IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
`COALITION FOR AFFORDABLE DRUGS X LLC,
`Petitioner,
`
`v.
`
`ANACOR PHARMACEUTICALS, INC.,
`Patent Owner.
`
`Case No. IPR2015-01776
`Patent No. 7,582,621
`
`DECLARATION OF MAHMOUD A. GHANNOUM, PH.D., E.M.B.A.
`IN SUPPORT OF PATENT OWNER RESPONSE
`PURSUANT TO 37 C.F.R. § 42.120
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`Table of Contents
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`PRELIMINARY STATEMENT ..................................................................... 1
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`QUALIFICATIONS AND EXPERIENCE ..................................................... 1
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`
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`I.
`
`II.
`
`III. RELATIONSHIP TO THE PARTIES ............................................................ 6
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`IV. THE ’621 PATENT ......................................................................................... 6
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`V.
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`LEVEL OF ORDINARY SKILL .................................................................... 8
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`VI. BACKGROUND ............................................................................................. 8
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`A. Onychomycosis ..................................................................................... 8
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`B.
`
`C.
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`Different fungal organisms, including different species, have
`different and complex physiologies and morphologies ......................19
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`Efficacy and non-toxicity are major challenges in developing a
`treatment for fungal infections ............................................................23
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`D. Antifungals have complex and unpredictable types of activity
`against different fungal pathogens ......................................................27
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`E.
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`Developing a treatment for onychomycosis was complex and
`unpredictable .......................................................................................34
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`VII. THE CITED ART .......................................................................................... 42
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`A. Austin ..................................................................................................42
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`B.
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`C.
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`Brehove................................................................................................44
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`Freeman ...............................................................................................44
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`VIII. A POSA WOULD NOT HAVE CONSIDERED AUSTIN TO BE
`ANALOGOUS ART ..................................................................................... 46
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`IX. A POSA WOULD NOT HAVE USED AUSTIN AS A STARTING
`POINT ............................................................................................................ 50
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`X. A POSA WOULD NOT HAVE COMBINED AUSTIN AND
`BREHOVE WITH ANY EXPECTATION OF SUCCESS .......................... 58
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`XI. A POSA WOULD NOT HAVE COMBINED AUSTIN WITH
`FREEMAN WITH ANY EXPECTATION OF SUCCESS .......................... 74
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`XII. TAVABOROLE IS UNEXPECTEDLY SAFE AND EFFECTIVE ............ 79
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`XIII. CONCLUSION .............................................................................................. 81
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`I, Mahmoud A. Ghannoum, hereby declare and state as follows:
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`PRELIMINARY STATEMENT
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`IPR2015-01776
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`
`
`I.
`
`1.
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`I have been retained as an expert on behalf of Patent Owner Anacor
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`Pharmaceuticals, Inc. (“Patent Owner” or “Anacor”), and I am being compensated
`
`at my usual and customary hourly rate for my expert services in connection with
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`this Inter Partes Review proceeding. My compensation is not dependent upon the
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`outcome of the present Inter Partes review proceeding.
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`2.
`
`I have reviewed the Petition for Inter Partes Review of Patent No.
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`7,582,621 (“the ’621 Patent”) filed by Coalition for Affordable Drugs X LLC
`
`(“Petitioner”), including Dr. Kahl’s Declaration and Dr. Murthy’s Declaration, as
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`well as the exhibits and articles cited in those documents. I have also reviewed the
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`articles and documents cited in this declaration.
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`3.
`
`I am aware of information generally available to, and relied upon by,
`
`persons of ordinary skill in the art at the relevant times. Some statements below
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`are expressly based on such awareness.
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`II. QUALIFICATIONS AND EXPERIENCE
`I received a Ph.D. in Microbial Physiology in 1978 and a Master of
`4.
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`Science degree in Medicinal Chemistry in 1974, both from Loughborough
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`University of Technology, Loughborough, England. I received a Bachelor of
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`Science degree in Biology/Chemistry at the American University of Beirut in
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`1973. In 2004, I received an Executive M.B.A. from Case Western Reserve
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`University.
