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 9,572,823
`Issue Date: February 21, 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. 9,572,823
`
`Case No. 2018-00171
`
`
`
`
`
`
`
`
`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 9,572,823
`Issue Date: February 21, 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. 9,572,823
`
`Case No. 2018-00171
`
`
`
`
`
`
`
`
`MYLAN - Ex. 1005, p. 1
`
`
`
`
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`TABLE OF CONTENTS
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`
`
`Introduction ...................................................................................................... 1
`
`
`
`
`I.
`
`
`II.
`
`
`Qualifications and Experience ......................................................................... 1
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`
`
` Materials Considered ....................................................................................... 3 III.
`
`IV.
`
` Statement of Legal Principles .......................................................................... 5
`
`V.
`
`
`
`The ’823 Patent ................................................................................................ 9
`
`VI.
`
` The Pertinent Prior Art .................................................................................. 20
`
`
`
` Claim Construction ........................................................................................ 33 VII.
`
`
`
` Grounds for Unpatentability .......................................................................... 34 VIII.
`
`
`
`
`
`i
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`MYLAN - Ex. 1005, p. 2
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`
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`
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`Declaration of S. Narasimha Murthy, Ph.D.
`
`
`
`
`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
`
`inter partes review of claims of U.S. Patent No. 9,572,823 (the ’823 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
`
`Ph.D. in Pharmaceutics from Bangalore University, India, in 2002. I completed my
`
`postdoctoral research in the department of Molecular and Cellular Biophysics at
`
`Roswell Park Cancer Institute, Buffalo, NY from 2002-2005.
`
`
`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
`
`at Ohio Northern University, Ohio from 2005-2006, and an Assistant Professor of
`
`Pharmaceutics at the University of Mississippi from 2006-2011. I was an Associate
`
`Professor of Pharmaceutics from 2011-2016 at the University of Mississippi and
`
`continuing as Professor of Pharmaceutics and Drug Delivery since 2016 until the
`
`present. I founded the Institute for Drug Delivery and Biomedical Research in
`
`Bangalore, India in 2013.
`
`
`
`1
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`MYLAN - Ex. 1005, p. 3
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`
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`
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`Declaration of S. Narasimha Murthy, Ph.D.
`
`
`4.
`
`I have received numerous research grants directed to the topical ad-
`
`ministration of therapeutics, including “Nail Penetration of Antifungal Drugs”
`
`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
`
`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
`
`Therapeutic Agents (2011) and Topical Nail Products and Ungual Drug Delivery
`
`(2012). I have also authored eleven (11) book chapters directed to topical and other
`
`routes of administration of therapeutics.
`
`
`6.
`
`Since the late 1990s, my research interests have been based on intra-
`
`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.
`
`My CV is attached as Exhibit 1006.
`
`I am competent to make this declaration based upon my personal
`
`knowledge and expertise in the area of product development, drug delivery mecha-
`
`nisms, topical drug formulations, and in vitro and in vivo evaluation of therapeutic
`
`agents to treat onychomycosis and other nail diseases.
`
`
`
`2
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`MYLAN - Ex. 1005, p. 4
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`
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`
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`Declaration of S. Narasimha Murthy, Ph.D.
`
`B.
`
`
`
`Engagement
`
`
`9.
`
`I am being compensated $500 per hour for services I provide in this
`
`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.
`
`
`10.
`
`MATERIALS CONSIDERED
`
`In preparing this Declaration, I reviewed the following documents and
`
`information, and the Petition:
`
`DESCRIPTION
`EXHIBIT
`Ex. 1001 U.S. Patent No. 9,572,823
`
`SHORT FORM
`
`’823 Patent
`
`Ex. 1002 Prosecution History of the ’823 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. 1014
`
`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”)
`
`Samour ’887
`
`‘621 Patent
`
`
`
`
`
`‘657 Patent
`
`
`
`3
`
`MYLAN - Ex. 1005, p. 5
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`
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`
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`Declaration of S. Narasimha Murthy, Ph.D.
`
`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. 1025
`
`Ex. 1026
`
`Ex. 1022 Biobor JF® Material Safety Data Sheet (2004)
`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)
`
`Ex. 1027
`
`Ex. 1028
`
`
`
`4
`
`
`
`
`
`
`
`‘894 Patent
`
`Murdan 2002
`
`
`
`
`
`
`
`
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`
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`MYLAN - Ex. 1005, p. 6
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`
`
`
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`Declaration of S. Narasimha Murthy, Ph.D.
