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 MAJELLA E. LANE, PH.D.
`IN SUPPORT OF PATENT OWNER’S RESPONSE
`
`
`
`
`
`
`

`

`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`
`TABLE OF CONTENTS
`
`INTRODUCTION ........................................................................................... 1
`
`ACADEMIC AND PROFESSIONAL QUALIFICATIONS ......................... 2
`
`
`I.
`
`II.
`
`III. THE ’938 PATENT ......................................................................................... 4
`
`IV. TECHNICAL BACKGROUND ..................................................................... 7
`
`A.
`
`B.
`
`C.
`
`Structure of the Nail Plate ..................................................................... 7
`
`Role of Keratin ...................................................................................... 9
`
`Factors Affecting Nail Permeability ................................................... 10
`
`1. Molecular Weight ..................................................................... 11
`
`2.
`
`3.
`
`Keratin-Binding Affinity .......................................................... 17
`
`Other Factors ............................................................................. 20
`
`D.
`
`The Challenge of Transungual Drug Delivery .................................... 22
`
`V.
`
`THE CITED REFERENCES......................................................................... 25
`
`A. Austin .................................................................................................. 25
`
`B.
`
`C.
`
`D.
`
`Brehove................................................................................................ 26
`
`Freeman ............................................................................................... 27
`
`Samour ................................................................................................. 28
`
`VI. RESPONSE TO PETITIONER’S GROUNDS ............................................. 29
`
`A.
`
`B.
`
`The Cited Art Teaches Away from 5% Tavaborole ........................... 29
`
`A POSA Would Have Used More than 5% Tavaborole to
`Overcome Tavaborole’s Expected High Keratin-Binding
`Affinity ................................................................................................ 35
`
`i
`
`

`

`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`VII. CONCLUSION .............................................................................................. 40
`
`
`
`ii
`
`

`

`I, Majella E. Lane, Ph.D., hereby state and declare as follows:
`
`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`
`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. 9,549,938 (“the ’938 patent”) filed by Petitioner FlatWing
`
`Pharmaceuticals, LLC (“FlatWing”). This declaration contains my opinions relat-
`
`ed to the validity of claims 3, 5, and 6 of the ’938 patent.
`
`2.
`
`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.
`
`3.
`
`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 (Ex. 1003) and Dr. S. Narasimha Murthy (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.
`
`4.
`
`I have additionally reviewed the declaration of Dr. Paul J. Reider
`
`(“Reider Decl.,” Ex. 2013) filed in support of Anacor’s response to FlatWing’s pe-
`
`tition. I am also aware of knowledge generally available to and relied upon by per-
`
`sons of ordinary skill in the art (“POSA”) at the time of the invention.
`
`1
`
`

`

`This declaration is based on information currently available to me. I
`
`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`
`5.
`
`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
`
`6.
`
`I received a Ph.D. in 1997 from Trinity College, Dublin, where my re-
`
`search focused on drug transport across biological membranes (in particular skin
`
`and mucosa), topical and transdermal formulations, mathematical modeling of top-
`
`ical and transdermal drug delivery, and prediction of percutaneous drug penetra-
`
`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
`
`Lecturer in Pharmaceutics at the School of Pharmacy at the University College of
`
`London (“UCL”). I have held those positions since 2010 and 2008, respectively.
`
`From 2005 to 2008, I was a Lecturer in Pharmaceutics at UCL. Prior to that, I was
`
`the director of the Master’s program in Pharmaceutical Technology at Trinity Col-
`
`lege, Dublin from 1998 to 2005, after having first worked there as a Lecturer in
`
`Pharmaceutical Chemistry starting in 1995, and a Lecturer in Pharmaceutics start-
`
`ing in 1997. A copy of my curriculum vitae is attached as Exhibit 2045.
`
`2
`
`

`

`8. My areas of expertise include ungual drug absorption, transdermal
`
`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`
`drug delivery, topical drug delivery, membrane transport, and biophysical ap-
`
`proaches towards the elucidation of drug-drug, drug-excipient and drug-membrane
`
`interactions. My research focus includes the development of optimal drug formu-
`
`lations for effective delivery of therapeutics, in particular through skin, nail, and
`
`mucous membranes. Through my work at the Skin Research Group at UCL, I
`
`have conducted or participated in more than 100 studies using a range of biophysi-
`
`cal techniques to probe and study the mechanisms of skin and nail penetration and
`
`modulation. Another research focus is determining the action of penetration
`
`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-
`
`tum Corneum, and the Technical Advisory Group of Skin Health in the Developing
`
`World. I am also the Topical Expert of the Chemistry, Pharmacy, and Standards
`
`Expert Advisory Group for the Commission on Human Medicines. I am currently
`
`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
`
`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,
`
`3
`
`

