UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`FlatWing Pharmaceuticals, LLC
`
`Petitioner
`
`v.
`
`Anacor Pharmaceuticals Inc.
`
`Patent Owner
`
`Patent No. US 9,566,289
`Issue Date: February 14, 2017
`
`Title: Boron-Containing Small Molecules
`
`
`
`DECLARATION OF NARASIMHA MURTHY, PH.D
`IN SUPPORT OF PETITION FOR INTER PARTES
`REVIEW OF U.S. PATENT NO. 9,566,289
`
`Case No. 2018-00169
`
`
`
`
`
`
`
`
`FlatWing Ex. 1005, p. 1
`
`
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`FlatWing Pharmaceuticals, LLC
`
`Petitioner
`
`v.
`
`Anacor Pharmaceuticals Inc.
`
`Patent Owner
`
`Patent No. US 9,566,289
`Issue Date: February 14, 2017
`
`Title: Boron-Containing Small Molecules
`
`
`
`DECLARATION OF NARASIMHA MURTHY, PH.D
`IN SUPPORT OF PETITION FOR INTER PARTES
`REVIEW OF U.S. PATENT NO. 9,566,289
`
`Case No. 2018-00169
`
`
`
`
`
`
`
`
`FlatWing Ex. 1005, p. 1
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`
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`
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`TABLE OF CONTENTS
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`
`
`Introduction ...................................................................................................... 1
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`
`
`
`I.
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`II.
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`Qualifications and Experience ......................................................................... 1
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`
`
` Materials Considered ....................................................................................... 3 III.
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`IV.
`
` Statement of Legal Principles .......................................................................... 6
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`V.
`
`
`
`The ’289 Patent .............................................................................................. 10
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`VI.
`
` The Pertinent Prior Art .................................................................................. 22
`
`
`
` Claim Construction ........................................................................................ 36 VII.
`
`
`
` Grounds for Unpatentability .......................................................................... 38 VIII.
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`i
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`FlatWing Ex. 1005, p. 2
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`Declaration of S. Narasimha Murthy, Ph.D.
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`
`I.
`
`
`1.
`
`INTRODUCTION
`
`I, S. Narsimha Murthy, Ph.D., hereby declare that the following is true
`
`and correct. I am over the age of 18, competent to make this declaration, and I am
`
`familiar with the facts below. I offer this declaration in support of the Petition for
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`inter partes review of claims of U.S. Patent No. 9,566,289 (the ’289 Patent).
`
`
`II.
`
`QUALIFICATIONS AND EXPERIENCE
`
`A.
`
` Background and Work Experience
`
`
`2.
`
`I received a Bachelor of Pharmacy from Bangalore University, India,
`
`in 1992, a Master of Pharmacy from Bangalore University, India, in 1994, and a
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`Ph.D. in Pharmaceutics from Bangalore University, India, in 2002. I completed my
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`postdoctoral research in the department of Molecular and Cellular Biophysics at
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`Roswell Park Cancer Institute, Buffalo, NY from 2002-2005.
`
`
`3.
`
`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
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`at Ohio Northern University, Ohio from 2005-2006, and an Assistant Professor of
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`Pharmaceutics at the University of Mississippi from 2006-2011. I was an Associate
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`Professor of Pharmaceutics from 2011-2016 at the University of Mississippi and
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`continuing as Professor of Pharmaceutics and Drug Delivery since 2016 until the
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`present. I founded the Institute for Drug Delivery and Biomedical Research in
`
`Bangalore, India in 2013.
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`
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`1
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`FlatWing Ex. 1005, p. 3
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`Declaration of S. Narasimha Murthy, Ph.D.
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`4.
`
`I have received numerous research grants directed to the topical ad-
`
`ministration of therapeutics, including “Nail Penetration of Antifungal Drugs”
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`sponsored by Arno Therapeutics (2014-15), “Bioadhesive Properties of Nail Lac-
`
`quers” sponsored by Chanelle Group, France (2010), “Rapid Transdermal Delivery
`
`of Drugs” sponsored by Transport Pharmaceuticals Inc. (2008-09), and “Electret
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`Effects on the Skin Permeability” sponsored by Rad Elec. Inc. (2005-06).
`
`
`5.
`
`I have served as the Chief Editor of two books: Dermatokinetics of
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`Therapeutic Agents (2011) and Topical Nail Products and Ungual Drug Delivery
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`(2012). I have also authored eleven (11) book chapters directed to topical and other
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`routes of administration of therapeutics.