`
`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)
`STATEMENT OF LEGAL PRINCIPLES
`
`
`
`
`
`Mertin 1997
`
`Groziak 2001
`
`
`
`
`
`I am a technical expert and do not offer any legal opinions here. How-
`
`Ex. 1029
`
`Ex. 1030
`
`Ex. 1031
`
`Ex. 1032
`
`Ex. 1033
`
`Ex. 1034
`
`IV.
`
`
`
`
`11.
`
`ever, I understand the framework to be applied for determining invalidity and re-
`
`lated matters. I have applied this framework in developing my technical opinions
`
`expressed in this Declaration.
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`
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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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`A.
`
` Claim Construction
`I understand that in a proceeding for inter partes review, a claim in an
`
`
`12.
`
`unexpired patent is to be given its broadest reasonable construction in light of the
`
`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-
`
`tions, if any.
`
`A.
`
` Obviousness
`
`
`13.
`
`I understand that a claimed invention is unpatentable and invalid as
`
`“obvious” if the differences between the invention and the prior art are such that
`
`the subject matter as a whole would have been obvious at the time the invention
`
`was made to a person having ordinary skill in the art (“POSITA”) to which the
`
`subject matter of the patent pertains. Obviousness, as I understand it, is based on
`
`the scope and content of the prior art, the differences between the prior art and the
`
`claim, the level of ordinary skill in the art at the time of the invention (presumably
`
`the patent application filing date), and secondary indicia of obviousness to the ex-
`
`tent they exist.
`
`
`14.
`
`I understand that obviousness can be established by combining or
`
`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-
`
`standing that where there is a reason to modify or combine the prior art to achieve
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`
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`6
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`MYLAN - Ex. 1005, p. 8
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`
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`Declaration of S. Narasimha Murthy, Ph.D.
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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.
`
`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
`
`art to combine the invalidating references exists. I also understand that this sugges-
`
`tion or motivation may come from such sources as explicit statements in the prior
`
`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
`
`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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`16.
`
`It is also my understanding that determining obviousness can include
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`consideration of unexpected results, commercial success, long felt but unsolved
`
`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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`
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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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`there is any commercial success, in my opinion it is due to factors such as pricing,
`
`advertising and marketing, and not the features in combination.
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`17.
`
`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 ’823 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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`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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`B.
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`
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`Level of Ordinary Skill in the Art
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`19.
`
`I am well-positioned to opine as to what a person having ordinary skill
`
`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
`
`pharmaceutics. I have been a researcher and university professor in the field of
`
`pharmaceutics for over 23 years. In 2005, at the time of filing of the earliest docu-
`
`ment to which the ’823 Patent claims priority, I had almost eleven years of experi-
`
`
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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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`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.
`
`I understand that the level of ordinary skill in the art for a particular
`
`patent may be based on various factors, including the following: (1) type of prob-
`
`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
`
`case, every factor may not be present, and one or more factors may predominate.
`
`
`21.
`
`I believe that a POSITA at the time the ’823 Patent was filed would
`
`have an either a Master’s or Ph.D. degree in chemistry, pharmacology, or biochem-
`
`istry, and at least two years of experience in research, development, or production
`
`of pharmaceuticals.
`
`V.
`
`
`
`
`22.
`
`THE ’823 PATENT
`
`The ’823 Patent describes methods and compounds useful for treating
`
`fungal infections, and more specifically, topical formulations for treatment of ony-
`
`chomycosis and/or cutaneous fungal infections using boron-containing small mol-
`
`ecules. (Ex. 1001, Title, Abstract.) The ’823 Patent’s claims are directed to the use
`
`of such topical formulations for treating onychomycosis caused by Trichophyton
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`rubrum or Trichophyton mentagrophytes.
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`
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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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`A.
`
` Priority Date
`
`
`23.
`
`I understand the earliest claimed priority date for the ’823 Patent is
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`February 16, 2005. (Ex. 1001, p. 2.) However, I have not considered the extent to
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`which the claims of the ’823 Patent, as a continuation-in-part application, are sup-
`
`ported by U.S. Provisional Application No. 60/654,060, filed February 16, 2005, or
`
`any other applications to which the ’823 Patent claims priority.
