Filed on behalf of Petitioner COALITION FOR AFFORDABLE DRUGS X LLC
`
`
`By: Jeffrey D. Blake, Esq.
` MERCHANT & GOULD P.C.
`
`191 Peachtree Street N.E., Suite 4300
` Atlanta, GA 30303
`
`jblake@merchantgould.com
` Main Telephone: (404) 954-5100
` Main Facsimile: (404) 954-5099
`
`
`
`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 IPR2015-01776 (Patent 7,582,621 B2)
`________________________________________________________
`
`DECLARATION OF S. NARASIMHA MURTHY PH.D. IN SUPPORT OF
`PETITIONER’S REPLY TO PATENT OWNER’S RESPONSE
`
`
`
`
`
`
`
`
`
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1044 - Page 1 of 65
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`

`
`Declaration of S. Narasimha Murthy, Ph.D.
`In Support of Petitioner’s Reply to Patent Owner’s Response
`Inter Partes Review of Patent No. 7,582,621
`IPR2015-01776
`
`
`
`TABLE OF CONTENTS
`
`I.  INTRODUCTION ................................................................................................ 4 
`
`II.  BACKGROUND AND EXPERIENCE ............................................................... 5 
`
`III. COMPENSATION AND RELATIONSHIP TO THE PARTIES ....................... 8 
`
`IV.  MATERIALS CONSIDERED ........................................................................... 9 
`
`V. LEGAL STANDARDS ...................................................................................... 13 
`
`A.  Legal Principles of Claim Construction ........................................................ 13 
`
`B.  Legal Principles of Obviousness ................................................................... 13 
`
`C.  Level of Ordinary Skill in the Art ................................................................. 14 
`
`VI.  THE ’621 PATENT .......................................................................................... 15 
`
`A.  The ’060 Provisional...................................................................................... 16 
`
`B.  The ’621 Patent .............................................................................................. 20 
`
`VII. THE PRIOR ART ............................................................................................. 20 
`
`A.  Austin ............................................................................................................. 20 
`
`B.  Brehove .......................................................................................................... 26 
`
`C.  Freeman ......................................................................................................... 33 
`
`VIII. A POSITA WOULD REASONABLY EXPECT A LOW MOLECULAR
`WEIGHT COMPOUND TO SUCCESSFULLY PENETRATE THE NAIL
`PLATE ................................................................................................................ 38 
`
`
`
`
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1044 - Page 2 of 65
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`

`
`Declaration of S. Narasimha Murthy, Ph.D.
`In Support of Petitioner’s Reply to Patent Owner’s Response
`Inter Partes Review of Patent No. 7,582,621
`IPR2015-01776
`
`
`
`IX.  A POSITA WOULD HAVE A REASONABLE EXPECTATION OF
`SUCCESSFULLY TREATING ONYCHOMYCOSIS BASED ON THE
`POTENCY OF TAVABOROLE AGAINST CANDIDA ALBICANS
`DISCLOSED BY AUSTIN ................................................................................ 53 
`
`X. A POSITA WOULD HAVE REASON TO COMBINE AUSTIN AND
`BREHOVE OR FREEMAN TO ARRIVE AT A REASONABLE EXPECTION
`OF SUCCESSFULLY TREATING ONYCHOMYCOSIS WITH
`TAVABOROLE ................................................................................................. 62 
`
`XI.  CONCLUSION ................................................................................................. 64 
`
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`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1044 - Page 3 of 65
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`

`
`Declaration of S. Narasimha Murthy, Ph.D.
`In Support of Petitioner’s Reply to Patent Owner’s Response
`Inter Partes Review of Patent No. 7,582,621
`IPR2015-01776
`
`
`
`I, S. Narasimha Murthy, Ph.D., hereby state the following:
`
`I.
`
`INTRODUCTION
`
`1.
`
`I provide this declaration in support of Petitioner’s Reply to Patent
`
`Owner’s Response in the Inter Partes Review of U.S. Patent No. 7,582,621
`
`(hereinafter, “the ’621 Patent”).
`
`2.
`
`I previously provided a declaration dated June 15, 2015, in support of
`
`the petition filed by Coalition for Affordable Drugs X LLC. My previous
`
`declaration is Ex. 1008 and is incorporated herein by reference.
`
`3.
`
`I am competent to make this declaration based upon my personal
`
`knowledge and technical expertise, which I addressed in my first declaration, dated
`
`June 15, 2015.
`
`4.
`
`As was the case for my original declaration, this declaration was
`
`drafted with the help of attorneys. As I explained during my deposition, the
`
`drafting process involved my review of the patents and the literature and several
`
`initial teleconferences with attorneys, during which I discussed the technology and
`
`explained my opinions. (See Ex. 2032, at 474:17 – 475:22.) Following these
`
`teleconferences, the attorneys compiled my opinions into a draft declaration for my
`
`review, revision and comment. (See id. at 475:22 – 476:9.) I worked together with
`
`the attorneys to review and revise multiple drafts to ensure that all of my
`
`
`
`
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`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1044 - Page 4 of 65
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`