`
`
`6.
`
`Since the late 1990s, my research interests have been based on intra-
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`dermal, transdermal, and ungual (nail) drug delivery. My research has resulted in
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`over 85 publications in peer reviewed journals.
`
`
`7.
`
`
`8.
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`My CV is attached as Exhibit 1006.
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`I am competent to make this declaration based upon my personal
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`knowledge and expertise in the area of product development, drug delivery mecha-
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`nisms, topical drug formulations, and in vitro and in vivo evaluation of therapeutic
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`agents to treat onychomycosis and other nail diseases.
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`
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`2
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`FlatWing Ex. 1005, p. 4
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`Declaration of S. Narasimha Murthy, Ph.D.
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`B.
`
`
`
`Engagement
`
`
`9.
`
`I am being compensated $500 per hour for services I provide in this
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`case, and $1000 per day if travel is required. This compensation is not contingent
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`upon my performance, the outcome of this petition for inter partes review, or any
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`issues involved in or relating to this petition for inter partes review.
`
` MATERIALS CONSIDERED
`III.
`
`
`10.
`
`In preparing this Declaration, I reviewed the following documents and
`
`information, and the Petition:
`
`DESCRIPTION
`EXHIBIT
`Ex. 1001 U.S. Patent No. 9,566,289
`
`SHORT FORM
`
`‘289 Patent
`
`Ex. 1002 Prosecution History of the ‘289 Patent
`
`
`
`Ex. 1007 Austin et al., PCT Pub. No. WO 1995/033754
`
`Austin ‘574
`
`Ex. 1008 Brehove, U.S. Patent Pub. No. 2002/0165121
`
`Brehove ‘121
`
`Ex. 1009 Freeman et al., PCT Pub. No. WO 2003/009689
`
`Freeman ‘689
`
`Ex. 1010 Samour et al., U.S. Patent No. 6,224,887
`Ex. 1011 Handbook of Pharmaceutical Excipients (Arthur H.
`Kibbe ed., 3d ed. 2000)
`Ex. 1012 U.S. Patent No. 7,582,621
`
`Samour ‘887
`Excipients Hand-
`book
`‘621 Patent
`
`Ex. 1013 Prosecution History of the ‘621 Patent
`Final Written Decision, Coalition for Affordable
`Drugs X LLC v. Anacor Pharmaceuticals, Inc.,
`IPR2015-01776 (P.T.A.B. Feb. 23, 2017), Paper 70
`
`Ex. 1014
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`
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`3
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`FlatWing Ex. 1005, p. 5
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`Declaration of S. Narasimha Murthy, Ph.D.
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`Ex. 1015 U.S. Patent No. 7,767,657 (“the ‘657 Patent”)
`
`‘657 Patent
`
`Ex. 1016 Prosecution History of the ‘657 Patent
`
`Ex. 1017
`
`Final Written Decision, Coalition for Affordable
`Drugs X LLC v. Anacor Pharmaceuticals, Inc.,
`IPR2015-01780 (P.T.A.B. Feb. 23, 2017), Paper 70
`Final Written Decision, Coalition for Affordable
`Drugs X LLC v. Anacor Pharmaceuticals, Inc.,
`IPR2015-01785 (P.T.A.B. Feb. 23, 2017), Paper 70
`Ex. 1019 U.S. Patent No. 4,202,894
`
`Ex. 1018
`
`Ex. 1020
`
`Murdan, Sudaxshina. “Drug delivery to the nail fol-
`lowing topical application.” International journal of
`pharmaceutics 236, no. 1 (2002): 1-26.
`
`Ex. 1021 Biobor JF® Specification Sheet (2015)
`
`Ex. 1022 Biobor JF® Material Safety Data Sheet (2004)
`Ex. 1023 Remington: The Science and Practice of Pharmacy
`(Lippincott Williams & Wilkins eds., 21st ed. 2005)
`Ex. 1024 Hawley’s Condensed Chemical Dictionary (John
`Wiley & Sons, Inc., 13th ed. 1997)
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=6440876, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/64408
`76 (retrieved on May 26, 2017)
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=3198, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/3198
`(retrieved on May 26, 2017)
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=11499245, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/11499
`245 (retrieved on May 26, 2017)
`
`Ex. 1025
`
`Ex. 1026
`
`Ex. 1027
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`4
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`‘894 Patent
`
`Murdan 2002
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`FlatWing Ex. 1005, p. 6
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`Declaration of S. Narasimha Murthy, Ph.D.