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`5.
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`I am currently the Director of the Center for Medical Mycology at
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`University Hospitals Case Medical Center and Professor in the Department of
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`Dermatology at Case Western Reserve University. I have held those positions for
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`20 years after joining those institutions in 1996. From 1991 to 1996, I was a
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`Research Professor Mycologist at Harbor-UCLA and UCLA School of Medicine.
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`I was a Professor in the Department of Botany & Microbiology at Kuwait
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`University from 1980 to 1991, after having worked there as Associate Professor
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`(1985–1990) and Assistant Professor (1980–1985). From 1978–1980, I was
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`Assistant Professor at the Higher Institute of Technology in Malta.
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`6.
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`I served as Advisor to the Clinical and Laboratory Standards Institute
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`(“CLSI,” formerly National Committee for Clinical and Laboratory Standards
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`“NCCLS”) Consensus Microbiology Committee in 2013 and as President of The
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`Medical Mycology Society of the Americas in 2011. In 2009, I served as
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`Chairman of the Subcommittee on Antifungal Susceptibility Testing at CLSI, and I
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`also served as Lecturer for the Food and Drug Administration (FDA), Contact Lens
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`Microbiology Workshop of 2009. I have also presented to the FDA on antifungal
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`resistance. A copy of my curriculum vitae is attached hereto as Exhibit 2029.
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`7.
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`I have conducted or participated in more than one hundred (100)
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`clinical and preclinical studies of medically important fungi. My research focus
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`includes determining the mechanism of action of different topical and systemic
`
`antifungal agents. This includes evaluating the antifungal activity of various drugs
`
`and their effect on growth, time kill, morphology/ultrastructure, protein synthesis
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`testing, and pre-clinical studies of novel antifungal agents, including in vitro and in
`
`vivo evaluations using reference and clinical isolates from an extensive fungal
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`culture collection. Another focus of my research is the determination of virulence
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`factors responsible for the pathogenesis of medically important fungi including
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`dermatophytes, Candida albicans, Cryptococcus neoformans, Aspergillus,
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`Fusarium, and other systemic and opportunistic fungal pathogens. In addition, in
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`connection with my position as Director of the Center for Medical Mycology, I
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`provide laboratory mycology services for national and international clinical trials
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`conducted by organizations in the pharmaceutical and biotech industries. Further,
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`as part of the Clinical Laboratory Improvement Amendments (CLIA) and The
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`College of American Pathology (CAP) certified clinical Laboratory, the Center for
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`Medical Mycology provides diagnostic and antifungal susceptibility services to
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`clinicians to help them in the management of patients suffering from superficial
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`and systemic fungal infections.
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`8.
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`I have served on the National Institutes of Health (NIH) Study
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`Sections as a reviewer for the last twenty years. I am currently a member of a
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`number of biomedical societies, including the American Society for Microbiology,
`
`the Infectious Disease Society of America, the American Academy of
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`Dermatology, and the International Society for Human and Animal Mycology. I
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`am also currently a member of the European Society of Clinical Microbiology and
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`Infectious Diseases. In 2013, I was appointed as a permanent member to the Drug
`
`Development and Resistance Study Section of the NIH through 2019. In addition,
`
`I served as a member of the Veteran Affairs Merit Review Research Awards
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`Committee-Infectious Diseases from 1997 to 2000.
`
`9.
`
`I have been involved in organizing scientific meetings in the field of
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`medical mycology, including meetings concerning fungus such as Candida and
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`fungal infections such as candidiasis, and symposia at the Interscience Conference
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`for Antimicrobial Agents and Chemotherapy and the American Academy of
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`Dermatology. Additionally, each year I am invited to speak at national and
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`international meetings where I provide updates on my research and the diagnosis,
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`epidemiology, and treatment of fungal infections.
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`10.
