UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ARGENTUM PHARMACEUTICALS LLC
`Petitioner,
`
`v.
`
`KAKEN PHARMACEUTICAL CO., LTD. and
`VALEANT PHARMACEUTICALS INTERNATIONAL, INC.
`Patent Owner
`
`U.S. Patent No. 7,214,506
`Issue Date: May 8, 2007
`Title: Method for Treating Onychomycosis
`
`DECLARATION OF MAURIZIO DEL POETA, M.D.
`
`ARGENTUM EX1047
`
`Page 1
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`

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`Contents
`I. 
`Qualifications, Background, and Experience .................................................. 1 
`II. 
`Scope of Assignment ....................................................................................... 2 
`III.  Materials Considered ....................................................................................... 3 
`IV.  Summary of Opinions ...................................................................................... 9 
`V. 
`Legal Principles Used in Analysis ................................................................. 10 
`A.  Patent Claims in General ............................................................................. 10 
`B.  Person of Ordinary Skill in the Art ............................................................. 11 
`C.  Claim Construction ...................................................................................... 12 
`D.  Prior Art ....................................................................................................... 13 
`E.  Priority ......................................................................................................... 13 
`F.  Patentability ................................................................................................. 14 
`VI.  A Person of Ordinary Skill in the Relevant Art ............................................. 17 
`A.  Relevant Field .............................................................................................. 18 
`B.  Person of Ordinary Skill in the Art ............................................................. 18 
`VII.  Background of the Relevant Technology ....................................................... 19 
`VIII.  The ’506 Patent .............................................................................................. 23 
`A.  The Claims of the ’506 Patent ..................................................................... 26 
`B.  Problem Addressed by the ’506 Patent ....................................................... 28 
`C.  Solution Set Forth in the ’506 Patent .......................................................... 29 
`IX.  Priority Date of the ’506 Patent ..................................................................... 34 
`X.  Obviousness Analysis .................................................................................... 37 
`A.  Summary of Opinions.................................................................................. 37 
`B.  Ground 1: The Methods of Claims 1 and 2 of the ’506 Patent Would Have
`Been Obvious Over Japanese Pat. App. Pub. No. 10- 226639 in View of Ogura
`
`39 
`i.  Summary of JP ’639 ................................................................................. 39 
`ii. 
`Summary of Ogura ................................................................................ 42 
`
`
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`i
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`Page 2
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`iii.  The Combination of JP ’639 and Ogura ............................................... 44 
`C.  Ground 2: The Methods of Claims 1 and 2 of the ’506 Patent Would Have
`Been Obvious Over U.S. Pat. No. 5,391,367 in View of Ogura ........................ 47 
`i.  Summary of the ’367 Patent ..................................................................... 47 
`ii. 
`Summary of Ogura ................................................................................ 48 
`iii.  The Combination of the ’367 Patent and Ogura ................................... 48 
`D.  Ground 3: The Methods of Claims 1 and 2 of the ’506 Patent Would Have
`Been Obvious Over Hay 1985 in View of Ogura ............................................... 51 
`i.  Summary of Hay 1985 ............................................................................. 51 
`ii. 
`Summary of Ogura ................................................................................ 52 
`iii.  The Combination of Hay 1985 and Ogura ............................................ 52 
`E.  Ground 4: The Methods of Claims 1 and 2 of the ’506 Patent Would Have
`Been Obvious Over JP ’639 in view of the Kaken Abstracts ............................. 55 
`i.  Summary of JP ’639 ................................................................................. 55 
`ii. 
`Summary of the Kaken Abstracts ......................................................... 55 
`iii.  The Combination of JP’639 and the Kaken Abstracts .......................... 57 
`F.  Ground 5: The Methods of Claims 1 and 2 of the ’506 Patent Would Have
`Been Obvious over the ’367 Patent in View of the Kaken Abstracts. ................ 60 
`i.  Summary of the ’367 Patent ..................................................................... 60 
`ii. 