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`Ex. 1028
`
`Ex. 1029
`
`Ex. 1030
`
`Meds. & Healthcare Prods. Regulatory Agency,
`Curanail 5% Nail Lacquer (Amorolfine Hydrochlo-
`ride) PL 10590/0049, UK Public Assessment Re-
`port (approved July 4, 2006)
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=22497760, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/22497
`760 (retrieved on May 26, 2017)
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=61764, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/61764
`(retrieved on May 26, 2017)
`Mertin, Dirk, and Lippold, Bernhard C. “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.” Journal of pharmacy and
`pharmacology 49, no. 9 (1997): 866-872
`Groziak, Michael P. “Boron therapeutics on the
`horizon,” American journal of therapeutics 8, no. 5
`(2001): 321-328
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=66827, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/66827
`(retrieved on May 26, 2017)
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=2775922, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/27759
`22 (retrieved on May 26, 2017)
`Ex. 1035 Aldrich Handbook of Fine Chemicals and Labora-
`tory Equipment (Sigma-Aldrich, 2004)
`
`Ex. 1031
`
`Ex. 1032
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`Ex. 1033
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`Ex. 1034
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`
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`Mertin 1997
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`Groziak 2001
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`
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`5
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`FlatWing Ex. 1005, p. 7
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`Declaration of S. Narasimha Murthy, Ph.D.
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`IV.
`
`
`
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`11.
`
`STATEMENT OF LEGAL PRINCIPLES
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`I am a technical expert and do not offer any legal opinions here. How-
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`ever, I understand the framework to be applied for determining invalidity and re-
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`lated matters. I have applied this framework in developing my technical opinions
`
`expressed in this Declaration.
`
`A.
`
` Claim Construction
`
`
`12.
`
`I understand that in a proceeding for inter partes review, a claim in an
`
`unexpired patent is to be given its broadest reasonable construction in light of the
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`specification of the patent in which it appears. I reserve the right to amend or alter
`
`my analysis and opinions in view of the Patent Owner’s proposed claim construc-
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`tions, if any.
`
`B.
`
` Obviousness
`
`
`13.
`
`I understand that a claimed invention is unpatentable and invalid as
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`“obvious” if the differences between the invention and the prior art are such that
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`the subject matter as a whole would have been obvious at the time the invention
`
`was made to a person having ordinary skill in the art (“POSITA”) to which the
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`subject matter of the patent pertains. Obviousness, as I understand it, is based on
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`the scope and content of the prior art, the differences between the prior art and the
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`claim, the level of ordinary skill in the art at the time of the invention (presumably
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`6
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`FlatWing Ex. 1005, p. 8
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`Declaration of S. Narasimha Murthy, Ph.D.
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`the patent application filing date), and secondary indicia of obviousness to the ex-
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`tent they exist.
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`14.
`
`I understand that obviousness can be established by combining or
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`modifying the teachings of the prior art to achieve the claimed invention when
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`there is a reason to make such a combination or modification. It is also my under-
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`standing that where there is a reason to modify or combine the prior art to achieve
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`the claimed invention (i.e., a motivation to combine), there must also be a reasona-
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`ble expectation of success for a finding of obviousness.
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`15.
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`
`
`I understand that a claimed invention may be obvious if some teach-
`
`ing, suggestion, or motivation that would have led a person ordinarily skilled in the
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`art to combine the invalidating references exists. I also understand that this sugges-
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`tion or motivation may come from such sources as explicit statements in the prior
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`art or from the knowledge of one of ordinary skill in the art. Alternatively, any
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`need or problem known in the field at the time and addressed by the patent may
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`provide a reason for combining elements of the prior art. I also understand that
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`when there is a design need or market pressure and a finite number of predictable
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`solutions, a person of ordinary skill in the art may be motivated to apply his skill
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`and common sense in trying to combine the known options in order to solve the
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`problem.
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`
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`7
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`FlatWing Ex. 1005, p. 9
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`Declaration of S. Narasimha Murthy, Ph.D.
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`16.