`

`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`Pharmacy, and Standards Committee of the U.K. Medicines and Health Regulatory
`
`Agency, which is the British equivalent of the Food and Drug Administration
`
`(“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
`
`Sciences, Cosmetics, Current Drug Delivery, Drug Delivery Letters, the Interna-
`
`tional Journal of Nanomaterials, Nanotechnology and Nanomedicines, the Journal
`
`of Biophysical Chemistry, the Journal of Drug Targeting, the Journal of Pharma-
`
`ceutical Science, and the International Journal of Pharmaceutics.
`
`11.
`
`I have published more than 130 peer-reviewed articles addressing var-
`
`ious aspects of overcoming the barrier properties of skin and nail.
`
`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 ’938 PATENT
`
`13. 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
`
`4
`
`

`

`penetration of the active agent through the . . . nail plate and/or excessive binding
`
`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`
`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.
`
`14. As the inventors of the ’938 patent 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.”
`
`’938 patent (Ex. 1001) at 132:14–23.
`
`15. 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).
`
`5
`
`

`

`I understand that claims 3, 5, and 6 of the ’938 patent depend directly
`
`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`
`16.
`
`or indirectly on independent claim 1 and therefore incorporate all limitations of the
`
`claim(s) from which they depend.
`
`17. Claim 1 of the ’938 patent recites:
`
`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.
`
`18. 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].
`
`19. 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].
`
`6
`
`

`

`20. Claim 6 of the ’938 patent recites:
`
`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`
`6. The method of claim 5, wherein the pharmaceuti-
`cal composition further comprises ethanol and propylene
`glycol.
`
`21.
`
`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
`
`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.
`
`Structure of the Nail Plate
`
`22. The human nail is composed of densely packed layers of keratinized
`
`cells. Walters et al., Physicochemical characterization of the human nail: permea-
`
`tion pattern for water and the homologous alcohols and differences with respect to
`
`the stratum corneum, J. Pharm. Pharmacol. vol. 35, pp. 28–33, at 29 (1983) (Ex.
`
`2031); see also Sudaxshina Murdan, Drug delivery to the nail following topical
`
`application, Int’l J. Pharm., vol. 236, pp. 1–26, at 2–3 (2002) (Ex. 1020). Keratin-
`
`ized cells, unlike most other human cells, contain no organelles or nuclei and are
`
`comprised substantially of keratin fibrils, embedded in a protein matrix. Bo For-
`
`slind, Biophysical Studies of the Normal Nail, Acta Derm Venerol, vol. 5, pp. 161–
`
`7
`
`

`

`68, at 161–62 (1970) (Ex. 2043). These cells are tightly fused together to form the
`
`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`
`hard, slightly elastic structure of the nail plate. Id.
`
`23. More specifically, the nail plate is composed of three very tightly knit,
`
`keratinized layers. See Runne & Orfanos, The Human Nail: Structure, Growth and
`
`Pathological Changes, Curr. Prob. Derm. vol. 9, pp. 102–49, at 104–06 (1981)
`
`(Ex. 2029). The outermost dorsal layer is hard and thin, and only a few cells
`
`thick. Id. at 105. The intermediate layer is softer, thicker, more flexible than the
`
`dorsal layer, and comprises the majority of the nail’s thickness. Id. The innermost
`
`ventral layer is very thin and connects the nail plate to the nail bed. Id.
`
`24. The nail plate has been described as a hydrophilic gel membrane, or a
`
`hydrogel. See, e.g., Walters et al. 1983 (Ex. 2031) at 31. There is very little lipid
`
`in the nail; the total lipid content of the nail plate is not more than 1%. See Murdan
`
`2002 (Ex. 1020) at 4. The principal reason for the nail’s elasticity and flexibility is
`
`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
`
`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.
`
`25. The nail plate overlays the nail bed. The nail bed is a thin, soft, non-
`
`keratinized epithelium, which acts as a holder and a slide for the growing nail plate
`
`and contributes to its growth. Id. at 104. The nail bed is typically the site of nail
`
`8
`
`

