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 9,566,290
`Issue Date: February 14, 2017
`
`Title: Boron-Containing Small Molecules
`
`
`
`DECLARATION OF NARASIMHA MURTHY, PH.D
`IN SUPPORT OF PETITION FOR INTER PARTIES
`REVIEW OF U.S. PATENT NO. 9,566,290
`
`Case No. 2018-00170
`
`
`
`
`
`
`
`
`MYLAN - Ex. 1005, p. 1
`
`
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`FlatWing Pharmaceuticals, LLC
`
`Petitioner
`
`v.
`
`Anacor Pharmaceuticals Inc.
`
`Patent Owner
`
`Patent No. US 9,566,290
`Issue Date: February 14, 2017
`
`Title: Boron-Containing Small Molecules
`
`
`
`DECLARATION OF NARASIMHA MURTHY, PH.D
`IN SUPPORT OF PETITION FOR INTER PARTIES
`REVIEW OF U.S. PATENT NO. 9,566,290
`
`Case No. 2018-00170
`
`
`
`
`
`
`
`
`MYLAN - Ex. 1005, p. 1
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`TABLE OF CONTENTS
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`
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`Introduction ...................................................................................................... 1
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`
`
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`I.
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`II.
`
`
`Qualifications and Experience ......................................................................... 1
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`
`
` Materials Considered ....................................................................................... 3 III.
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`IV.
`
` Statement of Legal Principles .......................................................................... 6
`
`V.
`
`
`
`The ’290 Patent .............................................................................................. 10
`
`VI.
`
` The Pertinent Prior Art .................................................................................. 22
`
`
`
` Claim Construction ........................................................................................ 35 VII.
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`
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` Grounds for Unpatentability .......................................................................... 36 VIII.
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`
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`
`
`i
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`MYLAN - Ex. 1005, p. 2
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`Declaration of S. Narasimha Murthy, Ph.D.
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`
`I.
`
`INTRODUCTION
`
`
`1.
`
`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
`
`inter partes review of claims of U.S. Patent No. 9,566,290 (the ’290 Patent).
`
`
`II.
`
`QUALIFICATIONS AND EXPERIENCE
`
`A. Background and Work Experience
`I received a Bachelor of Pharmacy from Bangalore University, India, in
`
`
`2.
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`1992, a Master of Pharmacy from Bangalore University, India, in 1994, and a Ph.D.
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`in Pharmaceutics from Bangalore University, India, in 2002. I completed my post-
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`doctoral research in the department of Molecular and Cellular Biophysics at Roswell
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`Park Cancer Institute, Buffalo, NY from 2002-2005.
`
`
`3.
`
`I was an Assistant Professor of Pharmaceutics at the M.S.R. College of
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`Pharmacy, India from 1994-2002. I was an Assistant Professor of Pharmaceutics at
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`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 Ban-
`
`galore, India in 2013.
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`
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`1
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`MYLAN - 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 admin-
`
`istration of therapeutics, including “Nail Penetration of Antifungal Drugs” sponsored
`
`by Arno Therapeutics (2014-15), “Bioadhesive Properties of Nail Lacquers” spon-
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`sored by Chanelle Group, France (2010), “Rapid Transdermal Delivery of Drugs”
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`sponsored by Transport Pharmaceuticals Inc. (2008-09), and “Electret Effects on the
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`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.
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`
`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.
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`
`7.
`
`
`8.
`
`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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`MYLAN - Ex. 1005, p. 4
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`Declaration of S. Narasimha Murthy, Ph.D.
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`Engagement
`
`B.
`I am being compensated $500 per hour for services I provide in this
`
`
`9.
`
`case, and $1000 per day if travel is required. This compensation is not contingent
`
`upon my performance, the outcome of this petition for inter partes review, or any
`
`issues involved in or relating to this petition for inter partes review.
`
`
`III.
`
`MATERIALS CONSIDERED
`
`
`10.
`
`In preparing this Declaration, I reviewed the following documents and
`
`information, and the Petition:
`
`DESCRIPTION
`EXHIBIT
`Ex. 1001 U.S. Patent No. 9,566,290
`
`SHORT FORM
`
`‘290 Patent
`
`Ex. 1002 Prosecution History of the ‘290 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. 1012 U.S. Patent No. 7,582,621
`
`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. 1015 U.S. Patent No. 7,767,657 (“the ‘657 Patent”)
`
`Ex. 1014
`
`Samour ‘887
`
`‘621 Patent
`
`
`
`
`
`‘657 Patent
`
`
`
`3
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`MYLAN - Ex. 1005, p. 5
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`
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`Declaration of S. Narasimha Murthy, Ph.D.