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`It is also my understanding that determining obviousness can include
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`consideration of unexpected results, commercial success, long felt but unsolved
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`need, or the failure of others to achieve the claimed invention. I also understand
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`that, in order to be relevant to the issue of obviousness, such factors must have
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`some connection or nexus to the claimed invention. In my opinion, there are no
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`unexpected results of the claimed combinations, and no long-felt but unresolved
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`needs, no failure of others to achieve the claimed combination. To the extent that
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`there is any commercial success, in my opinion it is due to factors such as pricing,
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`advertising and marketing, and not the features in combination.
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`17.
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`I further understand that whether there are any relevant differences be-
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`tween the prior art and the claimed invention is to be analyzed from the view of a
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`person of ordinary skill in the relevant art at the time of the invention. As such, my
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`opinions regarding a person of ordinary skill in the art are as of the alleged time of
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`the invention of the ’289 Patent (i.e., at or before the earliest priority date of the pa-
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`tent), even if they are stated in the present tense.
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`18.
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`
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`I understand that a person of ordinary skill in the art is presumed to
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`have the skill and experience of an ordinary worker in the field and is deemed to
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`have knowledge of all pertinent art at the time of the invention. The person of or-
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`dinary skill in the art is one who thinks along the lines of conventional wisdom in
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`the art.
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`8
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`FlatWing Ex. 1005, p. 10
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`Declaration of S. Narasimha Murthy, Ph.D.
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`C.
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`
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`Level of Ordinary Skill in the Art
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`19.
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`I am well-positioned to opine as to what a person having ordinary skill
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`in the art at the time of the invention would understand and do. As noted above, I
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`have earned a bachelor’s and master’s degree in pharmacy and a doctoral degree in
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`pharmaceutics. I have been a researcher and university professor in the field of
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`pharmaceutics for over 23 years. In 2005, at the time of filing of the earliest docu-
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`ment to which the ’289 Patent claims priority, I had almost eleven years of experi-
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`ence in this field and consider myself as having been a person having ordinary skill
`
`in the art at that time.
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`20.
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`I understand that the level of ordinary skill in the art for a particular
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`patent may be based on various factors, including the following: (1) type of prob-
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`lems encountered in the art; (2) prior art solutions to those problems; (3) rapidity
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`with which innovations are made; (4) sophistication of the technology; and (5) ed-
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`ucational level of active workers in the field. I further understand that in a given
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`case, every factor may not be present, and one or more factors may predominate.
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`21.
`
`I believe that a POSITA at the time the ’289 Patent was filed would
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`have an either a Master’s or Ph.D. degree in chemistry, pharmacology, or biochem-
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`istry, and at least two years of experience in research, development, or production
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`of pharmaceuticals.
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`9
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`FlatWing Ex. 1005, p. 11
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`Declaration of S. Narasimha Murthy, Ph.D.
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`V.
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`22.
`
`THE ’289 PATENT
`
`The ’289 Patent describes methods and compounds useful for treating
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`fungal infections, and more specifically, topical formulations for treatment of ony-
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`chomycosis and/or cutaneous fungal infections using boron-containing small mol-
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`ecules. (Ex. 1001, Title, Abstract.) The ’289 Patent’s claims are directed to phar-
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`maceutical formulations including the compound 1,3-dihydro-5-fluoro-1-hydroxy-
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`2,1-benzoxaborole.
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`A.
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` Priority Date
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`23.
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`I understand the earliest claimed priority date for the ’289 Patent is
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`February 16, 2005. (Ex. 1001.) However, I have not considered the extent to which
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`the claims of the ’289 Patent, as a continuation-in-part application, are supported
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`by U.S. Provisional Application No. 60/654,060, filed February 16, 2005, or any
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`other applications to which the ’289 Patent claims priority.
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`B.
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` The ’289 Patent’s Disclosure
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`24.
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`The ’289 Patent is entitled “Boron-Containing Small Molecules.” (Ex.
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`1001.)
`
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`25.
`
`In the background, the ’289 Patent cites problems with prior art treat-
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`ment methods and compounds, such as adverse effects related to long-term oral
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`administration of antifungals, (id. at 1:58-2:9), issues with surgical removal of all
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`10
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`FlatWing Ex. 1005, p. 12
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`Declaration of S. Narasimha Murthy, Ph.D.
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`or part of the nail, (id. at 2:9-15), and issues with topical treatments, including
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`maintaining nail contact and nail penetration (id. at 2:17-24; id. at 2:31-41).
`
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`26.