`
`Declaration of S. Narasimha Murthy, Ph.D.
`In Support of Petitioner’s Reply to Patent Owner’s Response
`Inter Partes Review of Patent No. 7,582,621
`IPR2015-01776
`
`
`
`recommendations and opinions were incorporated into both my original declaration
`
`(see id.) and this declaration.
`
`5.
`
`This Declaration is based on information currently available to me. I
`
`reserve the right to continue my investigation and analysis, which may include a
`
`review of documents and information not yet produced. 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.
`
`BACKGROUND AND EXPERIENCE
`
`6.
`
`I received a Bachelor of Pharmacy from Bangalore University, India,
`
`in 1992, a Master of Pharmacy from Bangalore University, India, in 1994, and a
`
`Ph.D. in Pharmaceutics from Bangalore University, India, in 2002. I completed my
`
`postdoctoral research in the department of Molecular and Cellular Biophysics at
`
`Roswell Park Cancer Institute, Buffalo, NY from 2002-2005.
`
`7.
`
`I was an Assistant Professor of Pharmaceutics at the M.S.R. College
`
`of Pharmacy, India from 1994-2002. I was an Assistant Professor of Pharmaceutics
`
`at Ohio Northern University, Ohio from 2005-2006, and an Assistant Professor of
`
`Pharmaceutics at the University of Mississippi from 2006-2011. I have been an
`
`Associate Professor of Pharmaceutics at the University of Mississippi from 2011
`
`
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1044 - Page 5 of 65
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`

`
`Declaration of S. Narasimha Murthy, Ph.D.
`In Support of Petitioner’s Reply to Patent Owner’s Response
`Inter Partes Review of Patent No. 7,582,621
`IPR2015-01776
`
`
`
`until the present, and I founded the Institute for Drug Delivery and Biomedical
`
`Research in Bangalore, India in 2013. I was recently promoted to the position of
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`full Professor of Pharmaceutics and Drug Delivery in July 2016.
`
`8.
`
`I have received numerous research grants directed to the topical
`
`administration of therapeutics, including “Nail Penetration of Antifungal Drugs”
`
`sponsored by Arno Therapeutics (2014-15) (See Ex. 1075, Poster Presentation,
`
`“Trans-ungual Delivery of AR-12, a Novel Antifungal Drug,” October 29, 2015
`
`(Ex.1 from Murthy Deposition)), “Bioadhesive Properties of Nail Lacquers”
`
`sponsored by Chanelle Group, France (2010), “Rapid Transdermal Delivery of
`
`Drugs” sponsored by Transport Pharmaceuticals Inc. (2008-09), and “Electric
`
`Effects on the Skin Permeability” sponsored by Rad Elec. Inc. (2005-06).
`
`9.
`
`I have served as the Chief Editor of two books: Dermatokinetics of
`
`Therapeutic Agents (2011) and Topical Nail Products and Ungual Drug Delivery
`
`(2013) (Ex. 2041). I have also authored eleven (11) book chapters directed to
`
`topical administration of therapeutics and drug delivery technologies.
`
`10.
`
`I understand Patent Owner contends that my opinions should be
`
`disregarded because I stated in deposition that I am not a “chemist.” What this
`
`means is that I am not a synthetic chemist by profession, but I am an expert in
`
`pharmaceutics. As such, I have extensive coursework in the fields of organic
`
`
`
`
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`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1044 - Page 6 of 65
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`