`Summary of the Kaken Abstracts ......................................................... 60 
`iii.  The Combination of the ’367 Patent and the Kaken Abstracts ............. 60 
`G.  Ground 6: The Methods of Claims 1 and 2 of the ’506 Patent Would Have
`Been Obvious over the Hay 1985 in view of the Kaken Abstracts. ................... 62 
`i.  Summary of Hay 1985 ............................................................................. 62 
`ii. 
`Summary of the Kaken Abstracts ......................................................... 63 
`iii.  The Combination of Hay 1985 and the Kaken Abstracts ..................... 63 
`H.  Secondary Considerations ........................................................................... 65 
`i.  The Alleged Unexpected Results Relied on by the Applicants During
`Prosecution Were Actually Known Beneficial Results of the Use of KP-103
`
`66 
`ii.  The Data Presented in the ’506 Specification is Flawed and Does Not
`
`
`
`ii
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`Page 3
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`Provide Evidence of an Unexpected Effect ................................................... 69
`iii. Contrary to the Applicants’ Argument During Prosecution, the Data
`Demonstrate That the Claimed Compounds Do Not Eradicate the Infection
`
`72
`XI. Claim Charts .................................................................................................. 75
`XII. Conclusions .................................................................................................... 75
`
`iii
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`Page 4
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`1.
`
`I, Maurizio Del Poeta, M.D., do declare and state as follows.
`
`I.
`
`Qualifications, Background, and Experience
`
`2.
`
`I am over the age of eighteen (18) and otherwise competent to make
`
`this declaration.
`
`3. My name is Maurizio Del Poeta. I am currently a Professor at the
`
`College of Medicine at the Department of Molecular Genetics and Microbiology at
`
`Stony Brook University. I am also a Professor and Research Physiologist at VA
`
`Medical Center in New York. In addition, I co-founded and serve as the Chief
`
`Scientific Officer of MicroRid Technologies, Inc. I have published at least 80
`
`peer-reviewed journal articles and many other chapters and abstracts. I understand
`
`that my declaration is being submitted in connection with a Petition for Inter
`
`Partes Review of U.S. Patent No. 7,214,506 (the “’506 patent”) (Ex. 1001).
`
`4.
`
`I received a M.D. from the University of Ancona School of Medicine
`
`in Ancona, Italy.
`
`5.
`
`A more complete recitation of my professional experience including a
`
`list of my journal publications, patents, conference proceedings, book authorship,
`
`and committee memberships may be found in my Curriculum Vitae and
`
`Publication List, which are attached to my declaration as Appendix A.
`
`6.
`
`7.
`
`[intentionally omitted]
`
`[intentionally omitted]
`
`
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`1
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`8.
`
`9.
`
`10.
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`11.
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`12.
`
`[intentionally omitted]
`
`[intentionally omitted]
`
`[intentionally omitted]
`
`[intentionally omitted]
`
`[intentionally omitted]
`
`II.
`
`Scope of Assignment
`
`13.
`
`I have been retained in this matter by Argentum Pharmaceuticals LLC
`
`(“Petitioner”) as a scientific expert in the field of pharmaceutical formulations and
`
`methods, including treatment of fungal infections of the nail and skin using topical
`
`formulations. I am being compensated for my work in this matter at my usual and
`
`customary rate of $400 per hour. I have no personal or financial stake or interest in
`
`the outcome of the Petition for Inter Partes Review or any related action. My
`
`compensation in no way depends upon my testimony or the outcome of the Petition
`
`for Inter Partes Review.
`
`14.
`
`I have been advised that Kaken Pharmaceutical Co., Ltd. (“Kaken” or
`
`“Patent Owner”) owns the ’506 patent. I have also been advised that the ’506
`
`patent is believed to be licensed to Valeant Pharmaceuticals International, Inc. and
`
`that its subsidiary, Valeant Pharmaceuticals North America LLC, is the New Drug
`
`Application (“NDA”) holder of the Jublia® NDA (collectively, “Valeant”). I have
`
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`2
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`no personal or financial stake or interest in Argentum, Kaken, Valeant, or the ’506
`
`patent.
`
`15.