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`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. 1025
`
`Ex. 1026
`
`Ex. 1027
`
`Ex. 1028
`
`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)
`Meds. & Healthcare Prods. Regulatory Agency,
`Curanail 5% Nail Lacquer (Amorolfine Hydrochlo-
`ride) PL 10590/0049, UK Public Assessment Re-
`port (approved July 4, 2006)
`
`4
`
`
`
`
`
`
`
`‘894 Patent
`
`Murdan 2002
`
`
`
`
`
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`MYLAN - Ex. 1005, p. 6
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`Declaration of S. Narasimha Murthy, Ph.D.
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`Ex. 1029
`
`Ex. 1030
`
`Ex. 1031
`
`Ex. 1032
`
`Ex. 1033
`
`Ex. 1034
`
`Ex. 1036
`
`Ex. 1037
`
`Ex. 1038
`
`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)
`Alley, Michael R. et al. “Recent progress on the
`topical therapy of onychomycosis.” Expert Opinion
`on Investigational Drugs 16, no. 2 (2007): 157-167
`Rock, Fernando L. et al. “An Antifungal agent in-
`hibits an aminoacyl-tRNA synthetase by trapping
`tRNA in the editing site.” Science 316 (2007):1759-
`1761
`Queller, Jenna N. & Bhatia, Neal. “The dermatolo-
`gist’s approach to onychomycosis,” Journal of
`Fungi 1 (2015): 173-184
`
`
`
`
`
`Mertin 1997
`
`Groziak 2001
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`
`
`
`
`Alley 2007
`
`Rock 2007
`
`Queller 2015
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`5
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`MYLAN - Ex. 1005, p. 7
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`Declaration of S. Narasimha Murthy, Ph.D.
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`Ex. 1039
`
`Elewski, Boni E. et al. “Efficacy and safety of
`tavaborole topical solution 5%, a novel boron-based
`antifungal agent, for the treatment of toenail ony-
`chomycosis; Results from 2 randomized phase-III
`studies.” Journal of American Academic Dermatol-
`ogy 73, no. 1 (2015): 62-69
`Ex. 1040 FDA Medical Review of NDA 240-427
`Ex. 1041 FDA Clinical Pharmacology and Biopharmaceutics
`Review(s) of NDA 240-427
`
`Ex. 1042 NDA 240-427 Product Label
`
`Elewski 2015
`
`
`
`
`
`
`
`IV.
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`
`
`STATEMENT OF LEGAL PRINCIPLES
`
`
`11.
`
`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 related
`
`matters. I have applied this framework in developing my technical opinions ex-
`
`pressed in this Declaration.
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`A. Claim Construction
`I understand that in a proceeding for inter partes review, a claim in an
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`12.
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`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
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`my analysis and opinions in view of the Patent Owner’s proposed claim construc-
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`tions, if any.
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`B. Obviousness
`I understand that a claimed invention is unpatentable and invalid as
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`
`13.
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`“obvious” if the differences between the invention and the prior art are such that the
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`6
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`MYLAN - Ex. 1005, p. 8
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`Declaration of S. Narasimha Murthy, Ph.D.
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`subject matter as a whole would have been obvious at the time the invention was
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`made to a person having ordinary skill in the art (“POSITA”) to which the subject
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`matter of the patent pertains. Obviousness, as I understand it, is based on the scope
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`and content of the prior art, the differences between the prior art and the claim, the
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`level of ordinary skill in the art at the time of the invention (presumably the patent
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`application filing date), and secondary indicia of obviousness to the extent they ex-
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`ist.
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`14.
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`I understand that obviousness can be established by combining or modi-
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`fying the teachings of the prior art to achieve the claimed invention when there is a
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`reason to make such a combination or modification. It is also my understanding that
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`where there is a reason to modify or combine the prior art to achieve the claimed
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`invention (i.e., a motivation to combine), there must also be a reasonable expectation
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`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 teaching,
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`suggestion, or motivation that would have led a person ordinarily skilled in the art to
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`combine the invalidating references exists. I also understand that this suggestion or
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`motivation may come from such sources as explicit statements in the prior art or
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`from the knowledge of one of ordinary skill in the art. Alternatively, any need or
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`problem known in the field at the time and addressed by the patent may provide a
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`reason for combining elements of the prior art. I also understand that when there is a
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`7
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`MYLAN - Ex. 1005, p. 9
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`Declaration of S. Narasimha Murthy, Ph.D.