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`Declaration of S. Narasimha Murthy, Ph.D.
`In Support of Petitioner’s Reply to Patent Owner’s Response
`Inter Partes Review of Patent No. 7,582,621
`IPR2015-01776
`
`
`
`chemistry, physical chemistry, medicinal chemistry and pharmaceutics. (See Ex.
`
`2032, at 456:5-12, 460:8-23, 470:3-12.) In particular, I have studied the antiseptic,
`
`antibacterial and antifungal applications of boron compounds and therapeutics,
`
`including boric acid, borax, tetraboric acid, and sodium borates such as sodium
`
`perborate and sodium polyborate. (See id. at 456:13 – 457:16.) I have experience
`
`preparing and teaching with regard to formulations including boric acid
`
`suppositories, boric acid ointment and borax glycerin, some of which are used for
`
`treating fungal infections. (See id. at 457:17 – 462:3, 463:1 – 464:6.) With respect
`
`to the development of potential drug candidates for treating onychomycosis, I have
`
`selected and chemically modified compounds into prodrugs with physical chemical
`
`properties suitable for formulation and nail penetration without affecting their
`
`pharmacological properties. (See id. at 464:7 – 467:17, 470:13 – 472:12.) For
`
`instance, I converted the poorly-soluble drug itraconazole into a soluble form to
`
`make it more suitable for topical formulation. (See id. at 471:2-25.) I have also
`
`worked together with clinicians, toxicologists and pharmacologists to select and
`
`develop drugs for pharmaceutical application in humans. (See id. at 472:15 –
`
`474:10.)
`
`11. My CV is in the record as Exhibit 1009.
`
`12.
`
`I am competent to make this declaration based upon my personal
`
`
`
`
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`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1044 - Page 7 of 65
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`

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`Declaration of S. Narasimha Murthy, Ph.D.
`In Support of Petitioner’s Reply to Patent Owner’s Response
`Inter Partes Review of Patent No. 7,582,621
`IPR2015-01776
`
`
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`knowledge and expertise in the area of product development, drug delivery
`
`mechanisms, topical drug formulations, and in vitro and in vivo evaluation of
`
`therapeutic agents to treat onychomycosis and other nail diseases.
`
`III.
`
`COMPENSATION AND RELATIONSHIP TO THE PARTIES
`13. As I previously stated and reiterate here, I am being compensated at
`
`my standard consulting rate of $350 per hour for the time I spend studying
`
`materials and issues associated with this matter and for the time I spend providing
`
`testimony. I expect to be reimbursed for reasonable expenses associated with
`
`travel, including lodging, transportation, and other expenses incurred in connection
`
`with this matter. My compensation is not contingent upon the outcome of this
`
`matter.
`
`14. As I previously stated and reiterate here, I understand that Anacor
`
`Pharmaceuticals Inc. (“Anacor”) is the assignee of the ’621 Patent. I have not
`
`worked for Anacor, nor do I have any vested interest in any entity related to the
`
`“Coalition For Affordable Drugs X LLC.” To the best of my knowledge,
`
`information, and belief, I have no financial interest in Anacor or any entity related
`
`to the “Coalition For Affordable Drugs X LLC.”
`
`
`
`
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1044 - Page 8 of 65
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`