`
`B.
`
` The ’823 Patent’s Disclosure
`
`
`24.
`
`The ’823 Patent is entitled “Boron-Containing Small Molecules.” (Ex.
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`1001.)
`
`
`25.
`
`In the background, the ’823 Patent cites problems with prior art treat-
`
`ment methods and compounds, such as adverse effects related to long-term oral
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`administration of antifungals, (id. at 1:62-2:13), issues with surgical removal of all
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`or part of the nail, (id. at 2:14-20), and issues with topical treatments, including
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`maintaining nail contact and nail penetration (id. at 2:21-28; id. at 2:35-45).
`
`
`26.
`
`The ’823 Patent discloses a number of potential boron-containing
`
`small molecules but only claims a single compound: 1,3-dihydro-5-fluoro-1- hy-
`
`droxy-2,1-benzoxaborole. (Id. at 317:53-318:63.) The ’823 Patent refers to 1,3-
`
`dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole as “C10.” (Id. at 178:21-28.) The
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`’823 Patent alleges that “C10” is a novel compound. (Id. at 187:8-9.) I disagree be-
`
`
`
`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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`cause 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole (C10) was previously
`
`disclosed as a preferred antifungal compound by Austin. (Ex. 1007, Abstract.)
`
`
`27.
`
`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:
`
`(Id. at 24:5-14; see also Ex. 1022, at 3.)
`
`
`
`
`28.
`
`In addition to referring to 1,3-dihydro-5-fluoro-1-hydroxy-2,1- ben-
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`zoxaborole as C10, the ’823 Patent also refers to this compound as “compound 1.”
`
`(See, e.g., Ex. 1001, 135:51-66.)
`
`
`29.
`
`The ’823 Patent discloses methods of treating ungual and periungual
`
`infections, and more specifically, onychomycosis, using its disclosed compounds.
`
`(Id. at 130:32-40.) The ’823 Patent recognizes that “[o]nychomycosis is a disease
`
`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 129:37-40.) The ’823 Patent alleges that
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`“anti-fungal drugs cannot readily penetrate the nail plate to reach the infection sites
`
`under the nail.” (Id. at 129:67-130:3.) I disagree because Brehove discloses anti-
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`
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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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`fungal drugs capable of treating onychomycosis through topical application to the
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`nail and surrounding skin of a human. (See, e.g., Ex. 1008, Abstract.)
`
`
`30.
`
`The ’823 Patent also discloses methods for determining the antifungal
`
`activity of compounds and the keratin binding properties of compounds. (Ex. 1001,
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`186:44-188:5.) The ’823 Patent admits these methods were well known in the prior
`
`art. (Id. at 186:47-50 (“All MIC testing followed the National Committee for Clin-
`
`ical Laboratory Standards (NCCLS) guidelines for anti- microbial testing of yeasts
`
`. . . and filamentous fungi . . . .”); id. at 186:64-67 (“The affinities of the com-
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`pounds for keratin powder was determined by a method described in Tatsumi, An-
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`timicrobial Agents and Chemotherapy, 46(12): 3797-3801 (2002).”).) I agree. De-
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`termining 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
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`more than routine experimentation.
`
`31.
`
`
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`The ’823 Patent further discloses the determination of solubility, sta-
`
`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 188:7-189:56.) 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-
`
`tine experimentation.
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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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`32.
`
`The ’823 Patent further discloses methods for determining the effica-
`
`cy of nail penetration by antifungal compounds. (Id. at 131:66-132:13; id. at
`
`189:58-194:4.) The ’823 Patent admits these methods were well known in the prior
`
`art. (Id. at 189:61-63 (“Two nail penetration studies were performed based on the
`
`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-
`
`pounds, including antifungal compounds, was well known in the art before Febru-
`
`ary 16, 2005, and is nothing more than routine experimentation.
`
`33.
`
`
`
`The ’823 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-
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`fined herein, does not interfere with the effectiveness of the biological ac-
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`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,
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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
`
`
`
`13
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`MYLAN - Ex. 1005, p. 15
`
`
`
`Declaration of S. Narasimha Murthy, Ph.D.