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`design need or market pressure and a finite number of predictable solutions, a person
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`of ordinary skill in the art may be motivated to apply his skill and common sense in
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`trying to combine the known options in order to solve the problem.
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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 that,
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`in order to be relevant to the issue of obviousness, such factors must have some con-
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`nection or nexus to the claimed invention. In my opinion, there are no unexpected
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`results of the claimed combinations, and no long-felt but unresolved needs, no fail-
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`ure of others to achieve the claimed combination. To the extent that there is any
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`commercial success, in my opinion it is due to factors such as pricing, advertising
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`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-
`
`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 ’290 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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`8
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`MYLAN - Ex. 1005, p. 10
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`Declaration of S. Narasimha Murthy, Ph.D.
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`have knowledge of all pertinent art at the time of the invention. The person of ordi-
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`nary skill in the art is one who thinks along the lines of conventional wisdom in the
`
`art.
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`C. Level of Ordinary Skill in the Art
`I am well-positioned to opine as to what a person having ordinary skill
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`
`19.
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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 ’290 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
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`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 pa-
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`tent may be based on various factors, including the following: (1) type of problems
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`encountered in the art; (2) prior art solutions to those problems; (3) rapidity with
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`which innovations are made; (4) sophistication of the technology; and (5) education-
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`al level of active workers in the field. I further understand that in a given case, every
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`factor may not be present, and one or more factors may predominate.
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`21.
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`I believe that a POSITA at the time the ’290 Patent was filed would
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`have an either a Master’s or Ph.D. degree in chemistry, pharmacology, or biochemis-
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`9
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`MYLAN - Ex. 1005, p. 11
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`Declaration of S. Narasimha Murthy, Ph.D.
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`try, and at least two years of experience in research, development, or production of
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`pharmaceuticals.
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`V.
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`
`
`THE ’290 PATENT
`
`
`22.
`
`The ’290 Patent describes methods and compounds useful for treating
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`fungal infections, and more specifically, topical formulations for treatment of ony-
`
`chomycosis and/or cutaneous fungal infections using boron-containing small mole-
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`cules. (Ex. 1001, Title, Abstract.) The ’290 Patent’s claims are directed to the use of
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`such topical formulations for treating onychomycosis caused by Trichophyton
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`rubrum or Trichophyton mentagrophytes.
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`Priority Date
`
`A.
`I understand the earliest claimed priority date for the ’290 Patent is Feb-
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`23.
`
`
`
`ruary 16, 2005. (Ex. 1001, p. 2.) However, I have not considered the extent to which
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`the claims of the ’290 Patent, as a continuation-in-part application, are supported by
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`U.S. Provisional Application No. 60/654,060, filed February 16, 2005, or any other
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`applications to which the ’290 Patent claims priority.
`
`The ’290 Patent’s Disclosure
`
`B.
`The ’290 Patent is entitled “Boron-Containing Small Molecules.” (Ex.
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`24.
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`
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`1001.)
`
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`25.
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`In the background, the ’290 Patent cites problems with prior art treat-
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`ment methods and compounds, such as adverse effects related to long-term oral ad-
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`10
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`MYLAN - Ex. 1005, p. 12
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`Declaration of S. Narasimha Murthy, Ph.D.
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`ministration of antifungals, (id. at 1:62-2:13), issues with surgical removal of all or
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`part of the nail, (id. at 2:14-20), and issues with topical treatments, including main-
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`taining nail contact and nail penetration (id. at 2:21-28; id. at 2:35-45).
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`26.
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`The ’290 Patent discloses a number of potential boron-containing small
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`molecules but only claims a single compound: 1,3-dihydro-5-fluoro-1- hydroxy-2,1-
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`benzoxaborole. (Id. at 321:25-322:43.) The ‘290 Patent refers to 1,3-dihydro-5-
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`fluoro-1-hydroxy-2,1-benzoxaborole as “C10.” (Id. at 179:60-67.) The ’290 Patent
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`alleges that “C10” is a novel compound. (Id. at 189:29-30.) I disagree because 1,3-
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`dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole (C10) was previously disclosed as a
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`preferred antifungal compound by Austin. (Ex. 1007, Abstract.)