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`Declaration of S. Narasimha Murthy, Ph.D.
`In Support of Petitioner’s Reply to Patent Owner’s Response
`Inter Partes Review of Patent No. 7,582,621
`IPR2015-01776
`
`MATERIALS CONSIDERED
`
`
`
`IV.
`
`15. All of the exhibits that I have considered and relied on in this
`
`proceeding (including any supplemental exhibits) are the kinds of documents that I
`
`typically rely on when forming opinions, such as the opinions I offer in this
`
`proceeding.
`
`16.
`
`I reviewed the following documents and information, as well as Patent
`
`Owner’s Response:
`
`EXHIBIT
`Ex. 1001
`Ex. 1002
`
`Ex. 1003
`
`Ex. 1004
`
`Ex. 1008
`
`Ex. 1012
`Ex. 1028
`
`Ex. 1045
`
`Ex. 1046 
`
`
`
`DESCRIPTION
`U.S. Patent No. 7,582,621 (“the ’621 Patent”)
`Patent Cooperation Treaty Pub. No. WO 1995/033754 to
`Austin et al. (“Austin”)
`U.S. Patent Pub. No. 2002/0165121 to Brehove
`(“Brehove”)
`Patent Cooperation Treaty Pub. No. WO 2003/009689 A1
`to Freeman et al. (“Freeman”)
`Declaration of S. Narasimha Murthy Ph.D. in support of
`Petition for Inter Partes Review of Patent No. 7,582,621
`Prosecution history, Office Action dated August 26, 2008
`Sudaxshina Murdan, Drug Delivery to the Nail Following
`Topical Application, 236 Int’l J. Pharmaceutics 1 (2002)
`(“Murdan”)
`Deposition Transcripts of Dr. Majella Lane dated July 7-8,
`2016
`Transcript, Deposition of Mahmoud A. Ghannoum, Ph.D.
`(July 18 and 19, 2016)
`
`FILED
`
`
`
`
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`
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`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1044 - Page 9 of 65
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`Declaration of S. Narasimha Murthy, Ph.D.
`In Support of Petitioner’s Reply to Patent Owner’s Response
`Inter Partes Review of Patent No. 7,582,621
`IPR2015-01776
`
`
`
`Ex. 1047 
`
`Ex. 1050
`
`
`Ex. 1064
`
`Ex. 1065
`
`Ex. 1066
`
`Ex. 1075
`
`Ex. 1076
`
`Ex. 1077
`
`
`
`Transcript, Deposition of Howard I. Maibach, M.D., Ph.D.
`(July 13, 2016) 
`Ronald C. Wester et al., In Vivo Percutaneous Absorption
`of Boric Acid, Borax, and Disodium Octaborate
`Tetahydrate in Humans Compared to in Vitro Absorption
`in Human Skin from Infinite and Finite Doses,
`Toxicological Sci. 45, 42-51 (1998) (“Wester, Maibach et
`al.”) (Ex. 9 from Maibach Deposition)
`Certified Copy of U.S. Provisional Application No.
`60/654,060, filed February 16, 2005
`Dirk Mertin & Bernhard C. Lippold, 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, 49
`J. Pharmacy & Pharmacology 866 (1997) (Ex. 7 from Lane
`Deposition) (Ex. 1 from Ghannoum Deposition) (“Mertin
`& Lippold”)
`Stephen J. Baker et al., Progress on New Therapeutics for
`Fungal Nail Infections, 40 Annual Reports in Medicinal
`Chemistry 323 (Elsevier eds., 2005) (“Baker, Maibach
`2005”)
`A.S. Kushwaha et al., Trans-ungual Delivery of AR-12, a
`Novel Antifungal Drug, Poster Presentation, American
`Association of Pharmaceutical Scientists Conference
`(October 29, 2015) (Ex. 1 from Murthy Deposition)
`Yoichi Kobayashi et al., In vitro permeation of several
`drugs through the human nail plate: relationship between
`physicochemical properties and nail permeability of
`drugs, Eu. J. Pharma. Sci. 21:471-77 (2004) (Ex. 5 from
`Lane Deposition)
`Donald L. Greer, Ph.D., Evolving Role of
`Nondermatophytes in Onychomycosis, Int’l J. Derma., vol.
`34, no. 8 (Aug. 1995) (Ex. 5 from Ghannoum Deposition)
`
`
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`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1044 - Page 10 of 65
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`Declaration of S. Narasimha Murthy, Ph.D.
`In Support of Petitioner’s Reply to Patent Owner’s Response
`Inter Partes Review of Patent No. 7,582,621
`IPR2015-01776
`
`
`
`Ex. 1078
`
`
`Ex. 2001 
`Ex. 2021 
`
`Ex. 2032
`
`Ex. 2033
`
`Ex. 2035
`Ex. 2036
`Ex. 2040
`
`Ex. 2041
`
`Ex. 2049
`
`Ex. 2050
`
`Ex. 2065 
`
`
`
`R. Galimberti et al., The Activity of Ketoconazole in the
`Treatment of Onychomycosis, Reviews of Infectious
`Diseases, vol. 2, no. 4, 596-98 (Univ. of Chi. 1980) (Ex. 2
`from Ghannoum Deposition)
`FDA Approved Label for KERYDIN® (Rev. 3/2015) 
`Tatsumi et al., Therapeutic Efficacy of Topically Applied
`KP-103Against Experimental Tinea Unguium in Guinea
`Pigs in Comparison with Amorolfine and Terbinafine,
`Antimicrobial Agents and Chemotherapy, vol. 46, no. 12,
`pp. 3797-3801 (2002)
`Transcript, Deposition of S. Narasimha Murthy, Ph.D.
`(May 4, 5, 6, and 12, 2016)
`Transcript, Deposition of Stephen B. Kahl, Ph.D. (April 7
`and 8, 2016)
`Declaration of Mahmoud A. Ghannoum, Ph.D., E.M.B.A.
`Declaration of Majella Lane, Ph.D.
`Shivakumar, Repka, & Murthy, Transungual Drug
`Delivery: an Update, J. Drug Del. Sci. Tech., vol. 24, no.
`3, pp. 301–10 (2014) (Ex. 3 from Murthy Deposition)
`Topical Nail Products and Ungual Drug Delivery (S.
`Narasimha Murthy & Howard I. Maibach eds., 2013) (Ex.
`4 from Murthy Deposition)
`Ghannoum et al., A Large-Scale North American Study of
`Fungal Isolates From Nails: The Frequency of
`Onychomycosis, Fungal Distribution, and Antifungal
`Susceptibility Patterns, J. Am. Acad. Dermatol., vol. 43,
`no. 4, pp. 641-48 (2000)
`Segal et al., Treatment of Candida Nail Infection with
`Terbinafine, J. Am. Acad. Dermatol., vol. 35, no. 6, pp.
`958-61 (1996) (“Segal”)
`Scher et al., Onychomycosis: Diagnosis and Definition of
`Cure, J. Am. Acad. Dermatol., vol. 56, no. 6, pp. 939–44
`
`
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`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1044 - Page 11 of 65
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`Declaration of S. Narasimha Murthy, Ph.D.
`In Support of Petitioner’s Reply to Patent Owner’s Response
`Inter Partes Review of Patent No. 7,582,621
`IPR2015-01776
`
`
`
`(2007) 
`Boni E. Elewski, Onychomycosis: Pathogenesis,
`Diagnosis, and Management, Clin. Microbiol. Rev., vol.
`11, no. 3, pp. 415-29 (1998) (“Elewski”)
`Naglik et al., Candida albicans Secreted Aspartyl
`Proteinases in Virulence and Pathogenesis, Microbio. &
`Molecular Bio. Revs., vol. 67, no. 3, pp. 400–28 (2003)
`NCCLS (now CLSI), Reference Method for Broth
`Dilution Antifungal Susceptibility Testing of Yeasts;
`Approved Standard—Second Edition, NCCLS document
`M27-A2 (2002)
`Nimura et al., Comparison of In Vitro Antifungal
`Activities of Topical Antimycotics Launched in 1990s in
`Japan, Int’l J. Antimicrob. Agents, vol. 18, pp. 173–78
`(2001) 
`Crane & Sanders, Evaluation of a Biocidal Turbine-Fuel
`Additive, Aviation Medical Report—AM 67-21, pp. 1–10
`(Federal Aviation Administration, Office of Aviation
`Medicine 1967), available at
`http://www.faa.gov/data_research/research/med_humanfac
`s/oamtechreports/1960s/media/am67-21.pdf
`Baker et al., Discovery of a New Boron-Containing
`Antifungal Agent, 5-Fluoro-1,3-Dihydro-1-Hydroxy-2,1-
`Benzoxaborole (AN2690), for the Potential Treatment of
`Onychomycosis, J. Med. Chem., vol. 49, pp. 4447-50
`(2006)
`European Commission Scientific Committee on Consumer
`Products, Opinion on Toluene (April 15, 2008)
`
`Ex. 2070
`
`Ex. 2078
`
`Ex. 2088
`
`Ex. 2105 
`
`Ex. 2112
`
`Ex. 2157
`
`Ex. 2193 
`
`
`
`17.
`
`I also have knowledge of information generally available to, and
`
`relied upon by, persons of ordinary skill in the art at the relevant times. Some of
`
`
`
`
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`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1044 - Page 12 of 65
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`