`
`I understand that the ’506 patent is currently subject to a pending IPR,
`
`Acrux DDS Pty Ltd. v. Kaken Pharmaceutical Co., Ltd., IPR2017-00190 (the
`
`“Acrux IPR”). I understand that the Acrux IPR was instituted on May 1, 2017 and
`
`that Petitioner Argentum seeks to join the Acrux IPR. To retain paragraph
`
`numbering with Dr. Walters’ declaration, I have intentionally omitted paragraphs
`
`6-12 above.
`
`III. Materials Considered
`
`16.
`
`In forming the opinions expressed below, I have reviewed the
`
`materials submitted by Acrux in the Acrux IPR, including the Declaration of Dr.
`
`Kenneth Walters. In formulating my opinion, I considered the following
`
`documents:
`
`(1) A Certified English translation of Japanese Patent Application
`
`No. 11/214369 (filed July 28, 1999) (“JP priority document”)
`
`(Ex. 1002).
`
`(2) A Certified English translation of Japanese Patent Application
`
`Publication No. 10-226639 (filed December 1, 1997 and
`
`published August 25, 1998) (“JP ’639”) (Ex. 1011).
`
`(3)
`
`“Synthesis and Antifungal Activities of (2R,3R)-2-Aryl-1-
`
`
`
`3
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`Page 7
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`

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`azolyl-3- (substituted amino)-2-butanol Derivatives as Topical
`
`Antifungal Agents,” by Ogura, H. et al., Chem. Pharm. Bull.,
`
`47(10) 1417-1425 (October 1999) (“Ogura”) (Ex. 1012).
`
`(4) U.S. Patent No. 5,391,367 to DeVincentis et al. (filed July 28,
`
`1993) (issued February 21, 1995) (“’367 patent”) (Ex. 1013).
`
`(5)
`
`“Tioconazole nail solution—an open study of its efficacy in
`
`onychomycosis,” by Hay, R.J., et al., Clinical and Experimental
`
`Dermatology, 10:111-115 (1985) (“Hay 1985”) (Ex. 1014);
`
`(6) Abstracts F78, F79 and F80 from Abstracts of the Interscience
`
`Conference on Antimicrobial Agents and Chemotherapy
`
`(ICAAC), 36th ICAAC, held on September 15-18 (1996)
`
`(“Kaken Abstracts”) (Ex. 1015).
`
`(7)
`
`“Management of Onychomycoses,” by Niewerth, M. and
`
`Korting, H.C., Drugs, 58(2):283-296 (1999) (“Niewerth and
`
`Korting”) (Ex. 1026).
`
`(8)
`
`“Diffusion of water through dead plantar, palmar and torsal
`
`human skin and through toe nails,” by Burch, G.E. and Winsor,
`
`T., Arch. Derm. Syphilol., 53: 39-41 (1946) (“Burch and
`
`Winsor”) (Ex. 1027).
`
`(9)
`
`“A comparative study of the physicochemical properties of
`
`
`
`4
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`Page 8
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`

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`human keratinized tissues,” by Baden H.P., et al., Biochim.
`
`Biophys. Acta., 322:269–278 (1973) (“Baden”) (Ex. 1028).
`
`(10) “The azole antifungal drugs,” by Hay, R.J., Journal of
`
`Antimicrobial Chemotherapy, 20: 1-5 (1987) (“Hay 1987”) (Ex.
`
`1029).
`
`(11) “Amorolfine nail lacquer: a novel formulation,” by Marty, J.L.,
`
`Journal of the European Academy of Dermatology and
`
`Venereology, 4 (Supp. 1) S17-S21 (1995) (“Marty”) (Ex. 1030).
`
`(12) “Epidemiology and ecology of onychomycosis,” by
`
`Summerbell, R.C., Dermatology, 194 (Supp. 1): 32-36 (1997)
`
`(“Summerbell”) (Ex. 1031).
`
`(13) “Ecology and epidemiology of dermatophyte infections,” by
`
`Aly, R., J. Am. Acad. Dermatol., 31:S21–S25 (1994) (“Aly”)
`
`(Ex. 1032).
