throbber
Filed on behalf of Petitioner COALITION FOR AFFORDABLE DRUGS X LLC
`
`
`By: Jeffrey D. Blake, Esq.
` MERCHANT & GOULD P.C.
`
`191 Peachtree Street N.E., Suite 4300
` Atlanta, GA 30303
`
`jblake@merchantgould.com
` Main Telephone: (404) 954-5100
` Main Facsimile: (404) 954-5099
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`___________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
`
`COALITION FOR AFFORDABLE DRUGS X LLC,
`Petitioner,
`
`v.
`
`ANACOR PHARMACEUTICALS, INC.,
`Patent Owner.
`___________________
`Case No.: Unassigned
`Patent No.: 7,582,621
`________________________________________________________
`
`DECLARATION OF S. NARASIMHA MURTHY PH.D. IN SUPPORT OF
`PETITION FOR INTER PARTES REVIEW OF PATENT NO. 7,582,621
`
`CFAD Exhibit 1008
`
`
`
`
`
`

`
`Declaration of S. Narasimha Murthy, Ph.D.
`Inter Partes Review of Patent No. 7,582,621
`
`I, S. Narasimha Murthy, Ph.D., hereby state the following:
`
`I.
`
`INTRODUCTION
`
`1.
`
`This declaration provides my expert opinions in support of the above-
`
`captioned petition for inter partes review (“IPR”) of U.S. Patent No. 7,582,621
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`(“the ’621 Patent”) filed by the Coalition For Affordable Drugs X LLC (“CFAD”),
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`which challenges the patentability of claims 1-12 of the ’621 Patent.
`
`2.
`
`I have been asked to prepare a written declaration including comments
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`related to the Petition regarding whether the claims of the ’621 Patent are
`
`unpatentable because they would have been obvious in view of the publications
`
`cited herein. This Declaration sets forth the bases and reasons for my opinions.
`
`3.
`
`This Declaration is based on information currently available to me. I
`
`reserve the right to continue my investigation and analysis, which may include a
`
`review of documents and information not yet produced. I further reserve the right
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`to expand or otherwise modify my opinions and conclusions as my investigation
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`and study continues, and to supplement my opinions and conclusions in response
`
`to any additional information that becomes available to me.
`
`II.
`
`BACKGROUND AND EXPERIENCE
`
`4.
`
`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
`
`
`
`2
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`

`
`Declaration of S. Narasimha Murthy, Ph.D.
`Inter Partes Review of Patent No. 7,582,621
`
`my postdoctoral research in the department of Molecular and Cellular Biophysics
`
`at Roswell Park Cancer Institute, Buffalo, NY from 2002-2005.
`
`5.
`
`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, University, MS from 2006-2011. I
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`have been an Associate Professor of Pharmaceutics at the University of
`
`Mississippi, University, MS from 2011 until the present and I founded the Institute
`
`for Drug Delivery and Biomedical Research in Bangalore, India in 2013.
`
`6.
`
`I have received numerous research grants directed to the topical
`
`administration of therapeutics, including “Nail Penetration of Antifungal Drugs”
`
`sponsored by Arno Therapeutics (2014-15), “Rapid Transdermal Delivery of
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`Drugs” sponsored by Transport Pharmaceuticals Inc. (2008-09), and “Electric
`
`Effects on the Skin Permeability” sponsored by Rad Elec. Inc. (2005-06).
`
`7.
`
`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 administration of therapeutics.
`
`8.
`
`Since the late 1990s, my research interests have been based on
`
`intradermal, transdermal, and ungual (nail) drug delivery. My research has resulted
`
`
`
`3
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`

`
`Declaration of S. Narasimha Murthy, Ph.D.
`Inter Partes Review of Patent No. 7,582,621
`
`in 85 publications peer reviewed journals.
`
`9. My CV is attached as Exhibit 1009.
`
`10.
`
`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
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`mechanisms, and in vitro and in vivo evaluation of therapeutic agents to treat
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`onychomycosis and other nail diseases.
`
`III.
`
`COMPENSATION AND RELATIONSHIP TO THE PARTIES
`
`11.
`
`I am being compensated at my standard consulting rate of $350 per
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`hour for the time I spend studying materials and issues associated with this matter
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`and for the time I spend providing testimony. I expect to be reimbursed for
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`reasonable expenses associated with travel, including lodging, transportation, and
`
`other expenses incurred in connection with this matter. My compensation is not
`
`contingent upon the outcome of this matter.
`
`12.
`
`I understand that Anacor Pharmaceuticals Inc. (“Anacor”) is the
`
`assignee of the ’621 Patent. I have not worked for Anacor or have any vested
`
`interest in any entity related to the “Coalition For Affordable Drugs X LLC.” To
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`the best of my knowledge, information, and belief, I have no financial interest in
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`Anacor or any entity related to the “Coalition For Affordable Drugs X LLC”
`
`IV.
`
`MATERIALS CONSIDERED
`
`13.
`
`I reviewed the following documents and information, and the Petition:
`
`
`
`4
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`