`
`I am currently a member of the Editorial Board of a number of peer-
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`reviewed biomedical journals, including Antimicrobial Agents and Chemotherapy
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`and the Journal of Chemotherapy. I have also served as a member of the Editorial
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`Board of other peer-reviewed biomedical journals, including Clinical Microbiology
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`Reviews, the Journal of Clinical Microbiology, and Mycoses. I was also an
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`associate editor of the Journal of Medical of Mycology and Mycoses.
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`11.
`
`I have published more than three hundred (300) peer-reviewed articles
`
`addressing various aspects of superficial and systemic fungal infections. I was co-
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`author or editor of five (5) scientific monographs. My publications include studies
`
`on superficial fungal infections caused by dermatophytes (Trichophyton species)
`
`and yeast (such as Candida) including onychomycosis epidemiology, diagnosis,
`
`antifungal susceptibility and treatments.
`
`12.
`
`I have been studying onychomycosis pathogenesis for the last 20
`
`years, and studying Candida pathogenesis, virulence determinants, and
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`susceptibility to drugs for the last 43 years.
`
`13.
`
`In June of 2016, I will receive the Rhoda Benham Award in Medical
`
`Mycology from the Medical Mycological Society of the Americas for outstanding
`
`contributions in the field of medical mycology. In 2009, I received the Prevent
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`Blindness America Investigator Award for “Prevention of Soft Contact Lens
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`Associated Fusarium Biofilms,” and the Billy Cooper Award of the Medical
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`Mycological Society of the Americas for contribution and the diagnosis of fungi. I
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`received an unrestricted Freedom to Discover award from Bristol-Myers Squibb in
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`2004. Further, I received the Kuwait Prize in Science (2003) from the Kuwait
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`Foundation for the Advancement of Sciences for my contribution in the field of
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`microbiology, and the A.H. Shawman Prize for Biological Sciences (1988),
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`awarded to young Arab scientists for excellence in biological science research.
`
`III. RELATIONSHIP TO THE PARTIES
`14. As a center of excellence for evaluating antifungals, our Center of
`
`Medical Mycology receives contracts to conduct studies on antifungal products
`
`under development from various companies. In this regard, the Center for Medical
`
`Mycology has contracted with Anacor to test tavaborole.
`
`IV. THE ’621 PATENT
`15. The inventors of the ’621 patent recognized a “need in the art for
`
`compounds which can effectively treat ungual and/or periungual infections.” ’621
`
`patent at 2:37–39 (Ex. 1001). The ’621 patent states that the invention provides “a
`
`method of treating a systemic infection or an ungual or periungual infection in a
`
`human comprising administering to the animal a therapeutically effective amount
`
`of a compound of the invention.” Id. at 5:17–20. Tavaborole (1,3-dihydro-5-
`
`fluoro-1-hydroxy-2,1-benzoxaborole) is one of the compounds disclosed for use in
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`the treatment methods of the invention. See, e.g., id. at 51:56–57; 59:41–60:42
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`(Example 16); 66:20–67:32 (Examples 19 & 20); FDA Approved Label for
`
`KERYDIN®, (Rev. 3/2015) at Sections 1, 11 (Ex. 2001).
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`16.
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`Independent claims 1, 11 and 12 of the ’621 patent recite:
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` 1. A method of treating an infection in an animal, said
`method comprising administering to the animal a
`therapeutically effective amount of 1,3-dihydro-5-fluoro-
`1-hydroxy-2,1-benzoxaborole, or a pharmaceutically
`acceptable salt thereof, sufficient to treat said infection.
`
`. . .
`
` 11. A method of treating onychomycosis in a human,
`said method comprising administering to the human a
`therapeutically effective amount of 1,3-dihydro-5-fluoro-
`1-hydroxy-2,1-benzoxaborole, or a pharmaceutically
`acceptable salt thereof, sufficient to treat said
`onychomycosis.
`
` 12. A method of inhibiting the growth of a fungus in a
`human, said method comprising administering to the
`human a therapeutically effective amount of 1,3-dihydro-
`5-fluoro-1-hydroxy-2,1-benzoxaborole, or a
`pharmaceutically acceptable salt thereof.