`

`infections such as onychomycosis. See Boni E. Elewski, Onychomycosis: Patho-
`
`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`
`genesis, Diagnosis, and Management, Clin. Microbiology Revs., vol. 11, pp. 415–
`
`29, at 417 (1998) (Ex. 2027) (“[T]he most common form of onychomycosis . . . is
`
`characterized by invasion of the nail bed and underside of the nail plate.”).
`
`B. Role of Keratin
`
`26. 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
`
`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
`
`together in a regular pattern to form intermediate filaments. See Wang et al., Kera-
`
`tin: Structure, mechanical properties, occurrence in biological organisms, and ef-
`
`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.
`
`27. One technique that has been used to improve drug permeation into the
`
`nail plate is the use of chemical agents that break apart the dense keratin network.
`
`See Murdan 2002 (Ex. 1020) at 15–16. These keratolytic agents disrupt the higher-
`
`order structure formed by keratin fibers. Although these agents can compromise
`
`the physical integrity of the nail, they have been shown to improve the transungual
`
`penetration of a number of compounds, including high molecular weight antifungal
`
`9
`
`

`

`agents. See Shivakumar et al., Approaches to Enhance Ungual and Trans-Ungual
`
`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`
`Drug Delivery, in Topical Nail Products and Ungual Drug Delivery 87, 93–94
`
`(Murthy & Maibach eds., 2013) (Ex. 2030).
`
`C.
`
`Factors Affecting Nail Permeability
`
`28. At the time of the invention, the field of transungual drug delivery
`
`was (and still is) very small. As a consequence, only a handful of studies have sys-
`
`tematically investigated the fundamental factors underlying nail permeability. The
`
`conflicting information gathered in these studies demonstrates that in 2005, there
`
`were no “ground rules” for formulators seeking to achieve penetration into the nail.
`
`29. The limited understanding and conflicting information concerning the
`
`state of the art of nail penetration would have precluded a POSA from rationally
`
`deciding which drug compounds could be used in transungual formulations, much
`
`less reasonably predicting which compounds could penetrate the nail. A POSA in
`
`2005, therefore, would have known that nail penetration is unpredictable.
`
`30.
`
`It was also understood in 2005 that a compound’s nail permeability is
`
`influenced by several different factors. Among these factors is molecular weight,
`
`which provides an indirect measure of a compound’s size and mobility. Another
`
`factor is the compound’s keratin-binding affinity, that is, the degree to which the
`
`compound “sticks” to the dense keratin network that comprises the overriding ma-
`
`jority of nail’s molecular structure. Other important factors include the com-
`
`10
`
`

`

`pound’s hydrophilicity/lipophilicity (“log P”), the nature of the vehicle being used
`
`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`
`to deliver the compound, and other physicochemical properties such as molecular
`
`charge. See Murdan 2002 (Ex. 1020) at 9.
`
`1. Molecular Weight
`
`31. One factor affecting the diffusion or permeability through the nail
`
`plate is a compound’s molecular weight. It was generally understood in 2005 that
`
`compounds with high molecular weight tend to diffuse more slowly than com-
`
`pounds with low molecular weight. However, transport through the nail was
`
`known to be complex and nonlinear. Thus, a POSA in 2005 would have under-
`
`stood that molecular weight could not be used reliably to compare the relative
`
`permeability of compounds, particularly those below 300 Da.
`
`32. This understanding of the POSA in 2005 is based on the few studies
`
`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
`
`n-alkanols through human cadaver nails. By using a homologous series—
`
`methanol, ethanol, n-propanol, and so on—Walters et al. sought to develop the
`
`“basic concept of the permeability of the human nail plate” by using structurally
`
`similar compounds. Walters et al. 1983 (Ex. 2031) at 28–29 & tbl.1. What they
`
`discovered was that the trend between molecular weight (roughly proportional to
`
`chain length) and permeability was nonlinear, as shown below. Id. at 30 fig.1.
`
`11
`
`