`
`(14) “Onychomycosis: therapeutic update,” by Scher, R.K., Journal
`
`of the American Academy of Dermatology, 40 (Suppl):S21–6
`
`(1999) (“Scher”) (Ex. 1033)
`
`(15) “New therapies for onychomycosis,” by Odom, R. B., Journal
`
`of the American Academy of Dermatology, 35:3(2): S26-S30
`
`(1996) (“Odom”) (Ex. 1034).
`
`
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`5
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`(16) “Miconazole alcoholic solution in the treatment of mycotic nail
`
`infections,” by Vanderdonckt, J., et al., Mykosen, 19(7):251-
`
`256 (1975) (“Vanderdonckt”) (Ex. 1035).
`
`(17) “Comparison of Two Topical Preparations for the Treatment of
`
`Onychomycosis: Melaleuca alternifolia (Tea Tree) Oil and
`
`Clotrimazole,” by Buck, D.S. et al., The Journal of Family
`
`Practice, 38(6): 601-605 (1994) (“Buck”) (Ex. 1036).
`
`(18) “Amorolfine- A Review of its Pharmacological Properties and
`
`Therapeutic Potential in the Treatment of Onychomycosis and
`
`Other Superficial Fungal Infections,” by Haria, M. and Bryson,
`
`H.M., Drugs, 49(1): 103-120 (1995) (“Haria”) (Ex. 1037).
`
`(19) “Ciclopirox nail lacquer 8%: in vivo penetration into and
`
`through nails and in vitro effect on pig skin.” Ceschin-Roques
`
`C.G., et al., Skin Pharmacol., 4: 89-94 (1991) (“Ceschin-
`
`Roques”) (Ex. 1017).
`
`(20) “Absorption of amorolfine through human nail,” Franz, T.J.,
`
`Dermatol., 184(Suppl 1): 18-20 (1992) (“Franz”) (Ex. 1018).
`
`(21) “Nail penetration of the antifungal oxiconazole after repeated
`
`topical application in healthy volunteers, and the effect of
`
`acetylcysteine,” by van Hoogdalem, E.J. et al., Eur. J. Pharm.
`
`
`
`6
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`Sci., 5: 119-127 (1997) (“van Hoogdalem”) (Ex. 1019).
`
`(22) “Enhancing effect of N-acetyl-L-cysteine or 2-mercaptoethanol
`
`on the in vitro permeation of 5-fluorouracil or tolnaftate
`
`through the human nail plate,” by Kobayashi Y. et al., Chem.
`
`Pharm. Bull., 46: 1797-1802 (1998) (“Kobayashi”) (Ex. 1024).
`
`(23) “In vitro permeability of the human nail and of a keratin
`
`membrane from bovine hooves: Influence of the partition
`
`coefficient octanol/water and the water solubility of drugs on
`
`their permeability and maximum flux,” by Mertin, D. and
`
`Lippold, B.C., Journal of Pharmacy and Pharmacology, 49(1):
`
`30-34 (1997) (“Merton and Lippold I”) (Ex. 1021).
`
`(24) “In vitro permeability of the human nail and of a keratin
`
`membrane from bovine hooves: Penetration of chloramphenicol
`
`from lipophilic vehicles and a nail lacquer,” by Mertin, D. and
`
`Lippold, B.C., Journal of Pharmacy and Pharmacology, 49(3):
`
`241-245 (1997) (“Mertin and Lippold II”) (Ex. 1022).
`
`(25) “In vitro permeability 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,”
`
`by Mertin, D. and Lippold, B.C., Journal of Pharmacy and
`
`
`
`7
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`Pharmacology, 49(9): 866-872 (1997) (“Mertin and Lippold
`
`III”) (Ex. 1023).
`
`(26) “The effect of keratolytic agents on the permeability of three
`
`imidazole antimycotic drugs through the human nail,” by
`
`Quintanar-Guerrero, D. et al., Drug. Dev. Ind. Pharm., 24: 685-
`
`690 (1998) (“Quintanar-Guerrero”) (Ex. 1020).