`
`The ’289 Patent discloses a number of potential boron-containing
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`small molecules but only claims a single compound: 1,3-dihydro-5-fluoro-1- hy-
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`droxy-2,1-benzoxaborole. (Id. at 323:1-324:33.) The ’289 Patent refers to 1,3-
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`dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole as “C10.” (Id. at 180:20-27.) The
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`’289 Patent alleges that “C10” is a novel compound. (Id. at 189:52-53.) I disagree
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`because 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole (C10) was previously
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`disclosed as a preferred antifungal compound by Austin. (Ex. 1007, Abstract.)
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`27.
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`The structure of 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole
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`(the same compound is disclosed by Austin as 5-fluoro-1,3-dihydro-1-hydroxy-2,1-
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`benzoxaborole) is:
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`(Id. at 24:5-14; see also Ex. 1027, at 3.)
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`
`
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`28.
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`In addition to referring to 1,3-dihydro-5-fluoro-1-hydroxy-2,1- ben-
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`zoxaborole as C10, the ’289 Patent also refers to this compound as “compound 1.”
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`(See, e.g., Ex. 1001, 137:51-66.)
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`11
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`FlatWing Ex. 1005, p. 13
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`Declaration of S. Narasimha Murthy, Ph.D.
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`29.
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`The ’289 Patent discloses methods of treating ungual and periungual
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`infections, and more specifically, onychomycosis, using its disclosed compounds.
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`(Id. at 132:21-28.) The ’289 Patent recognizes that “[o]nychomycosis is a disease
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`of the nail caused by yeast, dermatophytes, or other molds, and represents approx-
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`imately 50% of all nail disorders.” (Id. at 131:24-27.) The ’289 Patent alleges that
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`“anti-fungal drugs cannot readily penetrate the nail plate to reach the infection sites
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`under the nail.” (Id. at 131:54-57.) I disagree because Brehove discloses antifungal
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`drugs capable of treating onychomycosis through topical application to the nail and
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`surrounding skin of a human. (See, e.g., Ex. 1008, Abstract.)
`
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`30.
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`The ’289 Patent also discloses methods for determining the antifungal
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`activity of compounds and the keratin binding properties of compounds. (Ex. 1001,
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`189:18-190:50.) The ’289 Patent admits these methods were well known in the
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`prior art. (Id. at 189:22-25 (“All MIC testing followed the National Committee for
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`Clinical Laboratory Standards (NCCLS) guidelines for anti- microbial testing of
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`yeasts . . . and filamentous fungi . . . .”); id. at 189:40-43 (“The affinities of the
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`compounds for keratin powder was determined by a method described in Tatsumi,
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`Antimicrobial Agents and Chemotherapy, 46(12): 3797-3801 (2002).”).) I agree.
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`Determining the antifungal activity of compounds and the keratin binding proper-
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`ties of compounds was well known in the art before February 16, 2005, and is
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`nothing more than routine experimentation.
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`
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`12
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`FlatWing Ex. 1005, p. 14
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`Declaration of S. Narasimha Murthy, Ph.D.
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`31.
`
`The ’289 Patent further discloses the determination of solubility, sta-
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`bility, and log P values for compounds, specifically 1,3-dihydro-5-fluoro-1- hy-
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`droxy-2,1-benzoxaborole. (Id. at 190:52-192:44.) The determination of solubility,
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`stability, and log P values for a compound under consideration for topical applica-
`
`tion was standard practice before February 16, 2005, and is nothing more than rou-
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`tine experimentation.
`
`
`32.
`
`The ’289 Patent further discloses methods for determining the effica-
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`cy of nail penetration by antifungal compounds. (Id. at 133:64-134:11; id. at
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`192:48-197:7.) The ’289 Patent admits these methods were well known in the prior
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`art. (Id. at 192:53-56 (“Two nail penetration studies were performed based on the
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`protocol in Hui et al., Journal of Pharmaceutical Sciences, 91(1):189-195 (2002)
`
`(’Hui protocol’).”).) I agree. Determining the efficacy of nail penetration by com-
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`pounds, including antifungal compounds, was well known in the art before Febru-
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`ary 16, 2005, and is nothing more than routine experimentation.
`
`
`33.
`
`The ’289 Patent discloses pharmaceutical formulations for application
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`and delivery of its boron-containing compounds. (Id. at 167:5-173-3.) The ’289 Pa-
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`tent admits that formulating pharmaceutical compositions was well known in the
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`art of cosmetics and topical pharmaceuticals:
`
`The term “pharmaceutically acceptable carrier” or “pharmaceutically ac-
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`ceptable vehicle” refers to any formulation or carrier medium that provides
`
`
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`13
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`FlatWing Ex. 1005, p. 15
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`
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`Declaration of S. Narasimha Murthy, Ph.D.