`
`Declaration of S. Narasimha Murthy, Ph.D.
`Inter Partes Review of Patent No. 7,582,621
`
`
`EXHIBIT
`Ex. 1001
`Ex. 1002
`
`Ex. 1003
`
`Ex. 1004
`
`Ex. 1005
`Ex. 1012
`
`DESCRIPTION
`U.S. Patent No. 7,582,621 (“the ’621 Patent”)
`Patent Cooperation Treaty Pub. No. WO 1995/033754
`to Austin et al. (“Austin”)
`U.S. Patent Pub. No. 2002/0165121 to Brehove
`(“Brehove”)
`Patent Cooperation Treaty Pub. No. WO 2003/009689
`A1 to Freeman et al. (“Freeman”)
`U.S. Patent No. 6,042,845 to Sun et al. (“Sun”)
`Prosecution History: Office Action dated August 26,
`2008
`Prosecution History: Reply to Office Action dated
`January 23, 2009
`Prosecution History: Notice of Allowance dated April
`22, 2009
`BioborJF® Specification Sheet (2015)
`Ex. 1024
`BioborJF® Material Safety Data Sheet (2004)
`Ex. 1025
`Ex. 1027 Michael P. Groziak, Boron Therapeutics On The
`Horizon, 8 AM. J. OF THERAPEUTICS 321-28 (2001)
`(“Groziak”)
`Sudaxshina Murdan, Drug Delivery to the Nail
`Following Topical Application, 236 INT’L J. OF
`PHARM., 1-26 (2002) (“Murdan”)
`
`Ex. 1013
`
`Ex. 1014
`
`Ex. 1028
`
`FILED
`
`
`
`
`
`
`
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`
`
`
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`
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`
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`
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`14.
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`I am also aware of information generally available to, and relied upon
`
`by, persons of ordinary skill in the art at the relevant times. Some of my statements
`
`below are expressly based on such awareness.
`
`15.
`
`I reserve the right to supplement my opinions to address any
`
`information obtained, or positions taken, based on any new information that comes
`
`
`
`5
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`

`
`Declaration of S. Narasimha Murthy, Ph.D.
`Inter Partes Review of Patent No. 7,582,621
`
`to light throughout this proceeding.
`
`V.
`
`LEGAL STANDARDS
`
`16.
`
`I am not an attorney. I do not expect to offer any opinions on the law.
`
`I have been informed, however, of certain legal principles relating to standards of
`
`patentability that I relied on in forming the opinions set forth in this report.
`
`A. Legal Principles of Claim Construction
`
`17.
`
`I understand that a primary step in determining validity of patent
`
`claims is to properly construe the claims to determine claim scope and meaning.
`
`18.
`
`I understand that claims are to be given their broadest reasonable
`
`construction in light of the patent’s specification in an IPR proceeding.
`
`B.
`
`19.
`
`Legal Principles of Obviousness
`
`I understand that a claimed invention is unpatentable if the differences
`
`between the invention and the prior art are such that the subject matter of the claim
`
`as a whole would have been obvious at the time the invention was made to a
`
`person of ordinary skill in the art (“POSITA”) to which the subject matter pertains.
`
`20.
`
`It is also my understanding that obviousness is a question of law based
`
`on underlying factual issues including (1) the scope and content of the prior art, (2)
`
`the differences between the prior art and the asserted claims, (3) the level of
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`ordinary skill in the pertinent art, and (4) the existence of secondary considerations
`
`such as commercial success, long-felt but unresolved needs, failure of others, etc.
`
`
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`6
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`