`
`(27) “Measurement of water vapor loss through human nail in vivo,”
`
`by Spruit, D., J. Invest. Dermatol., 56(5): 359-361 (1971)
`
`(“Spruit”) (Ex. 1038).
`
`(28) “Bioavailability, skin and nail penetration of topically applied
`
`antimycotics,” Stuttgen, G. and Bauer, E., Mycoses 25: 74-80
`
`(1982) (“Stuttgen and Bauer”) (Ex. 1016).
`
`(29) “Physicochemical characterization of the human nail: I.
`
`Pressure sealed apparatus for measuring nail plate
`
`permeabilities,” by Walters, K.A., Flynn, G.L. and Marvel,
`
`J.R., J. Invest. Dermatol., 76: 76-79 (1981) (“Walters 1981”)
`
`(Ex. 1039).
`
`(30) “Physicochemical characterization of the human nail:
`
`Permeation pattern for water and the homologous alcohols and
`
`differences with respect to the stratum corneum,” by Walters,
`
`
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`8
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`K.A., Flynn, G.L. and Marvel, J.R., J. Pharm. Pharmacol. 35:
`
`28-33 (1983) (“Walters 1983”) (Ex. 1040).
`
`(31) “Penetration of the human nail: the effects of vehicle pH on the
`
`permeation of miconazole,” by Walters, K.A., Flynn, G.L. and
`
`Marvel, J.R., J Pharm Pharmacol, 37: 498-499 (1985)
`
`(“Walters 1985 I”) (Ex. 1041).
`
`(32) “Physicochemical characterization of the human nail: solvent
`
`effects on the permeation of homologous alcohols,” by Walters,
`
`K.A., Flynn, G.L. and Marvel, J.R., J. Pharm. Pharmacol., 37:
`
`771-775 (1985) (“Walters 1985 II”) (Ex. 1042).
`
`(33) Jublia® (efinaconazole) topical solution, 10% [package insert].
`
`Valeant Pharmaceuticals North America LLC; 5/2016 (Ex.
`
`1043).
`
`(34) “Onychomycosis: Pathogenesis, Diagnosis, and Management,”
`
`by Elewski, B., Clinical Microbiology Reviews, 11:415-429
`
`(1998) (“Elewski”) (Ex. 1048).
`
`I have also relied upon my education, background, and experience.
`
`IV. Summary of Opinions
`
`17.
`
`I agree in all material respects with the analysis and opinions set forth
`
`by Acrux’s expert, Dr. Walters, in the declaration that was submitted in the Acrux
`
`
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`9
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`IPR and share the same opinions below. In addition, I have also supplemented
`
`certain sections below. See paras. 41, 78, 95, 103, 113, 122, 127, 133, 140, 147,
`
`and 158. Based on my investigation and analysis and for the reasons set forth
`
`below, it is my opinion that claims 1 and 2 of the ’506 patent would have been
`
`obvious to one of ordinary skill in the art at the time of the alleged invention in
`
`view of the following combinations of references:
`
`1)
`
`2)
`
`3)
`
`4)
`
`5)
`
`6)
`
`JP ’639 in view of Ogura;
`
`The ’367 patent in view of Ogura;
`
`Hay 1985 in view of Ogura;
`
`JP ’639 in view of the Kaken Abstracts;
`
`The ’367 patent in view of the Kaken Abstracts; and
`
`Hay 1985 in view of the Kaken Abstracts.
`
`V.
`
`Legal Principles Used in Analysis
`
`18.
`
`I am not a patent attorney nor have I independently researched the law
`
`on patentability. Rather, Argentum’s attorneys have explained the legal principles
`
`to me that I have relied on in forming my opinions set forth in this declaration.
`
`A.
`19.
`
`Patent Claims in General
`I have been informed that patent claims are the numbered sentences at
`
`the end of each patent. I have been informed that the claims are important because
`
`the words of the claims define what a patent covers. I have also been informed that
`
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`the figures and text in the rest of the patent provide a description and/or examples
`
`and help explain the scope of the claims, but that the claims define the breadth of
`
`the patent’s coverage.
`
`20.