`
`Declaration of S. Narasimha Murthy, Ph.D.
`In Support of Petitioner’s Reply to Patent Owner’s Response
`Inter Partes Review of Patent No. 7,582,621
`IPR2015-01776
`
`
`
`my statements below are expressly based on such knowledge.
`
`18.
`
`I reserve the right to supplement my opinions to address any
`
`information obtained, or positions taken, based on any new information that comes
`
`to light throughout this proceeding.
`
`V.
`
`LEGAL STANDARDS
`
`19.
`
`I am not an attorney. I do not expect to offer any opinions on the law.
`
`I have been informed, however, of certain legal principles relating to standards of
`
`patentability that I relied on in forming the opinions set forth in this report.
`
`A. Legal Principles of Claim Construction
`
`20.
`
`I understand that a primary step in determining validity of patent
`
`claims is to properly construe the claims to determine claim scope and meaning. In
`
`this regard, I incorporate my previous statements regarding claim construction. See
`
`Ex. 1008, Section V.A.
`
`B.
`
`21.
`
`Legal Principles of Obviousness
`
`I understand that a claimed invention is unpatentable if the differences
`
`between the invention and the prior art are such that the subject matter of the claim
`
`as a whole would have been obvious at the time the invention was made to a
`
`person of ordinary skill in the art (“POSITA”) to which the subject matter pertains.
`
`In this regard, I incorporate my previous statements regarding obviousness. See Ex.
`
`
`
`
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`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1044 - Page 13 of 65
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`Declaration of S. Narasimha Murthy, Ph.D.
`In Support of Petitioner’s Reply to Patent Owner’s Response
`Inter Partes Review of Patent No. 7,582,621
`IPR2015-01776
`
`
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`1008, Section V.B.
`
`C. Level of Ordinary Skill in the Art
`
`22.
`
`It is my understanding that the ’621 Patent is to be interpreted based
`
`on how it would have been read by a POSITA at the time of the effective filing
`
`date of the earliest application to which the ’621 Patent claims priority. I was
`
`familiar with the technology at issue and the state of the art as of the earliest
`
`priority date of the ’621 Patent, i.e., February 16, 2005.
`
`23.
`
`I believe a POSITA at the time the ’621 Patent was filed would have
`
`had an advanced degree (Master’s or Ph.D.) or equivalent experience in chemistry,
`
`pharmacology, or biochemistry, and at least two years of experience with the
`
`research, development, or production of pharmaceuticals.
`
`24.
`
`I understand that the Patent Owner has proposed a different definition
`
`for the level of ordinary skill in the art, as follows:
`
`[A] POSA would have needed knowledge and experience in several
`areas: medicinal chemistry; the development of potential drug
`candidates suitable for treating onychomycosis; and in assessing,
`together with others, the toxicology, pharmacology, and clinical utility
`of such candidates, including parameters relating to transungual
`penetration.
`
`See Patent Owner’s Response, IPR2015-01776, Paper 32, at 21-22 (hereinafter
`
`
`
`
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1044 - Page 14 of 65
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`