`
`’621 patent (Ex. 1001) at 67:35–39; 68:35–44.
`
`17.
`
`I understand that claims 2–10 are dependent claims, which depend
`
`directly or indirectly from independent claim 1, and that, accordingly, each claim
`
`in the patent includes the administration of tavaborole, which is recited in claim 1
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`using its chemical name, for treating an infection.
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`18.
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`I understand that the ’621 patent claims priority to a provisional patent
`
`application filed on Feb. 16, 2005. I interpret the meaning of the ’621 patent
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`claims in accordance with the knowledge and understanding of a person of
`
`ordinary skill in the art (“POSA”) during February 2005, as described below.
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`V. LEVEL OF ORDINARY SKILL
`19. The relevant art for the ’621 patent is administering tavaborole to treat
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`fungal infections, such as onychomycosis. A POSA would have needed
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`knowledge and experience in several areas: medicinal chemistry; the development
`
`of potential drug candidates suitable for treating onychomycosis; and in assessing,
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`together with others, the toxicology, pharmacology, and clinical utility of such
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`candidates, including parameters relating to transungual penetration.
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`20. Based on my qualifications and experience, I consider myself
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`qualified to provide opinions on the understanding of a person of ordinary skill in
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`the relevant art during 2005 as it pertains to mycology, specifically the diagnosis,
`
`epidemiology, and the treatment of fungal infections, and the research and
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`development of antifungal drugs, including topical and systemic drugs, from test
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`tube evaluation to evaluation in the patient.
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`VI. BACKGROUND
`A. Onychomycosis
`21. A POSA in 2005 would have understood that onychomycosis is a
`
`fungal infection of the nail plate or nail bed. It accounts for up to 50% of nail
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`dystrophies in humans. Ghannoum et al., A Large-Scale North American Study of
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`Fungal Isolates From Nails: The Frequency of Onychomycosis, Fungal
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`Distribution, and Antifungal Susceptibility Patterns, J. Am. Acad. Derm., vol. 43,
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`no. 4, pp. 641–48, at 641 (2000) (Ex. 2049) (hereinafter “North American”); Scher,
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`Onychomycosis: Therapeutic Update, J. Am. Acad. Derm., vol. 40, no. 6 (part 2),
`
`pp. S21–S26, at S21 (1999) (Ex. 2056). Onychomycosis is primarily caused by a
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`particular group of fungi referred to as dermatophytes. Vander Straten et al.,
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`Cutaneous Infections: Dermatophytosis, Onychomycosis, and Tinea Versicolor,
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`Infect. Dis. Clinics N. Am., vol. 17, pp. 87–112, at 100 (2003) (Ex. 2027). A
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`dermatophyte is a fungal organism that causes infection of nail, skin and hair.
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`Baeza et al., cDNA Representational Difference Analysis Used in the Identification
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`of Genes Expressed by Trichophyton rubrum During Contact with Keratin,
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`Microbes & Infection, vol. 9, pp. 1415–21, at 1415 (2007) (Ex. 2057). Keratin is
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`an important and major proteinaceous component of nail, skin, and hair.
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`Dermatophytes utilize keratin as a nutrient source. Id. To be able to consume
`
`keratin, dermatophytes produce keratinase, an enzyme that degrades keratin.
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`Hamaguchi et al., Characterization of an Extracellular Keratinase from
`
`Microsporum canis, Jpn. J. Med. Mycol., vol. 41, pp. 257–62, at 257, 259 (2000)
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`(Ex. 2058). This ability allows dermatophytes to survive in keratinaceous tissues
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`of animals and humans, such as nails, hooves, and claws, as parasites and as
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`infectious organisms. See id.
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`22. A POSA in 2005 also would have known that about 90% to 95% of
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`onychomycosis cases are caused by dermatophytes. See Larsen et al., The
`
`Prevalence of Onychomycosis in Patients with Psoriasis and Other Skin Diseases,
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`Acta Derm. Venereol., vol. 83, pp. 206–09, at 206 (2003) (Ex. 2020)
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`(“Onychomycosis is mainly caused by dermatophytes, of which Trichophyton (T.)