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`the appropriate delivery of an effective amount of a [sic] active agent as de-
`
`fined herein, does not interfere with the effectiveness of the biological ac-
`
`tivity of the active agent, and that is sufficiently non-toxic to the host or pa-
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`tient. Representative carriers include water, oils, both vegetable and mineral,
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`cream bases, lotion bases, ointment bases and the like. These bases include
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`suspending agents, thickeners, penetration enhancers, and the like. Their
`
`formulation is well known to those in the art of cosmetics and topical phar-
`
`maceuticals. Additional information concerning carriers can be found in
`
`Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott,
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`Williams & Wilkins (2005) which is incorporated herein by reference.
`
`(Id. at 12:7-22.) Moreover, the ’289 Patent describes a number of non-toxic, phar-
`
`maceutically acceptable solvents, including ethanol and propylene glycol, which
`
`were well known to a POSITA:
`
`The pharmaceutical formulations of the invention can take a variety of forms
`
`adapted to the chosen route of administration. Those skilled in the art will
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`recognize various synthetic methodologies that may be employed to prepare
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`non-toxic pharmaceutical formulations incorporating the compounds de-
`
`scribed herein. Those skilled in the art will recognize a wide variety of non-
`
`toxic pharmaceutically acceptable solvents that may be used to prepare solv-
`
`
`
`14
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`FlatWing Ex. 1005, p. 16
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`
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`Declaration of S. Narasimha Murthy, Ph.D.
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`ates of the compounds of the invention, such as water, ethanol, propylene
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`glycol, mineral oil, vegetable oil and dimethylsulfoxide (DMSO).
`
`(Id. at 162:50-60.) I agree. Selecting from among acceptable solvents for formulat-
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`ing pharmaceutical compositions involves nothing more than routine experimenta-
`
`tion based on well-known protocols.
`
`
`
`The ’289 discloses that its topical formulations may contain “suitable chelat-
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`ing agents to form complexes with metal cations that do not cross a lipid bilayer;”
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`with its preferred chelating agents being ethylene diamine tetraacetic acid and cit-
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`ric acid. (Id. at 170:27-36.)
`
`C.
`
` The ’289 Patent’s Claims
`
`
`34.
`
`Independent claim 1 recites a “pharmaceutical formulation, compris-
`
`ing: 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole, or a pharmaceutically ac-
`
`ceptable salt thereof; and a pharmaceutically acceptable topical carrier.” A short
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`name for 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole is tavaborole.1 (See,
`
`e.g., Ex. 1007, at 9:31-34; Ex. 1027.)
`
`
`1 This declaration uses interchangeably the following names for the compound
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`recited in the claims of the ’290 Patent: 1,3-dihydro-5-fluoro-1-hydroxy-2,1-
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`benzoxaborole; 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole; tavaborole;
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`tavaborole; AN-2690.
`
`
`
`15
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`FlatWing Ex. 1005, p. 17
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`
`
`
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`Declaration of S. Narasimha Murthy, Ph.D.
`
`
`35.
`
`Claim 2 depends from claim 1 and narrows the formulation of claim 1
`
`to “wherein the pharmaceutically acceptable topical carrier comprises one or more
`
`members selected from polymers, thickeners, buffers, neutralizers, chelating
`
`agents, preservatives, surfactants or emulsifiers, antioxidants, waxes or oils, emol-
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`lients, sunscreens, and a solvent or mixed solvent system.”
`
`
`36.
`
`Claim 3 depends from claim 1 and narrows the formulation of claim 1
`
`to “wherein the pharmaceutically acceptable topical carrier comprises a solvent
`
`system and a chelating agent; wherein the solvent system comprises ethanol and
`
`propylene glycol; and wherein the chelating agent is ethylene diamine tetraacetic
`
`acid (EDTA) or a pharmaceutically acceptable salt thereof.”
`
`
`37.
`
`Independent claim 4 recites a pharmaceutical formulation, compris-
`
`ing: 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole, or a pharmaceutically ac-
`
`ceptable salt thereof; a solvent system and a chelating agent.”
`
`38.