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`Declaration of S. Narasimha Murthy, Ph.D.
`In Support of Petitioner’s Reply to Patent Owner’s Response
`Inter Partes Review of Patent No. 7,582,621
`IPR2015-01776
`
`
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`“Patent Owner’s Response”).
`
`25. According to either definition, I consider myself to have had at least
`
`such ordinary skill in the art with respect to the subject matter of the ’621 Patent at
`
`the time the patent was filed. (See Ex. 2032, at 468:5 – 474:16; see also Ex. 1047
`
`(Maibach Deposition Transcript), at 42:2-20 (“he’s a leader for a man of his age in
`
`the field of pharmaceutical chemistry.”); Ex. 1071 (Lane Deposition Transcript), at
`
`32:14-19 (“Dr. Murthy has all the qualifications that are required.”).)
`
`26. A person of ordinary skill in the art does not need any special
`
`experience or training in mycology or clinical trials. The ’621 Patent claims
`
`priority to a provisional patent application (the ’060 Provisional, discussed below)
`
`that contains no mycological or clinical data. The ’621 Patent does not include any
`
`clinical data.
`
`VI.
`
`THE ’621 PATENT
`
`27. The ’621 Patent describes methods and compounds useful for treating
`
`fungal infections, and more specifically, the topical treatment of onychomycosis
`
`and/or cutaneous fungal infections using boron-containing small molecules. (Ex.
`
`1001, at Abstract.)
`
`
`
`
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1044 - Page 15 of 65
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`

`
`Declaration of S. Narasimha Murthy, Ph.D.
`In Support of Petitioner’s Reply to Patent Owner’s Response
`Inter Partes Review of Patent No. 7,582,621
`IPR2015-01776
`
`A. The ’060 Provisional
`
`
`
`28.
`
`I understand the earliest priority date for the ’621 Patent is based on
`
`U.S. Provisional Application No. 60/654,060 (hereinafter “the ’060 Provisional”),
`
`entitled “Boron-Containing Small Molecules for Use in the Topical Treatment of
`
`Onychomycosis and Cutaneous Fungal Infections,” filed February 16, 2005. (Ex.
`
`1064.) The inventors of the ’060 Provisional are listed as “Yong-Kang Zhang” and
`
`“Stephen J. Baker.”
`
`29. The ’060 Provisional indicates that the “invention is directed to
`
`compounds that are active against fungi and have properties that allow the
`
`compound, when placed in contact with a patient, to reach the particular part of
`
`nail or skin infected by the fungus.” (Id., ¶ [0001].) The ’060 Provisional further
`
`states that “[o]nychomycosis is a fungal infection of the toe and finger nails. The
`
`causative pathogens in this infection include the dermatophytes, Trichophyton,
`
`Microsporum and Epidermophyton species and yeast-like fungi including Candida
`
`species.” (Id., ¶ [0002].)
`
`30. The identified problem addressed by the ’060 Provisional is
`
`characterized as:
`
`
`
`
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1044 - Page 16 of 65
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`