`

`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`
`
`33. Walters et al. thus found that the permeability coefficient of n-
`
`dodecanol (MW 186.34 Da) in a human nail was comparable to that of methanol
`
`(MW 32.04 Da), a compound nearly six-fold smaller in terms of molecular weight.
`
`Moreover, the permeability of n-dodecanol was an order of magnitude greater
`
`than n-pentanol (88.15 Da), a compound less than half its weight. Id. at 29 tbl.1.
`
`These results demonstrate that even as between structurally similar compounds,
`
`relative permeability cannot be predicted through molecular weight.
`
`34. Walters et al. explained n-dodecanol’s increased permeability by hy-
`
`pothesizing the existence of a “lipid pathway” through the nail. Id. at 32. As dis-
`
`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-
`
`12
`
`

`

`nal molecular size sensitivity . . . considering the narrow spread in [effective diffu-
`
`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`
`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-
`
`cient—a measure of the hydrophilicity or lipophilicity of the compound based on
`
`its preferential distribution in water versus a non-polar solvent such as octanol (or
`
`log P)—was the principal factor governing nail permeability.
`
`35. Subsequent work by Mertin & Lippold in 1997 using a different ho-
`
`mologous series disagreed with Walters et al. with respect to the importance of the
`
`partition coefficient. See Mertin & Lippold, In-vitro Permeability of the Human
`
`Nail of a Keratin Membrane from Bovine Hooves: Influence of the Partition Coef-
`
`ficient Octanol/Water and the Water Solubility of Drugs on their Permeability and
`
`Maximum Flux, J. Pharm. Pharmacol., vol. 49, pp. 30–34, at 32 (1997) (“Mertin &
`
`Lippold 1997b,” Ex. 2033). Consequently, Mertin & Lippold also disagreed with
`
`Walters et al. regarding the existence of a lipid pathway through the nail. Id.
`
`36.
`
`In contrast to the findings of Walters et al., Mertin & Lippold found
`
`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
`
`water solubility was the principal factor relevant to a drug’s maximum flux
`
`through the nail. Id. at 32–33 (“It has to be emphasized that the maximum flux of
`
`a substance firstly depends on its water solubility . . . .”). To date, the disagree-
`
`13
`
`

`

`ment between Walters et al. and Mertin & Lippold has not been resolved. See
`
`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`
`Murdan 2002 (Ex. 1020) at 11.
`
`37. At the same time, Mertin and Lippold also observed a nonlinear rela-
`
`tionship between molecular weight and nail permeability in bovine hoof, echoing
`
`the earlier results of Walters et al. Specifically, Mertin & Lippold found that octyl
`
`nicotinate (MW 235.3 Da) had the same or higher permeability than methyl nico-
`
`tinate (MW 13.1 Da). Mertin & Lippold 1997b (Ex. 2033) at 32 fig.1. Thus, Mer-
`
`tin & Lippold results demonstrate that the overall trend between molecular weight
`
`and permeability does not always obtain.
`
`38. Moreover, Mertin & Lippold further explained that the differences be-
`
`tween their findings and those of Walters et al. were attributable to their respective
`
`homologous series. They therefore agreed that the partition coefficient could pre-
`
`dominate “when the affinity of the substance to the nail plate”—its keratin-binding
`
`affinity—“decreases faster than its affinity to water with increasing lipophilicity.”
`
`Id. at 32. In other words, the chemical structure of a compound and its interaction
`
`with the nail’s keratin matrix cannot be ignored when it comes to nail penetration.
`
`39. Thus, although I agree that, broadly speaking, higher molecular
`
`weight compounds generally display lower nail permeability, a POSA would have
`
`understood that this general observation applies only as a statistical matter and
`
`cannot be used to predict the relative permeability of particular compounds, even
`
`14
`
`

`

`compounds deemed “structurally similar.” Any statistical correlation between mo-
`
`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`
`lecular weight and nail permeability is a coarse tool backed by conflicting and am-
`
`biguous data. This type of statistical correlation would not have been relied upon
`
`by a POSA to make precise relative judgments, particularly without first consider-
`
`ing the other factors known to influence nail permeability.
`
`40.
`
`Instead of making predictive judgments concerning permeability
`
`based on molecular weight, a POSA would have understood the correlation to
`
`mean that “macromolecules” having a mass greater than about 300 Da would have
`
`more difficulties penetrating the nail. See, e.g., Shivakumar et al., Transungual
`
`drug delivery: an update, J. Drug Del. Sci. Tech., vol. 24, pp. 301–10, at 303
`
`(2014) (Ex. 2007) (“Generally, molecules that exceed 300 Daltons in size may face
`
`hindrance while permeating the nail plate.”). A POSA would have also understood
`
`that the relative permeability of small molecules below this threshold would not be
`
`dominated by molecular weight; other factors would play a more significant role.
`
`41. Permeability data from a separate study by Mertin & Lippold provide
`
`an ample illustration of the logical error of taking the contrary position.
`
`15
`
`