`
`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 22:5-14; 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- benzox-
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`aborole as C10 in section 4.2.j of the specification (id. at 179:60-67), the ’290 Patent
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`11
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`MYLAN - Ex. 1005, p. 13
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`Declaration of S. Narasimha Murthy, Ph.D.
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`also refers to this compound as “compound 1.” (See, e.g., Ex. 1001, 137:4-20.) The
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`same compound is also disclosed in Figure 19A of the ’290 Patent as compound No.
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`2. (Id. at p. 61.)
`
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`29.
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`The ’290 Patent discloses methods of treating ungual and periungual in-
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`fections, and more specifically, onychomycosis, using its disclosed compounds. (Id.
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`at 130:44-54.) The ’290 Patent recognizes that “[o]nychomycosis is a disease of the
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`nail caused by yeast, dermatophytes, or other molds, and represents approximately
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`50% of all nail disorders.” (Id. at 130:50-53.) The ’290 Patent alleges that “anti-
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`fungal drugs cannot readily penetrate the nail plate to reach the infection sites under
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`the nail.” (Id. at 131:14-15.) I disagree because Brehove discloses antifungal drugs
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`capable of treating onychomycosis through topical application to the nail and sur-
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`rounding skin of a human. (See, e.g., Ex. 1008, Abstract.)
`
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`30.
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`The ’290 Patent further discloses methods of inhibiting microorganism
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`growth or killing microorganisms by contacting the microorganism with an inhibitor
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`of a tRNA synthetase. (Ex. 1001, 126:63-127:3.) The ’290 Patent describes tRNA
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`synthetase as follows:
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`Aminoacyl-tRNA synthetases (ARS) are a family of essential enzymes that
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`attach amino acids to the 3’ terminal adenosine end of tRNAs, the charged
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`tRNAs are then used by the translation machinery to synthesis proteins from
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`mRNA.
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`12
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`MYLAN - Ex. 1005, p. 14
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`Declaration of S. Narasimha Murthy, Ph.D.
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`(Id. at 3:8-12.) Specifically, the ’290 Patent discloses inhibiting or killing microor-
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`ganisms often responsible for onychomicosis, e.g., Candida species yeasts, Tri-
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`chophyton mentagrophytes, and Trichophyton rubrum. (Id. at 127:44-128:4.) The
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`’290 Patent further specifically discloses its method using as tRNA synthetase in-
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`hibitors the compounds listed in the ’290 Patent, including 1,3-dihydro-5-fluoro-1-
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`hydroxy-2,1-benzoxaborole (i.e., a compound described in Fig. 19 of the patent).
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`(Id. at 127:16-30.) In support of this disclosure, the ’290 Patent describes studies to
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`determine the mechanism of action of 1,3-dihydro-5-fluoro-1-hydroxy-2,1-
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`benzoxaborole in the model fungi Saccharomyces cerevisiae. (Id. at 225:46-
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`232:31.) The study concluded that CDC60 (i.e., leucyl-tRNA synthetase) was the
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`likely target for 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole. (Id. at 226:4-
`
`15.) The ‘290 Patent further discloses an assay for determining that 1,3-dihydro-5-
`
`fluoro-1-hydroxy-2,1-benzoxaborole inhibits fungal tRNA synthetase. (Id. at
`
`233:37-234:17.)
`
`31.
`
`
`
`The ’290 Patent also discloses methods for determining the antifungal
`
`activity of compounds and the keratin binding properties of compounds. (Ex. 1001,
`
`188:62-190:26.) The ’290 Patent admits these methods were well known in the prior
`
`art. (Id. at 189:63-65 (“All MIC testing followed the National Committee for Clini-
`
`cal Laboratory Standards (NCCLS) guidelines for anti- microbial testing of yeasts . .
`
`. and filamentous fungi . . . .”); id. at 189:17-20 (“The affinities of the compounds
`
`
`
`13
`
`MYLAN - Ex. 1005, p. 15
`
`
`
`
`
`Declaration of S. Narasimha Murthy, Ph.D.
`
`for keratin powder was determined by a method described in Tatsumi, Antimicrobial
`
`Agents and Chemotherapy, 46(12): 3797-3801 (2002).”).) I agree. Determining the
`
`antifungal activity of compounds and the keratin binding properties of compounds
`
`was well known in the art before February 16, 2005, and is nothing more than rou-
`
`tine experimentation.