`
`Declaration of S. Narasimha Murthy, Ph.D.
`In Support of Petitioner’s Reply to Patent Owner’s Response
`Inter Partes Review of Patent No. 7,582,621
`IPR2015-01776
`
`
`
`
`
`
`
`In the USA, onychomycosis is currently managed by only one FDA
`approved topical treatment, PENLAC®, which contains the active
`ingredient ciclopirox:
`
`
`
`PENLAC® is known to have very poor efficacy rates: it is only
`effective in 8% of all onychomycosis cases treated using this topical
`treatment. Thus, there remains a need for new antifungal agents that
`can applied safely to toe- and finger nails.
`
`(Id., ¶¶ [0003]-[0004].)
`
`31. With respect to molecular weight, the ’060 Provisional provides:
`
`Compounds with a molecular weight of less than 200 Da penetrate
`the nail plate in a manner superior to the commercially available
`treatment for onychomycosis (See Examples). In one embodiment of
`the present invention the antifungal compounds have a molecular
`weight of less than 170 Da. In another embodiment of this invention,
`the compounds have a molecular weight of from about 145 to about
`170 Da. In yet another embodiment the molecular weight is either
`151.93 or 168.39 Da.
`
`(Id., ¶ [0006].)
`
`
`
`
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1044 - Page 17 of 65
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`

`
`Declaration of S. Narasimha Murthy, Ph.D.
`In Support of Petitioner’s Reply to Patent Owner’s Response
`Inter Partes Review of Patent No. 7,582,621
`IPR2015-01776
`
`
`
`32. Without providing any actual nail penetration data, the ’060
`
`Provisional states:
`
`Penetration of the nail by the active ingredient may be effected by the
`polarity of the formulation. However, the polarity of the formulation
`is not expected have as much influence on nail penetration as some of
`the other factors, such as the molecular weight or the LogP of the
`active ingredient. The presence of penetration enhancing agents in the
`formulation are likely to increase penetration of the active agent when
`compared to similar formulations containing no penetration enhancing
`agent.
`
`(Id., ¶ [0022].)
`
`33. The ‘060 Provisional identifies two preferred compounds with
`
`“optimal physicochemical properties,” one of which is tavaborole. (See id., ¶
`
`[0017].) The ’060 Provisional describes the preparation and chemical properties of
`
`a number of compounds in Examples 1-15. (See id., ¶¶ [0032]-[0067].) Example
`
`14 is tavaborole. (See id., ¶ [0066].)
`
`34. Example 16 of the ’060 Provisional describes suitable formulations
`
`for the compounds. (See id., ¶ [0068].)
`
`35. Example A is entitled “Protocol for Anacor Antifungal MIC Testing”
`
`and describes the instrumentation, reagents, preparations, procedures and
`
`
`
`
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1044 - Page 18 of 65
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`

`
`Declaration of S. Narasimha Murthy, Ph.D.
`In Support of Petitioner’s Reply to Patent Owner’s Response
`Inter Partes Review of Patent No. 7,582,621
`IPR2015-01776
`
`
`
`calculations for minimum inhibitory concentration (MIC) testing. (See id. at 21-
`
`23.) However, the ’060 Provisional does not provide any MIC data for either of the
`
`preferred compounds (identified as “compound (1)” and “compound (2)”) or any
`
`other compound.
`
`36. Example B is entitled “Keratin Assay” and describes a protocol for
`
`determining the influence of keratin binding on MIC values. (See id. at 23-24.)
`
`However, the ’060 Provisional does not provide any data regarding the influence of
`
`keratin binding on the MIC values for compounds (1) and (2) or any other
`
`compound.
`
`37. Example C is entitled “The Solubility, Stability and LogP
`
`Determination of compounds of the present invention by LC/MS/MS” and
`
`describes various reagents, standards, methods, calculations and conditions for
`
`determining solubility, LogP and stability for compounds (1) and (2). (See id., ¶¶
`
`[0069]-[0078].) In the results section, data is provided regarding the solubility,
`
`LogP and stability of compounds (1) and (2). (See id., ¶¶ [0079]-[0081].)
`
`38. Example D is entitled “Determination of Penetration into Human
`
`Nail” and describes a protocol and apparatus for determining nail penetration. (See
`
`id., ¶¶ [0082]-[0090].) However, no nail penetration data was provided for
`
`compounds (1) and (2) or any other compound identified by the ’060 Provisional.
`
`
`
`
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1044 - Page 19 of 65
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`