`

`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`
`
`42. The table above is reproduced from Mertin & Lippold, In-vitro Per-
`
`meability of the Human Nail and of a Keratin Membrane from Bovine Hooves:
`
`Prediction of the Penetration Rate of Antimycotics through the Nail Plate and their
`
`Efficacy, J. Pharm. Pharmacol., vol. 49, pp. 866–72, at 868 tbl.1 (1997) (“Mertin &
`
`Lippold 1997a,” Ex. 1031). The data show that ciclopirox (MW 207.3 Da) has
`
`lower permeability in a human nail than a number of higher molecular weight an-
`
`timycotics: naftifine (MW 287.4 Da), tolnaftate (MW 307.4 Da), bifonazole (MW
`
`310.4 Da), and econazole (MW 381.7 Da).1 Thus, a POSA would not have con-
`
`
`1 See also Kobayashi et al., In vitro permeation of several drugs through the human
`
`nail plate: relationship between physicochemical properties and nail permeability
`
`16
`
`

`

`cluded that the relative permeability of any two antimycotic agents could be pre-
`
`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`
`dicted based on molecular weight alone. Instead, a POSA would view a com-
`
`pound’s molecular weight as just one of several factors to be considered, which
`
`factors include the compound’s keratin-binding affinity.
`
`2. Keratin-Binding Affinity
`
`43. The binding of a compound to the nail’s keratin matrix negatively im-
`
`pacts its nail penetration by reducing the concentration gradient driving the com-
`
`pound’s diffusion in accordance with Fick’s law of diffusion.2 See Murthy et al.,
`
`Iontophoretic Drug Delivery across Human Nail, J. Pharm. Sci., vol. 96, pp. 305–
`
`11, at 305–06 (2007) (Ex. 2008) (“[T]here 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 . . . Second, binding of the drug to keratin
`
`
`of drugs, Eur. J. Pharm. Sci., vol. 21 pp. 471–77, at 474 (2004) (Ex. 2032) (perme-
`
`ability of isosorbide dinitrate (MW 236.1 Da) greater than permeability of antipy-
`
`rine (MW 188.2 Da); difference between permeability of p-hydroxy benzoic amyl
`
`ester (MW 208.25 Da) and p-hydroxy benzoic acid ethyl ester (MW 166.18 Da)
`
`not statistically significant),
`
`2 Fick’s law of diffusion provides that the rate of diffusion or flux of a species
`
`across a membrane is proportional to its concentration gradient.
`
`17
`
`

`

`. . . .”); see also, e.g., Shivakumar et al. 2014 (Ex. 2007) at 303; Shivakumar et al.
`
`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`
`2013 (Ex. 2030) at 88. Another consequence of a compound’s binding to keratin is
`
`that it is not able to exert its therapeutic effect in the target area—in the case of on-
`
`ychomycosis, the nail bed. See Murthy et al. 2007 (Ex. 2008) at 306; see also
`
`Shivakumar et al. 2013 (Ex. 2030) at 88. For these reasons, a POSA in 2005
`
`would have not only been concerned with the question of a compound’s overall
`
`penetration into and through the nail, but the specific question of how much of the
`
`unbound fraction of the compound (the fraction not bound to keratin) would be
`
`available to penetrate in the first instance.
`
`44. Whether a compound possesses high keratin-binding affinity is largely
`
`a function of its chemical structure. In this regard, antifungal agents are generally
`
`known to have high keratin-binding affinity, which is a principal reason why topi-
`
`cal formulations for onychomycosis have failed. See Murthy et al. 2007 (Ex.
`
`2008) at 306 (“Antifungal drugs are reported to possess high-binding affinity to
`
`keratin.”). Terbinafine’s high keratin-binding affinity, for example, has effectively
`
`precluded its use as a topical treatment. Thus, while systemic treatment with oral
`
`terbinafine is currently recognized as the “gold standard” for treating onychomyco-
`
`sis due to its high potency against dermatophytes, an effective topical formulation
`
`has proven elusive. See, e.g., Sugiura et al., The Low Keratin Affinity of Efinacon-
`
`azole Contributes to Its Nail Penetration and Fungicidal Activity in Topical Ony-
`
`18
`
`