`
`
`
`Claim 5 depends from claim 4 and narrows the formulation of claim 4
`
`to “wherein the solvent system comprises ethanol.”
`
`
`39.
`
`Claim 6 depends from claim 4 and narrows the formulation of claim 4
`
`to “wherein the solvent system consists of ethanol.”
`
`
`40.
`
`Claim 7 depends from claim 4 and narrows the formulation of claim 4
`
`to “wherein the solvent system comprises ethanol and propylene glycol.”
`
`
`
`16
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`FlatWing Ex. 1005, p. 18
`
`
`
`Declaration of S. Narasimha Murthy, Ph.D.
`
`41.
`
`Claim 8 depends from claim 4 and narrows the formulation of claim 4
`
`to “wherein the chelating agent is ethylene diamine tetraacetic acid (EDTA) or a
`
`pharmaceutically acceptable salt thereof.”
`
`42.
`
`Claim 9 depends from claim 8 and narrows the formulation of claim 8
`
`to “wherein the ethylene diamine tetraacetic acid (EDTA) or a pharmaceutically
`
`acceptable salt thereof, is present in a concentration of from about 0.005% to about
`
`2.0% w/w.”
`
`43.
`
`Claim 10 depends from claim 4 and narrows the formulation of claim
`
`4 to “wherein the 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole, or a phar-
`
`maceutically acceptable salt thereof, is present in a concentration of about 5%
`
`w/w.”
`
`44.
`
`Claim 11 depends from claim 4 and narrows the formulation of claim
`
`4 to “wherein the formulation is suitable for the treatment of onychomycosis of a
`
`toenail due to Trichophyton rubrum or Trichophyton mentagrophytes by topical
`
`application of the formulation to the toenail.”
`
`45.
`
`Independent claim 12 recites a pharmaceutical formulation, compris-
`
`ing: “about 5% w/w 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole, or a
`
`pharmaceutically acceptable salt thereof; propylene glycol; ethanol; and ethylene
`
`diamine tetraacetic acid (EDTA) or a pharmaceutically acceptable salt thereof.”
`
`17
`
`FlatWing Ex. 1005, p. 19
`
`
`
`
`
`Declaration of S. Narasimha Murthy, Ph.D.
`
`
`46.
`
`Claim 13 depends from claim 12 and narrows the formulation of
`
`claim 12 to “wherein the formulation is suitable for the treatment of onychomyco-
`
`sis of a toenail due to Trichophyton rubrum or Trichophyton mentagrophytes by
`
`topical application of the formulation to the toenail.”
`
`47.
`
`
`
`Claim 14 depends from claim 12 and narrows the formulation of
`
`claim 12 to “wherein the ethylene diamine tetraacetic acid (EDTA) or a pharma-
`
`ceutically acceptable salt thereof, is present in a concentration of from about
`
`0.005% to about 2.0% w/w.”
`
`
`48.
`
`Claim 15 depends from claim 14 and narrows the formulation of
`
`claim 14 to “wherein the formulation is suitable for the treatment of onychomyco-
`
`sis of a toenail due to Trichophyton rubrum or Trichophyton mentagrophytes by
`
`topical application of the formulation to the toenail.”
`
`D.
`
` Prosecution History of the ’289 Patent and Related Applications
`
`
`1. The ’289 Patent
`
`
`49.
`
`I understand that the ’289 patent matured from U.S. Patent Applica-
`
`tion No. 15/046,322, which was filed on February 17, 2016, with a request for pri-
`
`oritized examination. (Ex. 1002, at 1-2.) The application received a non-final rejec-
`
`tion on July 6, 2016, rejecting all claims for nonstatutory double-patenting in view
`
`of U.S. Patent Nos. 7,767,657 (subsequently invalidated in IPR2015-01780 and
`
`IPR2015-01785) and 8,889,656. (Id. at 810-812.) After the filing of a terminal dis-
`
`
`
`18
`
`FlatWing Ex. 1005, p. 20
`
`
`
`
`
`Declaration of S. Narasimha Murthy, Ph.D.
`
`claimer, the ’289 patent was allowed and was subsequently issued on February 14,
`
`2017. (Id. at 882-83, 1434.)
`
`2. The ’621 Patent
`
`
`50.
`
`I understand that the ’289 patent claims priority as a continuation-in-
`
`part to U.S. Patent No. 7,582,621 (“the ’621 patent”).
`
`
`51.