`
`I have also been informed that an “independent claim” expressly sets
`
`forth all of the elements that must be met in order for something to be covered by
`
`that claim. I have also been informed that a “dependent claim” does not itself recite
`
`all of the elements of the claim but refers to another claim for some of its elements.
`
`In this way, the claim “depends” on another claim and incorporates all of the
`
`elements of the claim(s) from which it depends. I also have been informed that
`
`dependent claims add additional elements. I have been informed that, to determine
`
`all the elements of a dependent claim, it is necessary to look at the recitations of
`
`the dependent claim and any other claim(s) on which it depends.
`
`B.
`21.
`
`Person of Ordinary Skill in the Art
`I understand that the person of ordinary skill in the art is a
`
`hypothetical person who is presumed to have known the relevant art at the time of
`
`the invention. Factors that may be considered in determining the level of ordinary
`
`skill in the art may include: (A) the type of problems encountered in the art; (B)
`
`prior art solutions to those problems; (C) rapidity with which innovations are
`
`made; (D) sophistication of the technology; and (E) educational level of active
`
`
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`workers in the field. In a given case, every factor may not be present, and one or
`
`more factors may predominate.
`
`22.
`
`I understand that a person of ordinary skill in the art is also a person
`
`of ordinary creativity, not an automaton. I further understand that the hypothetical
`
`person having ordinary skill in the art to which the claimed subject matter pertains
`
`would, of necessity, have the capability of understanding the scientific and
`
`engineering principles applicable to the pertinent art.
`
`C. Claim Construction
`23.
`I understand that, in an inter partes review (“IPR”), claim terms are
`
`given their broadest reasonable interpretation consistent with the specification, and
`
`that, under the broadest reasonable interpretation standard, the words of a claim are
`
`generally given their ordinary and customary meaning as would be understood by a
`
`person of ordinary skill in the art in question at the time of the invention in the
`
`context of the entire disclosure.
`
`24.
`
`I also understand that, in determining the meaning of a disputed claim
`
`limitation, the intrinsic evidence of record is considered by examining the claim
`
`language itself, the written description, and the prosecution history. I further
`
`understand that a patentee may act as its own lexicographer and depart from the
`
`ordinary and customary meaning by defining a term with reasonable clarity,
`
`
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`deliberateness and precision, but that there is a presumption that a claim term
`
`carries its ordinary and customary meaning.
`
`D.
`25.
`
`Prior Art
`I have been informed that the law provides categories of information
`
`(known as “prior art”) that may be used to anticipate or render obvious patent
`
`claims. I have been informed that, to be prior art with respect to a particular patent,
`
`a reference must have been made, known, used, published, or patented, or be the
`
`subject of a patent application by another, before the priority date of the patent.
`
`26. Further, I have been informed that statements by a patent applicant or
`
`patentee, including statements in the patent that something is in the “prior art,” can
`
`constitute prior art that can be used to anticipate or render obvious patent claims.
`
`That is, prior art can be created by admissions of the patent applicant or patentee.
`
`27.
`
`I also understand that a person of ordinary skill in the art is presumed
`
`to have knowledge of all prior art.
`
`E.
`28.
`
`Priority
`I have been informed that in some circumstances, a patentee may have
`
`claimed priority to an earlier application filing date, the date of which is referred to
`
`as a “priority date.” I have been informed that the patentee bears the burden of
`
`demonstrating entitlement to the priority date.
`
`
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`29.
`
`I have been informed and understand that a patent is entitled to the
`
`benefit of the filing date of an earlier filed application only if the disclosure of the
`
`earlier application provides sufficient support for the claims of the patent.
`
`F.
`30.
`
`Patentability
`I have been informed that a determination of whether the claims of a
`
`patent are rendered obvious by prior art is a two-step analysis: (1) determining the
`
`meaning and scope of the claims, and (2) comparing the properly construed claims
`
`to the prior art. I have endeavored to undertake this process herein.
`
`31.
`
`I have been informed and understand that, even if every element of a
`
`claim is not found explicitly or implicitly in a single prior art reference, the claim
`
`may still be unpatentable if the differences between the claimed elements and the
`
`prior art are such that the subject matter as a whole would have been obvious at the
`
`time the invention was made to a person of ordinary skill in the art.