`
`rubrum plays the main role, while yeasts are responsible for about 5% and non-
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`dermatophyte moulds for 1-3%.”); Fletcher et al., Onychomycosis: The
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`Development of a Clinical Diagnostic Aid for Toenail Disease, Part I. Establishing
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`Discriminating Historical and Clinical Features, Brit. J. Derm., vol. 150, pp. 701–
`
`05, at 702 (2004) (Ex. 2038) (92% of isolates from patients with onychomycosis
`
`were dermatophytes). Some studies may report an incidence that is slightly lower.
`
`See Vander Straten et al. at 100 (Ex. 2027) (80% to 90%). However, a 2005
`
`POSA would have appreciated that the actual incidence of dermatophytes is likely
`
`higher than reported in such studies due to non-dermatophytes as contaminants and
`
`colonizers, which I discuss below. See infra ¶¶ 31, 33.
`
`23. The dermatophytes that cause onychomycosis include Trichophyton
`
`(T.) rubrum, T. mentagrophytes, and, to a lesser extent, Epidermophyton floccosum
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`and T. tonsurans. See, e.g., Vander Straten et al. at 100–05 (Ex. 2027); Kemna &
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`Elewski, A U.S. Epidemiologic Survey of Superficial Fungal Diseases, J. Am.
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`Acad. of Derm., vol. 35, no. 4, pp. 539–42, at 541, Table II (1996) (Ex. 2039). Of
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`these, T. rubrum is the main etiologic agent of onychomycosis, causing about 90%
`
`of onychomycosis cases attributed to dermatophytes. See Foster et al.,
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`Epidemiologic Surveillance of Cutaneous Fungal Infection in the United States
`
`from 1999 to 2002, Am. Acad. Derm., vol. 50, no. 5, pp. 748–52, at 749–50, Fig. 1
`
`(2004) (Ex. 2059) (>90% of the dermatophytes in fingernail onychomycosis were
`
`T. rubrum; and up to 81.4% of all microorganisms in toenail onychomycosis were
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`T. rubrum); Kemna & Elewski at 541, Table II (93.1% of dermatophyte isolates in
`
`onychomycosis cases were T. rubrum) (Ex. 2039); see also Larsen et al. at 206
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`(Ex. 2020).
`
`24. A 2005 POSA would have further understood that onychomycosis is
`
`characterized by thickening of the nail, discoloration, separation of nail plate from
`
`the nail bed, accumulation of subungual debris, nail plate dystrophy, and nail
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`brittleness. Onychomycosis is not merely a cosmetic condition because it affects
`
`the quality of life of patients. Nearly 50% of patients experience pain, 40% of
`
`patients experience nail pressure, and 74% of patients experience embarrassment.
`
`Drake et al., Effect of Onychomycosis on Quality of Life, J. Am. Acad. Derm., vol.
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`38, no. 5, Part 1, pp. 702–04, at Abstr.; 703 (1998) (Ex. 2064).
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`25. Onychomycosis can occur in the toenail or fingernail, as a POSA in
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`2005 would have known. E.g., Foster et al. at 749–50 (Ex. 2059). Toenail
`
`onychomycosis is more difficult to treat than fingernail onychomycosis. A POSA
`
`in 2005 would have expected this greater difficultly to be caused by toenail
`
`thickness, slower growth of toenails, and humidity within shoe wear.
`
`26.
`
`In 2005, as now, a POSA would have understood that an initial
`
`diagnosis of onychomycosis made by clinical inspection must be confirmed by
`
`mycological results. This is because other non-fungal nail dystrophies—for
`
`example, those caused by psoriasis, melanoma, and lichen planus—may present
`
`similarly to onychomycosis. See Vander Straten et al. at 106 (Ex. 2027); Scher et
`
`al., Onychomycosis: Diagnosis and Definition of Cure, J. Am. Acad. Derm., vol.