`
`32.
`
`
`
`The ’290 Patent further discloses the determination of solubility, stabil-
`
`ity, and log P values for compounds, specifically 1,3-dihydro-5-fluoro-1- hydroxy-
`
`2,1-benzoxaborole. (Id. at 190:28-192:13.) The determination of solubility, stability,
`
`and log P values for a compound under consideration for topical application was
`
`standard practice before February 16, 2005, and is nothing more than routine exper-
`
`imentation.
`
`33.
`
`
`
`The ’290 Patent further discloses methods for determining the efficacy
`
`of nail penetration by antifungal compounds. (Id. at 133:14-28; id. at 192:14-
`
`196:43.) The ’290 Patent admits these methods were well known in the prior art. (Id.
`
`at 192: 19-22 (“Two nail penetration studies were performed based on the protocol
`
`in Hui et al., Journal of Pharmaceutical Sciences, 91(1):189-195 (2002) (‘Hui proto-
`
`col’).”).) I agree. Determining the efficacy of nail penetration by compounds, includ-
`
`ing antifungal compounds, was well known in the art before February 16, 2005, and
`
`is nothing more than routine experimentation.
`
`
`
`14
`
`MYLAN - Ex. 1005, p. 16
`
`
`
`
`
`Declaration of S. Narasimha Murthy, Ph.D.
`
`
`34.
`
`The ’290 Patent admits that formulating pharmaceutical compositions
`
`was well known in the art of cosmetics and topical pharmaceuticals:
`
`The term “pharmaceutically acceptable carrier” or “pharmaceutically ac-
`
`ceptable vehicle” refers to any formulation or carrier medium that provides
`
`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-
`
`tient. Representative carriers include water, oils, both vegetable and mineral,
`
`cream bases, lotion bases, ointment bases and the like. These bases include
`
`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,
`
`Williams & Wilkins (2005) which is incorporated herein by reference.
`
`(Id. at 12:7-22.) Moreover, the ’290 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
`
`recognize various synthetic methodologies that may be employed to prepare
`
`
`
`15
`
`MYLAN - Ex. 1005, p. 17
`
`
`
`Declaration of S. Narasimha Murthy, Ph.D.
`
`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-
`
`ates of the compounds of the invention, such as water, ethanol, propylene
`
`glycol, mineral oil, vegetable oil and dimethylsulfoxide (DMSO).
`
`(Id. at 162:33-44.) I agree. Selecting from among acceptable solvents for formulat-
`
`ing pharmaceutical compositions involves nothing more than routine experimenta-
`
`tion based on well-known protocols.
`
`The ’290 Patent’s Claims
`
`C.
`Independent claim 1 recites a “method of treating a human having ony-
`
`35.
`
`chomycosis of a toenail caused by Trichophyton rubrum or Trichophyton men-
`
`tagrophytes, the method comprising: topically administering to the toenail a phar-
`
`maceutical composition comprising an amount of 1,3-dihydro-5-fluoro-1-hydroxy-
`
`2,1-benzoxaborole or a pharmaceutically acceptable salt thereof, effective to inhibit
`
`an aminoacyl tRNA synthetase in the Trichophyton rubrum or Trichophyton men-
`
`tagrophytes.” A short name for 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole
`
`is tavaborole.1 (See, e.g., Ex. 1007, at 9:31-34.)
`
`1 This declaration uses interchangeably the following names for the compound
`
`recited in the claims of the ’290 Patent: 1,3-dihydro-5-fluoro-1-hydroxy-2,1-
`
`16
`
`MYLAN - Ex. 1005, p. 18
`
`
`
`Declaration of S. Narasimha Murthy, Ph.D.
`
`36.
`
`Claim 2 depends from claim 1 and narrows the method of claim 1 to
`
`“wherein the pharmaceutical composition is in the form of a solution comprising 5%
`
`w/w of 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole or a pharmaceutically
`
`acceptable salt thereof.”
`
`37.
`
`Claim 3 depends from claim 1 and narrows the method of claim 1 to
`
`“wherein the pharmaceutical composition further comprises ethanol and propylene
`
`glycol.”
`
`38.
`
`Claim 4 depends from claim 1 and narrows the method of claim 1 to
`
`“wherein the aminoacyl tRNA synthetase is leucyl tRNA synthetase.
`
`39.