`
`32.
`
`I have been informed and understand that a patent claim is obvious
`
`when it is only a combination of old and known elements, with no change in their
`
`respective functions, and that these familiar elements are combined according to
`
`known methods to obtain predictable results. I have been informed and understand
`
`that the following four factors are considered when determining whether a patent
`
`claim is obvious: (1) the scope and content of the prior art; (2) the differences
`
`between the prior art and the claim; (3) the level of ordinary skill in the art; and (4)
`
`
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`additional considerations of objective evidence, sometimes referred to as
`
`“secondary considerations,” tending to prove obviousness or non-obviousness.
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`Additional considerations may include: unexpected, surprising, or unusual results;
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`nonanalogous art; teachings away from the invention; substantially superior
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`results; synergistic results; long-felt, but unmet, need; commercial success;
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`copying by others; and nearly-simultaneous invention by others. I have also been
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`informed and understand that there must be a connection between these additional
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`factors and the scope of the claim language.
`
`33.
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`In determining obviousness based on a combination of prior art
`
`references, I also understand that there must have been a reason to combine the
`
`teachings, and thus reasons for combining the references must be considered, along
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`with any evidence that one or more of the references would have taught away from
`
`the claimed invention at the time of the invention.
`
`34.
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`I have also been informed and understand that some examples of
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`rationales that may support a conclusion of obviousness include:
`
`(A)
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`combining prior art elements according to known methods to yield
`
`predictable results;
`
`(B)
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`simply substituting one known element for another to obtain
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`predictable results;
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`(C) using known techniques to improve similar devices (methods, or
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`products) in the same way;
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`(D)
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`applying a known technique to a known device (method, or product)
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`ready for improvement to yield predictable results;
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`(E)
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`choosing from a finite number of identified, predictable solutions,
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`with a reasonable expectation of success—in other words, whether
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`something is “obvious to try;”
`
`(F)
`
`using work in one field of endeavor to prompt variations of that work
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`for use in either the same field or a different one based on design
`
`incentives or other market forces if the variations are predictable to
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`one of ordinary skill in the art; and
`
`(G)
`
`arriving at a claimed invention as a result of some teaching,
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`suggestion, or motivation in the prior art that would have led one of
`
`ordinary skill to modify the prior art reference or to combine prior art
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`reference teachings.
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`I have also been informed that other rationales to support a conclusion of
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`obviousness may be relied upon, for instance, that common sense (where
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`substantiated) may be a reason to combine or modify prior art to achieve the
`
`claimed invention.
`
`35.
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`I am also informed that a basis to combine teachings need not be
`
`stated expressly in any prior art reference. However, I understand that there must
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`
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`be some evidence showing an articulated reasoning with rational underpinnings to
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`support a motivation to combine teachings and to support the legal conclusion of
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`obviousness.
`
`36.
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`In addition, I am informed and understand that in order to establish
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`that an element of a claim is “inherent” in the disclosure of a prior art reference, it
`
`must be clear to one skilled in the art that the missing element is the inevitable
`
`outcome of the process and/or thing that is explicitly described in the prior art. I
`
`understand that to establish inherency, it is not enough that a certain result or
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`characteristic may occur or be present in the prior art, nor may inherency be
`
`established by probabilities or possibilities.
`
`VI. A Person of Ordinary Skill in the Relevant Art
`
`37.
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`I understand that my assessment and determination of the patentability
`
`of the challenged claims of the ’506 patent must be undertaken from the
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`perspective of what would have been known or understood by someone of ordinary
`
`skill in the relevant field as of the earliest priority date to which the ’506 patent is
`
`entitled, which is July 11, 2000.1
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`
`
`
`1 I have summarized my analysis of the earliest priority document supporting
`
`claims 1 and 2 of the ’506 patent in section IX.
`
`
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`A. Relevant Field
`38.
`In my opinion, the field relevant to the claims of the ’506 patent is
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`treatment of fungal infections of the nail and skin.
`
`B.