`
`Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott,
`
`Williams & Wilkins (2005) which is incorporated herein by reference.
`
`(Id. at 12:17-31.) Moreover, the ’823 Patent describes a number of non-toxic,
`
`pharmaceutically 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
`
`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 161:19-29.) I agree. Selecting from among acceptable solvents for formulat-
`
`ing pharmaceutical compositions involves nothing more than routine experimenta-
`
`tion based on well-known protocols.
`
`C.
`
` The ’823 Patent’s Claims
`
`34.
`
`Independent claim 1 recites a “method of delivering a compound, in a
`
`human, from a dorsal layer of a nail plate to a nail bed to treat onychomycosis
`
`caused by Trichophyton rubrum or Trichophyton mentagrophytes, the method
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`14
`
`MYLAN - Ex. 1005, p. 16
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`
`
`Declaration of S. Narasimha Murthy, Ph.D.
`
`comprising: contacting the dorsal layer of the nail plate with a pharmaceutical
`
`composition comprising a compound that penetrates the nail plate, the compound
`
`being 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole or a pharmaceutically
`
`acceptable salt thereof, thereby treating onychomycosis due to Trichophyton
`
`rubrum or Trichophyton mentagrophytes.” 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; Ex.
`
`1027.)
`
`35.
`
`Claim 2 depends from claim 1 and narrows the method of claim 1 to
`
`“wherein the pharmaceutical composition is in the form of a topical solution com-
`
`prising 5% w/w of 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole, and where-
`
`in the pharmaceutical composition further comprises ethanol and propylene gly-
`
`col.”
`
`36.
`
`Claim 3 depends from claim 1 and narrows the method of claim 1 to
`
`“wherein the pharmaceutical composition further comprises ethanol and propylene
`
`glycol.”
`
`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-
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`benzoxaborole; 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole; 5-fluoro
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`benzoxaborole; tavaborole; AN-2690.
`
`15
`
`MYLAN - Ex. 1005, p. 17
`
`
`
`Declaration of S. Narasimha Murthy, Ph.D.
`
`37.
`
`Claim 4 depends from claim 1 and narrows the method of claim 1 to
`
`“wherein the contacting of the dorsal layer of the nail plate with the pharmaceutical
`
`composition occurs once a day.”
`
`38.
`
`Claim 5 depends from claim 1 and narrows the method of claim 1 to
`
`“wherein a cause of the onychomycosis is due to Trichophyton rubrum.”
`
`39.
`
`Claim 6 depends from claim 1 and narrows the method of claim 1 to
`
`“wherein a cause of the onychomycosis is due to Trichophyton mentagrophytes.”
`
`D.
`
` Prosecution History of the ’823 Patent and Related Applications
`
`1. The ’823 Patent
`
`40.
`
`I understand that the ’823 patent matured from U.S. Patent Applica-
`
`tion No. 15/091,394, which was filed on April 5, 2016, with a request for priori-
`
`tized examination. (Ex. 1002, at 1-2.) The application received a non-final rejec-
`
`tion 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 1006-10.) After the fil-
`
`ing of a terminal disclaimer, the ’823 patent was allowed and was subsequently is-
`
`sued on February 21, 2017. (Id. at 1108-15.)
`
`2. The ‘621 Patent
`
`41.
`
`I understand that the ’823 patent claims priority as a continuation-in-
`
`part to U.S. Patent No. 7,582,621 (“the ‘621 patent”).
`
`16
`
`MYLAN - Ex. 1005, p. 18
`
`
`
`
`
`Declaration of S. Narasimha Murthy, Ph.D.
`
`
`42.
`
`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.
`
`
`43.
`
`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 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-
`
`
`
`17
`
`MYLAN - Ex. 1005, p. 19
`
`
`
`
`
`Declaration of S. Narasimha Murthy, Ph.D.
`
`er relied on the Patent Owner’s argument in deciding to allow the pending claims
`
`which became claims 1-12 the ‘621 Patent. (Id. at 6-7.)
`
`44.
`
`
`
`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
`
`
`45.
`
`I understand that the ’823 Patent claims priority as a continuation to
`
`U.S. Patent No. 7,767,657 (“the ‘657 patent”).
`
`
`46.