`

`chomycosis Treatment, Antimicrobial Agents & Chemotherapy, vol. 58, pp. 3837–
`
`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`
`42, at 3841 (2014) (Ex. 2036) (“[T]erbinafine . . . is 98.9% keratin bound under the
`
`same in vitro experimental conditions. . . [and] has been shown to have limited
`
`success in treating [onychomycosis] when applied topically.”); Tatsumi et al.,
`
`Therapeutic Efficacy of Topically Applied KP-103 against Experimental Tinea
`
`Unguium in Guinea Pigs in Comparison with Amorolfine and Terbinafine, Antimi-
`
`crobial Agents & Chemotherapy, vol. 46, pp. 3797–801, at 3800 (2002) (Ex. 2037)
`
`(“Terbinafine and amorolfine showed a greatly decreased antifungal activity in the
`
`presence of 5% keratin. This was because the reference drugs have extremely high
`
`rates of binding to keratin of more than 90%.”).
`
`45. Conversely, the few antifungal agents known to possess low affinity
`
`for keratin have shown success as topical treatments for onychomycosis. In partic-
`
`ular, efinaconazole (MW 348.39 Da) has been recognized as an effective topical
`
`treatment for onychomycosis due to its low keratin binding and high degree of nail
`
`penetration, notwithstanding its higher molecular weight compared to terbinafine
`
`(MW 291.43 Da). See Pollak et al., Efinaconazole Topical Solution, 10%: Factors
`
`Contributing to Onychomycosis Success, J. Fungi, vol. 1, pp. 107–14, at 109
`
`(2015) (Ex. 2035) (“The low keratin affinity of efinaconazole contributes to its fa-
`
`vorable nail penetration.”); Sugiura et al. 2014 (Ex. 2036) at 3840 (“Th[e] low ker-
`
`atin affinity of efinaconazole correlated with faster nail penetration and fungicidal
`
`19
`
`

`

`activity in the presence of keratin.”); Tatsumi et al. 2002 (Ex. 2037) at 3801 (“The
`
`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`
`effectiveness of KP-103 for tinea unguium is presumably due to its high activity
`
`and good penetration into the nails . . . achieved by its lower keratin affinity.”).
`
`46. Accordingly, a POSA in 2005 would have understood low keratin-
`
`binding affinity to be critical to a compound’s nail permeability and would have
`
`paid significant attention to this factor. See Murthy et al. 2007 (Ex. 2008) at 306.
`
`A POSA would have further understood that any keratin binding would be a func-
`
`tion of the compound’s chemical structure and its intramolecular interaction with
`
`the structure of keratin, independent of the compound’s molecular weight.
`
`3. Other Factors
`
`47. Water solubility. As discussed, the nail plate has been described as a
`
`hydrophilic gel membrane or hydrogel. See Kobayashi et al. 2004 (Ex. 2032) at
`
`474; Mertin & Lippold 1997b (Ex. 2033) at 32; Walters et al. 1983 (Ex. 2031) at
`
`31. Accordingly, the solubility of a compound in water—a measure of how much
`
`of the compound can be dissolved in water—is a key factor a POSA would have
`
`considered in assessing a compound’s ability to penetrate the nail plate. See, e.g.,
`
`Mertin & Lippold 1997b (Ex. 2033) at 34 (“[M]aximum flux [of a compound
`
`through the nail plate] is primarily a function of [its] solubility in water.”).
`
`48. Hydrophilicity/lipophilicity. The hydrophilicity or lipophilicity of a
`
`compound is related to its water solubility, but is nonetheless an independent pa-
`
`20
`
`

`

`rameter relevant to the compound’s permeability through the nail. The standard
`
`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`
`measure of a compound’s hydrophilicity is the partition coefficient or log P of the
`
`compound’s distribution in