s keratin matrix negatively im-
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`pacts its nail penetration by reducing the concentration gradient driving the com-
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`1 See also Kobayashi et al., In vitro permeation of several drugs through the human
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`nail plate: relationship between physicochemical properties and nail permeability
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`of drugs, Eur. J. Pharm. Sci., vol. 21 pp. 471–77, at 474 (2004) (Ex. 2032) (perme-
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`ability of isosorbide dinitrate (MW 236.1 Da) greater than permeability of antipy-
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`rine (MW 188.2 Da); difference between permeability of p-hydroxy benzoic amyl
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`ester (MW 208.25 Da) and p-hydroxy benzoic acid ethyl ester (MW 166.18 Da)
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`not statistically significant),
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`pound’s diffusion in accordance with Fick’s law of diffusion.2 See Murthy et al.,
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`Iontophoretic Drug Delivery across Human Nail, J. Pharm. Sci., vol. 96, pp. 305–
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`11, at 305–06 (2007) (Ex. 2008) (“[T]here are at least two factors that could limit
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`the accumulation and activity of drugs in the nail on topical application. First, the
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`physicochemical properties of the drug . . . Second, binding of the drug to keratin
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`. . . .”); see also, e.g., Shivakumar et al. 2014 (Ex. 2007) at 303; Shivakumar et al.
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`2013 (Ex. 2030) at 88. Another consequence of a compound’s binding to keratin is
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`that it is not able to exert its therapeutic effect in the target area—in the case of on-
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`ychomycosis, the nail bed. See Murthy et al. 2007 (Ex. 2008) at 306; see also
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`Shivakumar et al. 2013 (Ex. 2030) at 88. For these reasons, a POSA in 2005
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`would have not only been concerned with the question of a compound’s overall
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`penetration into and through the nail, but the specific question of how much of the
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`unbound fraction of the compound (the fraction not bound to keratin) would be
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`available to penetrate in the first instance.
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`47. Whether a compound possesses high keratin-binding affinity is largely
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`a function of its chemical structure. In this regard, antifungal agents are generally
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`known to have high keratin-binding affinity, which is a principal reason why topi-
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`2 Fick’s law of diffusion provides that the rate of diffusion or flux of a species
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`across a membrane is proportional to its concentration gradient.
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`cal formulations for onychomycosis have failed. See Murthy et al. 2007 (Ex.
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`2008) at 306 (“Antifungal drugs are reported to possess high-binding affinity to
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`keratin.”). Terbinafine’s high keratin-binding affinity, for example, has effectively
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`precluded its use as a topical treatment. Thus, while systemic treatment with oral
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`terbinafine is currently recognized as the “gold standard” for treating onychomyco-
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`sis due to its high potency against dermatophytes, an effective topical formulation
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`has proven elusive. See, e.g.,