`
`Claim 5 depends from claim 4 and narrows the method of claim 4 to
`
`“The method of claim 1, wherein a cause of the onychomycosis is due to Tri-
`
`chophyton rubrum.”
`
`40.
`
`Claim 6 depends from claim 5 and narrows the method of claim 5 to
`
`“wherein a cause of the onychomycosis is due to Trichophyton mentagrophytes.”
`
`41.
`
`Claim 7 depends from claim 1 and narrows the method of claim 1 to
`
`“wherein the administering of the pharmaceutical composition occurs once a day.”
`
`42.
`
`Claim 8 depends from claim 6 and narrows the method of claim 6 to
`
`“wherein the administering of the pharmaceutical composition occurs once a day.”
`
`benzoxaborole; 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole; tavaborole;
`
`tavaborole; AN-2690.
`
`17
`
`MYLAN - Ex. 1005, p. 19
`
`
`
`Declaration of S. Narasimha Murthy, Ph.D.
`
`43.
`
`Claim 9 depends from claim 1 and narrows the method of claim 1 to
`
`“wherein the method inhibits an aminoacyl tRNA synthetase in Trichophyton
`
`rubrum.”
`
`44.
`
`Claim 10 depends from claim 1 and narrows the method of claim 1 to
`
`“wherein the method inhibits an aminoacyl tRNA synthetase in Trichophyton men-
`
`tagrophytes.”
`
`45.
`
`Claim 11 depends from claim 6 and narrows the method of claim 6 to
`
`“wherein the method inhibits an aminoacyl tRNA synthetase in Trichophyton
`
`rubrum.”
`
`46.
`
`Claim 11 depends from claim 6 and narrows the method of claim 6 to
`
`“wherein the method inhibits an aminoacyl tRNA synthetase in Trichophyton men-
`
`tagrophytes.”
`
`D.
`
`47.
`
`Prosecution History of the ’290 Patent and Related
`Applications
`The ’290 Patent
`
`E.
`I understand that the ’290 patent matured from U.S. Patent Application
`
`No. 15/134,286, which was filed on April 20, 2016, with a request for prioritized
`
`examination. (Ex. 1002, at 1-2.) The application received a non-final rejection on
`
`October 11, 2016, rejecting all claims for nonstatutory double-patenting in view of
`
`U.S. Patent Nos. 7,582,621 (subsequently invalidated in IPR2015-01776) and
`
`8,889,656 and various co-pending applications. (Id. at 1002-05.) After the filing of a
`
`18
`
`MYLAN - Ex. 1005, p. 20
`
`
`
`Declaration of S. Narasimha Murthy, Ph.D.
`
`terminal disclaimer, the ’290 patent was allowed and was subsequently issued on
`
`February 14, 2017. (Id. at 1091-93, 1143.)
`
`The ‘621 Patent
`
`F.
`I understand that the ’290 patent claims priority as a continuation-in-
`
`48.
`
`part to U.S. Patent No. 7,582,621 (“the ‘621 patent”).
`
`49.
`
`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 fungicide from An-
`
`swers.com discloses that a fungicide can be used for the agricultural or the pharma-
`
`ceutical industry. (Id. at 55.) I agree.
`
`50.
`
`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 treat
`
`19
`
`MYLAN - Ex. 1005, p. 21
`
`
`
`Declaration of S. Narasimha Murthy, Ph.D.
`
`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 us-
`
`ing 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 Examiner 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.)
`
`51.
`
`All claims of the ‘621 Patent were found by the Board to be obvious
`
`and unpatentable in IPR2015-01776 (Ex. 1014).
`
`G. The ‘657 Patent
`I understand that the ’290 Patent claims priority as a continuation to
`
`52.
`
`U.S. Patent No. 7,767,657 (“the ‘657 patent”).
`
`53.
`
`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 substan-
`
`tive 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 Exam-
`
`iner 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-dihydro-5-fluoro-
`
`20
`
`MYLAN - Ex. 1005, p. 22
`
`
`
`Declaration of S. Narasimha Murthy, Ph.D.
`
`1-hydroxy-2,1-benzoxaborole and pharmaceutical acceptable excipient.” (Id. at 41.)
`
`I agree. The Examiner also argued that “[t]he motivation to make the claimed com-
`
`pounds 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.
`
`54.
`
`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 com-
`
`pound to be suitable for administration to an animal, especially a human, merely
`
`because a compound has been shown to have antifungal
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