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`56, no. 6, pp. 939–44, at 940–41 (2007) (Ex. 2065) (hereinafter “Diagnosis”). For
`
`this reason, a POSA in 2005 seeking to identify a potential antifungal drug
`
`candidate would have understood that it is critical to conduct mycological
`
`laboratory testing involving culture and microscopic examination (potassium
`
`hydroxide (KOH)) of samples obtained from the infected nail. Vander Straten et
`
`al. at 106 (Ex. 2027); Diagnosis at 940–41 (Ex. 2065). Mycological culture refers
`
`to plating the nail sample obtained from the patient to show fungi is indeed present
`
`in the sample as a causative organism. Microscopic examination refers to
`
`examining a portion of the nail sample, treated with KOH, under a microscope to
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`show the presence of fungal hyphae. Diagnosis of onychomycosis is confirmed by
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`positive culture and positive KOH. This would be especially important—indeed,
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`indispensable—in conducting any scientific investigation of potential antifungal
`
`agents.
`
`27. A 2005 POSA would have understood that there are many nail
`
`dystrophies other than onychomycosis, for example, psoriasis, cancer, and lichen
`
`planus, and that would have needed to be differentiated from onychomycosis.
`
`Vander Straten et al. at 105 (Ex. 2027). These other dystrophies appear similar to
`
`onychomycosis upon clinical inspection and should therefore be confirmed or
`
`ruled out by mycological results as discussed above.
`
`28.
`
`In the very few cases of onychomycosis that are attributed to Candida
`
`spp., only Candida albicans (“C. albicans”) is the pathogen that causes
`
`onychomycosis, as I discuss below. Candida is a yeast. In 2005, a POSA would
`
`have known that yeasts are not dermatophytes. See, e.g., North American at 643–
`
`45; Tables II–IV (Ex. 2049). Yeasts, such as Candida, are fungi different from
`
`dermatophytes.
`
`29. Even though C. albicans can cause onychomycosis, the incidence of
`
`such infections is less than 5%. North American at 643, Table II (Ex. 2049) (3.2%
`
`C. albicans isolated (combined fingernail and toenail). E.g., Vander Straten et al.
`
`at 100 (Ex. 2027) (1–2% caused by yeasts (unspecified nail source)); Summerbell
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`et al., Onychomycosis, Tinea Pedis and Tinea Manuum Caused by Non-
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`Dermatophytic Filamentous Fungi, Mycoses, vol. 32, no. 8, pp. 609–19 (1989)
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`(Ex. 2066) (5.4% C. albicans isolated as etiologic agent (unspecified nail source)).
`
`Significantly, in some studies, no C. albicans were isolated from the toenail.
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`Foster et al. at 749–50, Fig. 1B (Ex. 2059) (no C. albicans isolated in toenail
`
`cases); Ellis et al., Non-Dermatophytes in Onychomycosis of the Toenails, Brit. J.
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`Derm., vol. 136, pp. 490–93, at 491 (1997) (Ex. 2067) (no C. albicans as possible
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`cause in toenail cases; 0.7% Candida (species unspecified) isolated as
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`contaminant/colonizer). While some studies may report an incidence that is
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`slightly higher, see Kemna & Elewski at Abstr., Table II (7.0%) (Ex. 2039), a 2005
`
`POSA would have appreciated that the incidence of C. albicans as the actual cause
`
`is likely lower than such reported numbers due to its potential presence in samples
`
`as a colonizer or contaminant, which I discuss below. See infra ¶¶ 31, 33.
`
`30. A 2005 POSA would further have recognized that the number of cases
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`of C. albicans in toenail onychomycosis is lower than the number in fingernail
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`onychomycosis. See, e.g., Foster et al. at 749–50, Fig. 1B (Ex. 2059); Ellis et al.,
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`at 491 (1997) (Ex. 2067). Therefore, in reviewing studies reporting rates of C.
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`albicans isolates without specifying the nail sample source a POSA would have
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`understood that the actual rate of C. albicans in the toenail cases was even lower
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`than the reported rate. See North American at 643, Table II (Ex. 2049) (3.2% C.