`
`I understand that U.S. Patent App. No. 11/357,687, which became the
`
`’621 Patent, was filed on February 16, 2006. (Ex. 1012.) I understand the first sub-
`
`stantive Office Action rejected the pending claims over U.S. Patent No. 5,880,188
`
`to Austin (“the ’188 Patent”) and the definition of “fungicide” from Answers.com.
`
`(Ex. 1013, at 53-55.) The Examiner argued that the ’188 Patent discloses the
`
`claimed 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole for use as an industrial
`
`fungicide. (Id.) I agree. The Examiner further argued that the definition of fungi-
`
`cide from Answers.com discloses that a fungicide can be used for the agricultural
`
`or the pharmaceutical industry. (Id. at 55.) I agree.
`
`
`52.
`
`To overcome this rejection, I understand that the Patent Owner argued
`
`that a POSITA would not choose an industrial fungicide for topical application to a
`
`human because some fungicides are dangerous to humans. Specifically the Patent
`
`Owner argued: “[t]hus, the art teaches that compounds that are useful for killing or
`
`inhibiting fungi may also harm animals. . . . Answers.com thus does not provide a
`
`motivation to modify the teachings of Austin to use any particular oxaborole to
`
`
`
`19
`
`FlatWing Ex. 1005, p. 21
`
`
`
`
`
`Declaration of S. Narasimha Murthy, Ph.D.
`
`treat an animal, and in fact teaches away from such modification.” (Ex. 1013, at
`
`18-19.) Therefore, the Patent Owner argued that a POSITA would be discouraged
`
`from using an industrial fungicide for the topical treatment of fungal infections in
`
`humans. (Id. at 17-19.) I disagree with the Patent Owner’s argument. The Examin-
`
`er relied on the Patent Owner’s argument in deciding to allow the pending claims
`
`which became claims 1-12 the ’621 Patent. (Ex. 1017, at 6-7.)
`
`53.
`
`
`
`All claims of the ’621 Patent were found by the Board to be obvious
`
`and unpatentable in IPR2015-01776 (Ex. 1014).
`
`3. The ’657 Patent
`
`
`54.
`
`I understand that the ’289 Patent claims priority as a continuation to
`
`U.S. Patent No. 7,767,657 (“the ’657 patent”).
`
`
`55.
`
`I understand that U.S. Patent App. No. 11/505,591, which became the
`
`’657 Patent, was filed on August 16, 2006. (Ex. 1015.) I understand the first sub-
`
`stantive Office Action rejected the pending claims over U.S. Patent No. 5,880,188
`
`to Austin (“the ’188 Patent”) and Austin et al. (CAS:124:234024). (Ex.1016, at 38-
`
`41.) The Examiner argued that the ’188 Patent discloses the claimed 1,3- dihydro-
`
`5-fluoro-1-hydroxy-2,1-benzoxaborole for use as a fungicide. (Id.) I agree. The
`
`Examiner further argued that “[o]ne having ordinary skill in the art would find the
`
`claims . . . prima facie obvious because one would be motivated to employ the
`
`compositions of Austin et al. to obtain [the] instant formulation comprising 1,3-
`
`
`
`20
`
`FlatWing Ex. 1005, p. 22
`
`
`
`
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`Declaration of S. Narasimha Murthy, Ph.D.
`
`dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole and pharmaceutical acceptable ex-
`
`cipient.” (Id. at 41.) I agree. The Examiner also argued that “[t]he motivation to
`
`make the claimed compounds derived from the known compounds/compositions
`
`would possess similar activity (i.e., fungicide or treating fungal infection) to that
`
`which is claimed in the reference.” (Id.) I agree.
`
`
`56.
`
`To overcome this rejection, I understand that the Patent Owner argued
`
`that a POSITA would not choose an industrial fungicide for topical application to a
`
`human because some fungicides are dangerous to humans. Specifically, the Patent
`
`Owner argued that “one of skill in the art would not presumptively consider a
`
`compound to be suitable for administration to an animal, especially a human,
`
`merely because a compound has been shown to have antifungal effects in paint or
`
`aviation fuel.” (Ex. 1016, at 24.) The Patent Owner also repeated arguments made
`
`during prosecution of the ’621 Patent, stating “the art teaches that compounds that
`
`are useful for killing or inhibiting fungi may also harm animals, and thus teaches
`
`away from assuming that any fungicide can be used in a pharmaceutical formula-
`
`tion as claimed
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