`
`Declaration of S. Narasimha Murthy, Ph.D.
`In Support of Petitioner’s Reply to Patent Owner’s Response
`Inter Partes Review of Patent No. 7,582,621
`IPR2015-01776
`
`B.
`
`The ’621 Patent
`
`
`
`39. The ’621 Patent is entitled “Boron-Containing Small Molecules.” (Ex.
`
`1001.) I reiterate and incorporate my previous discussion in my original
`
`declaration concerning the ’621 Patent.
`
`VII. THE PRIOR ART
`
`A. Austin
`
`40.
`
`In contrast to assertions made in the ’621 Patent, 1,3-dihydro-5-
`
`fluoro-1-hydroxy-2,1-benzoxaborole (hereinafter, “tavaborole”) was not a novel
`
`compound in February of 2005. Rather, at least as early as December 14, 1995,
`
`Austin disclosed tavaborole (5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole)
`
`as a preferred fungicide. (Ex. 1002, Abstract.)
`
`41. Patent Owner has asserted three primary arguments against Austin that
`
`I would like to address. First, the Patent Owner alleges that Austin is not relevant
`
`or analogous art because the disclosed compounds, including tavaborole, are
`
`indicated for use as industrial fungicides. Second, the Patent Owner argues that
`
`Austin discloses “millions” of compounds including “tens of thousands” of
`
`compounds identified as “preferred” and, accordingly, a POSITA would not
`
`reasonably select tavaborole “out of this sea of compounds” as a starting point for
`
`treating onychomycosis. Third, the Patent Owner argues that a POSITA would not
`
`
`
`
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1044 - Page 20 of 65
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`

`
`Declaration of S. Narasimha Murthy, Ph.D.
`In Support of Petitioner’s Reply to Patent Owner’s Response
`Inter Partes Review of Patent No. 7,582,621
`IPR2015-01776
`
`
`
`reasonably pursue tavaborole for pharmaceutical applications without data
`
`regarding the selective toxicity of tavaborole. I disagree with all of these
`
`arguments.
`
`42. As to the Patent Owner’s first argument, in my opinion Austin is
`
`relevant prior art to the ’621 Patent and analogous prior art at a minimum. First, the
`
`Examiner of the ’621 Patent considered the Austin reference (U.S. equivalent
`
`version) relevant to the patentability of the claims of the ’621 Patent and, in fact,
`
`rejected all claims over Austin. (See Ex. 1012, Office Action dated August 26,
`
`2008 (rejecting the claims over U.S. Patent 5,880,188 to Austin in view of
`
`“Answre.com [sic]”).)
`
`43. Second, in a paper announcing the discovery of a “new boron-
`
`containing antifungal agent, 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole
`
`(AN2690), for the potential treatment of onychomycosis,” the inventors of the ’621
`
`Patent cited Austin as a source of the process for synthesizing at least one
`
`benzoxaborole derivative. (See Ex. 2157, at 4447 n.19, 4447-48, 4450.) In
`
`particular, the inventors stated that the “7-fluoro derivative (19n) was synthesized
`
`through directed ortho metalation of 3-fluorobenzyl alcohol (20) (Scheme 3),”
`
`citing PCT Pub. No. WO 95/33754 to Austin (endnote 19). As both the inventors
`
`and the Examiner found Austin relevant to the technology, I believe that Austin is
`
`
`
`
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1044 - Page 21 of 65
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`

`
`Declaration of S. Narasimha Murthy, Ph.D.
`In Support of Petitioner’s Reply to Patent Owner’s Response
`Inter Partes Review of Patent No. 7,582,621
`IPR2015-01776
`
`
`
`relevant prior art, or at a minimum, analogous prior art.
`
`44. With regard to the Patent Owner’s second argument, in my opinion
`
`Au