`Person of Ordinary Skill in the Art
`39. Based on my experience in the field, analysis of the ’506 patent, and
`
`review of the prior art, it is my opinion that a person of ordinary skill in the art in
`
`the relevant field as of July 11, 2000 would have had familiarity with the biology
`
`and pathology of common fungal agents that infect the nail and skin, and a
`
`familiarity with antifungal agents and their clinical use. The person of ordinary
`
`skill would have had (i) a bachelor’s or master’s degree in medicinal chemistry,
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`biochemistry, pharmacology, pharmacy, and/or biology, and at least 3-5 years of
`
`experience working with topical antifungal agents, or (ii) a M.D., Pharm. D., or
`
`Ph.D. in medicinal chemistry, biochemistry, pharmacology, pharmaceutics, and/or
`
`biology and at least 1 year of work experience working with topical antifungal
`
`agents. Unless otherwise specified, when I state that something would be known to
`
`or understood by one skilled in the art or possessing ordinary skill in the art, I am
`
`referring to someone with this level of knowledge and experience.
`
`40. With almost 25 years of experience working
`
`in
`
`the
`
`topical
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`pharmaceutical formulations field, I am well acquainted with the level of ordinary
`
`skill that would have been required to design, develop, and/or implement the
`
`
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`subject matter of the ’506 patent. I have direct experience with the relevant subject
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`matter and am capable of rendering an informed opinion regarding what the level
`
`of ordinary skill in the art was for the relevant field at the time of the alleged
`
`invention. I am also capable of rendering an informed opinion regarding what one
`
`of ordinary skill in the art would have understood at the time of the alleged
`
`invention.
`
`VII. Background of the Relevant Technology
`
`41. The human nail can be afflicted by several disease states including
`
`infections due to bacteria, viruses or fungi. Onychomycosis, also referred to as
`
`tinea unguium, is a fungal infection of the nail usually caused by a group of
`
`keratinophilic fungi known as dermatophytes. (Scher (Ex. 1033)). The species that
`
`most often cause onychomycosis in North America and parts of Europe are
`
`Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton
`
`floccosum. (Summerbell (Ex. 1031)). Particularly, T. mentagrophytes have affinity
`
`for the keratin of animals and humans. (Aly (Ex. 1032)). Onychomycosis can also
`
`be caused by nondermatophytes such as C. albicans. (Elewski (Ex. 1048 at 417)).
`
`Thus, a desirable antifungal drug for onychomycosis would be one that is effective
`
`against both dermatophytes and nondermatophytes.
`
`42. The nail plate (commonly called the nail) is a horny appendage of the
`
`skin that is composed mainly of keratin. The chemical composition of the nail
`
`
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`plate has many similarities to hair. Both are keratinous tissues that have little lipid
`
`content (0.5 to 1.5%, depending on age) and are hydrophilic in nature. See, e.g.,
`
`Baden (Ex. 1028).
`
`43. While systemic, e.g., oral, antifungal drugs were available well before
`
`2000, as noted in the Background Art section of the ’506 patent, the orally
`
`administered drugs of the prior art were known to cause side effects including
`
`gastrointestinal disorders and hepatotoxicity. See Ex. 1001 at 2:25-392. In view of
`
`the problems encountered in the treatment of onychomycosis with orally
`
`administered antifungal drugs, persons of ordinary skill in the art developed topical
`
`formulations for treating onychomycosis during the 1980s and 1990s. See, e.g.,
`
`Hay 1985 (Ex. 1014). Onychomycosis has been topically treated by pairing a
`
`potent antifungal agent with an appropriate delivery vehicle that topically delivers
`
`the antifungal active ingredient into the nail plate and the nail bed. See, e.g., Hay
`
`1985 (Ex. 1014), Vanderdonckt (Ex. 1035), Walters 1985 I (Ex. 1041).
`
`44. Early investigations of nail plate permeability showed that the human
`
`nail plate was significantly more permeable to water than was the stratum corneum
`
`(Burch and Winsor (Ex. 1027); Spruit (Ex. 1038); Walters 1981 (1039)). When the
`
`relative thickn