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`albicans isolated (combined fingernail and toenail); Vander Straten et al. at 100
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`(Ex. 2027) (1–2% caused by yeasts (unspecified nail source)); Summerbell et al. at
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`609–19 (Ex. 2066) (5.4% C. albicans isolated as etiologic agent (unspecified nail
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`source)); Kemna & Elewski at Abstr., Table II (7.0% C. albicans isolated
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`(unspecified nail source)) (Ex. 2039).
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`31. A 2005 POSA also would have known that the medical significance
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`of yeasts, including C. albicans, lies mainly in causing opportunistic/nosocomial
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`disseminated infections in hospitalized patients who are immunocompromised, for
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`example cancer patients, transplant patients, and HIV-infected patients. As I
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`discuss in detail above, in very few cases, C. albicans causes onychomycosis. See
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`supra ¶¶ 28–30. In certain reports, the mere isolation of a Candida spp. from the
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`nail is confused as a cause of infection because such reports do not identify the
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`organism at the species level or do not account for the fact that some Candida spp.
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`are merely colonizers or contaminants that do not cause onychomycosis. In this
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`regard, certain publications inaccurately report that Candida parapsilosis is a
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`causative agent of onychomycosis. As reported in McGinley et al., C. parapsilosis
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`represents normal flora in the hand and subungual areas of healthy adults and is the
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`major yeast found in these locations. McGinley et al., Composition and Density of
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`Microflora in the Subungual Space of the Hand, J. Clin. Microbiol., vol. 26, no. 5,
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`pp. 950–953, at Abstr.; 951; 952, Table 3 (1988) (Ex. 2068). A 2005 POSA would
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`have appreciated that, since C. parapsilosis occurs as a normal flora on body
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`surfaces, isolation of this species from diseased nail samples is considered a
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`contaminant and should be disregarded as a cause of the disease. North American
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`at 647 (Ex. 2049) (discussing Strausbaugh et al., High Frequency of Yeast
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`Carriage on Hands of Hospital Personnel, J. Clin. Microbiol., vol. 32, no. 9, pp.
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`2299–300 (1994) (Ex. 2069)).
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`32. A 2005 POSA would have also known that the very few remaining
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`cases of onychomycosis infections not caused by dermatophytes are caused by
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`non-dermatophyte molds. Of these molds, Scopulariopsis and Scytalidium are
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`known to be etiologic agents of onychomycosis. See Elewski, Onychomycosis:
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`Pathogenesis, Diagnosis, and Management, Clin. Microbiol. Rev., vol. 11, no. 3,
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`pp. 415–29, at 421 (1998) (Ex. 2070); Summerbell, Nondermatophytic Molds
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`Causing Dermatophytosis-Like Nail and Skin Infection, in Laboratory Handbook
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`of Dermatophytes, Chap. 8, pp. 213–56, at 213–14 (Kane, et al. eds. 1997) (Ex.
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`2071) (hereinafter “Nondermatophytic Molds”); North American at 647 (Ex.
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`2049); Ellis et al. at 490 (Ex. 2067). The other molds, such as Acremonium,
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`Aspergillus, and Fusarium are typically considered contaminants. See id. Before
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`identifying non-dermatophyte molds as etiologic agents, in addition to the
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`laboratory analysis described above, a 2005 POSA would have conducted
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`additional tests on a second sample to confirm that these non-dermatophyte molds
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`were in fact causing the onychomycosis. Nondermatophytic Molds at 214–18 (Ex.
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`2071); North American at 647 (Ex. 2049); see supra ¶ 26.
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`33.
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`In 2005, a POSA would have additionally known that each
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`onychomycosis case is almost always caused by a single organism. In very
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`infrequent situations, more than one fungal species is isolated from patients with
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`onychomycosis. Isolation of dermatophytes and a yeast or a non-dermatophyte
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`mold, i.e., mixed species, from the same specimen occurs at an extremely low rate.