`
`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-
`
`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
`
`
`
`18
`
`MYLAN - Ex. 1005, p. 20
`
`
`
`
`
`Declaration of S. Narasimha Murthy, Ph.D.
`
`would possess similar activity (i.e., fungicide or treating fungal infection) to that
`
`which is claimed in the reference.” (Id.) I agree.
`
`
`47.
`
`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.” (Id. at 25.) Therefore, the Patent Owner again argued that a
`
`POSITA would be discouraged from using an industrial fungicide for the topical
`
`treatment of fungal infections in humans. (Id. at 23-25.) I disagree with the Patent
`
`Owner’s argument.
`
`
`48.
`
`In response to a rejection under Section 112, paragraph 1, I under-
`
`stand the Patent Owner argued that the claims were “fully enabled by the specifica-
`
`tion coupled with knowledge in the art” and that “formulations may be made based
`
`on excipients, additives and methods known in the art.” (Id. at 22.)
`
`
`
`19
`
`MYLAN - Ex. 1005, p. 21
`
`
`
`
`
`Declaration of S. Narasimha Murthy, Ph.D.
`
`
`49.
`
`The Examiner relied on the Patent Owner’s argument in deciding to
`
`allow the pending claims which became claims 1-24 the ‘657 Patent. (Id. at 6-7.)
`
`50.
`
`
`
`All claims of the ‘657 Patent were found by the Board to be obvious
`
`and unpatentable in IPR2015-01780 and IPR2015-01785 (Ex. 1017 & Ex. 1018).
`
`VI.
`
`
`
`THE PERTINENT PRIOR ART
`
`A.
`
` Patent Cooperation Treaty Pub. No. WO 1995/033754 to Austin et
`al. (“Austin”)
`
`51.
`
`
`
`1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole
`
`(hereinafter,
`
`“tavaborole”) was not a novel compound in February of 2005, as the ’823 Patent
`
`claims. In fact, tavaborole was not only known, but was disclosed as a “preferred”
`
`fungicide. Specifically, Austin discloses tavaborole (referred to in Austin as 5-
`
`fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole and 5-fluoro benzoxaborole) as a
`
`preferred fungicide. (Ex. 1007, Abstract.) Austin further discloses that compounds
`
`containing an “oxaborole ring” are “particularly effective” as fungicides. (Id. at
`
`3:35-40.) The “preferred” oxaborole ring compounds disclosed by Austin are “5-
`
`and 6-fluoro or bromo- 1,3-dihydro-1-hydroxy-2,1- benzoxaborole.” (Id. at Ab-
`
`stract.) 5-fluoro-1,3-dihydro-1-hydroxy-2,1- benzoxaborole is the compound recit-
`
`ed in claims 1-6 of the ’823 Patent, which I refer to as tavaborole.
`
`52.
`
`
`
`Austin discloses how to prepare various benzoxaborole derivatives
`
`which include the compound of claims 1-6 of the ’823 Patent. (Id. at 24:1-15.) Aus-
`
`
`
`20
`
`MYLAN - Ex. 1005, p. 22
`
`
`
`
`
`Declaration of S. Narasimha Murthy, Ph.D.
`
`tin discloses the preparation of benzoxaborole derivatives having the following
`
`general structure, where R8 represents one or more substituents in the phenyl ring:
`
`
`(Id.; id. at 38:15-26.) Example 64 of Austin is tavaborole, namely, where R9 is hy-
`
`drogen and R8 is a single fluorine at the 5 position of the phenyl ring. For example,
`
`Austin discloses the melting point and elemental analysis of tavaborole in Table 5
`
`at Example 64. (Id. at 25, Table 5.)
`
`
`53.
`
`Importantly, Austin teaches that tavaborole, the compound of claims
`
`1-6 in the ’823 Patent, has strong antifungal activity. (Id. at 39, Table 9.) For exam-
`
`ple, the antifungal activity of tavaborole is disclosed in Table 9 at Example 64.
`
`(Id.) Table 9 discloses that tavaborole is an effective antifungal agent against each
`
`of the five (5) fungi tested: Aspergillus niger (AN); Aureobasidium pullulans (AP);
`
`Candida albicans (CA); Gliocladium roseum (GR); and Penicillium pinophylum
`
`(PP). (Id. at 38–39.)
`
`
`54.
`
`Tavaborole is effective ag
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