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`In this regard, Ellis et al. reported that “the presence of a dermatophyte on direct
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`microscopy or culture has long been accepted as evidence that it is the pathogen
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`responsible for disease even in mixed infections.” Ellis et al. at 492 (Ex. 2067).
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`This understanding is also shown in Weitzman & Summerbell, which “supported
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`the view that dermatophytic fungi are still the main aetiological agents of
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`onychomycosis and stressed that the growth of a non-dermatophyte on culture
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`following a positive result on direct microscopy is not sufficient to diagnose a non-
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`dermatophyte infection.” Ellis et al. at 492 (Ex. 2067) (citing Weitzman &
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`Summerbell, The Dermatophytes, Clin. Microbiol. Rev., vol. 8, no. 2, pp. 240–59
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`(1995) (Ex. 2072)). Indeed, Ellis et al. reported isolation of a dermatophyte mixed
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`with the yeast Candida famata or with a non-dermatophyte mold at a rate of only
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`2.5% of patients tested in a clinical trial. Id. at 491. And Candida (species
`
`unspecified) was present with dermatophytes in only 0.7% of 76 patients in whom
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`mixed species were cultured as contaminants. Id. at 491–92; Table 3. No C.
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`albicans was found in the trial, whether as a possible cause of infection or as a
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`contaminant/colonizer. Id. The data from Ellis et al.’s trial “strongly support the
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`notion that non-dermatophytes and yeasts do not have a significant role in fungal
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`infections of the toenail.” Id. at 492–93. Ellis et al. concluded that “[m]ixed
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`infections . . . were very rare.” Id. at 492.
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`34. There are generally three clinical types of onychomycosis: distal
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`subungual; proximal subungual; and white superficial, as a 2005 POSA would
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`have known. Distal subungual is the most common type of onychomycosis,
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`comprising more than 90% of all onychomycosis cases. Vander Straten et al. at
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`105 (Ex. 2027). The most frequent fungus causing distal subungual
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`onychomycosis is T. rubrum. Distal subungual onychomycosis can also be caused
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`by T. mentagrophytes and Epidermophyton floccosum. Id. Proximal subungual
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`onychomycosis is most commonly caused by T. rubrum and other Trichophyton
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`species. Id. at 101. Proximal subungual is the least common type of
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`onychomycosis in healthy individuals. Id. White superficial onychomycosis
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`occurs in about 10% of cases and is most commonly caused by T. mentagrophytes,
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`but it can also be caused by molds. Id. at 105.
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`35. As discussed above, a 2005 POSA would have known that the vast
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`majority of onychomycosis cases are caused by dermatophytes, and most of those
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`are caused by T. rubrum. See supra ¶¶ 22–23. A POSA seeking to develop a
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`formulation for the treatment of onychomycosis would have been interested only in
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`antifungal agents having demonstrated efficacy against dermatophytes, particularly
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`T. rubrum, and efficacy only against C. albicans would have been inconsequential.
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`See North American at 645–47 (Ex. 2049); Gupta et al., Pulse Itraconazole vs.
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`Continuous Terbinafine for the Treatment of Dermatophyte Toenail
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`Onychomycosis in Patients with Diabetes Mellitus, J. Euro. Acad. Derm. &
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`Venereol., vol. 20, pp. 1188–1193, at 1191 (2006) (Ex. 2073) (hereinafter “Pulse
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`Itraconazole”). Confirming this expectation, in 2005, all approved drug products
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`for the treatment of onychomycosis, whether for oral or topical administration,
`
`were indicated for treating infections caused by dermatophytes. See FDA
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`Approved Label for SPORANOX®, (Supplements 034, 035 Action Date
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`07/14/2004) at 8–9 (Ex. 2074); FDA Approved Label for LAMISIL®, (Supplement
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`012, Action Date 01/21/2004) at 5 (Ex. 2075); FDA Approved Label for Gris-
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`PEG®, (Supplement 046, Action Date 03/26/2003) (Ex. 2076); FDA Approved
`