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`Declaration of S. Narasimha Murthy, Ph.D.
`Inter Partes Review of Patent No. 7,582,621
`
`
`21.
`
`I understand that for a combination of references to render obvious the
`
`claimed invention, a POSITA must have been able to arrive at the claims by
`
`altering or combining the applied references.
`
`22.
`
`I understand that an obviousness evaluation can be based on a
`
`combination of multiple prior art references. I understand that the prior art
`
`references themselves may provide a reason to combine them, but other times, the
`
`reason to combine two or more prior art references is based on ordinary skill and
`
`common sense. I further understand that an obviousness analysis recognizes that
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`market demand, rather than scientific literature, often drives innovation, and that a
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`motivation to combine references may be supplied by the direction of the
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`marketplace.
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`23.
`
`I understand that if a technique has been used to improve one product,
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`and a POSITA would recognize that it would improve similar products in the same
`
`way, using the technique is obvious unless its actual application is beyond his or
`
`her skill.
`
`24.
`
`I also understand that practical and common sense considerations
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`should guide a proper obviousness analysis, because familiar items may have
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`obvious uses beyond their primary purposes. I further understand that a POSITA
`
`looking to overcome a problem can often fit together the teachings of multiple
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`
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`7
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`Declaration of S. Narasimha Murthy, Ph.D.
`Inter Partes Review of Patent No. 7,582,621
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`publications. I understand that obviousness therefore takes into account the
`
`inferences and creative steps a POSITA would employ under the circumstances.
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`25.
`
`I understand that a particular combination may be proven obvious
`
`merely by showing that it was obvious to try the combination. For example, when
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`there is a design need or market pressure to solve a problem and there are a finite
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`number of identified, predictable solutions, a POSITA has good reason to pursue
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`the known options within his or her technical grasp because the result is likely the
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`product not of innovation but of ordinary skill and common sense.
`
`26.
`
`I also understand that the combination of familiar elements according
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`to known methods is likely to be obvious when it does no more than yield
`
`predictable results. When a work is available in one field of endeavor, design
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`incentives and other market forces can prompt variation of it, either in the same
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`field or a different one. If a POSITA can implement a predictable variation, the
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`patent claims are likely obvious.
`
`27.
`
`It is further my understanding that a proper obviousness analysis
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`focuses on what was known or obvious to a POSITA, not just the patentee.
`
`Accordingly, I understand that any need or problem known in the field of endeavor
`
`at the time of invention and addressed by the patent can provide a reason for
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`combining the elements in the manner claimed.
`
`28.
`
`I further understand that whether there is a reasonable expectation of
`
`
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`8
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`Declaration of S. Narasimha Murthy, Ph.D.
`Inter Partes Review of Patent No. 7,582,621
`
`success in combining references in a particular way is also relevant to the analysis.
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`29. My analysis of the prior art is determined at the time the invention
`
`was made.
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`30.
`
`I understand that secondary indicia of non-obviousness may include
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`(1) a long felt but unmet need in the prior art that was satisfied by the invention of
`
`the patent; (2) commercial success of processes covered by the patent; (3)
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`unexpected results achieved by the invention; (4) praise of the invention by others
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`skilled in the art; (5) taking of licenses under the patent by others; (6) deliberate
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`copying of the invention; (7) failure of others to find a solution to the long felt
`
`need; and (8) skepticism by experts.
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`31.
`
`I also understand that there must be a nexus between any such
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`secondary considerations and the invention.
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`32.
`
`In sum, my understanding is that prior art teachings are properly
`
`combined where a POSITA having the understanding and knowledge reflected in
`
`the prior art and motivated by the general problem facing the inventor, would have
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`been led to make the combination of elements recited in the claims.
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`C. Level Of Ordinary Skill In The Art
`
`33.
`
`It is my understanding that the ’621 Patent is to be interpreted based
`
`on how it would have been read by a POSITA at the time of the effective filing
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`date of the earliest application to which the ’621 Patent claims priority. I was
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`9
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`Declaration of S. Narasimha Murthy, Ph.D.
`Inter Partes Review of Patent No. 7,582,621
`
`familiar with the technology at issue and the state of the art at the earliest priority
`
`date of the ’621 Patent, February 16, 2005.
`
`34.
`
`I believe a POSITA at the time the ’621 Patent was filed would have
`
`had an advanced degree (Master’s or Ph.D.) or equivalent experience in chemistry,
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`pharmacology, or biochemistry, and at least two years of experience with the
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`research, development, or production of pharmaceuticals.
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`35.
`
`I consider myself to have had at least such ordinary skill in the art
`
`with respect to the subject matter of the ’621 Patent at the time the patent was filed.
`
`VI.
`
`THE ’621 PATENT AND RELEVANT ART
`
`36. The ’621 Patent describes methods and compounds useful for treating
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`fungal infections, and more specifically, the topical treatment of onychomycosis
`
`and/or cutaneous fungal infections using boron-containing small molecules. (Ex.
`
`1001 at Abstract.)
`
`A.
`
`37.
`
`Priority Date
`
`I understand the earliest priority date for the ’621 Patent is February
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`16, 2005. (Ex. 1001.)
`
`B.
`
`The ’621 Patent
`
`38. The ’621 Patent is entitled “Boron-Containing Small Molecules.” (Id.)
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`39. The ’621 Patent discloses a genus of potential boron-containing small
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`molecules but only claims a single compound: 1,3-dihydro-5-fluoro-1-hydroxy-
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`
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`10
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`

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`Declaration of S. Narasimha Murthy, Ph.D.
`Inter Partes Review of Patent No. 7,582,621
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`2,1-benzoxaborole. (Id. at Cols. 67:34 – 68:44.) The ’621 Patent refers to 1,3-
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`dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole as “C10.” (Id. at Col. 51:55-57.)
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`The ’621 Patent alleges that “C10” is a novel compound. (Id. at Col. 59:45-48.) I
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`disagree because 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole (C10) was
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`previously disclosed as a preferred anti-fungal compound by Austin. (Ex. 1002 at
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`Abstract.)
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`40. 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-
`
`benzoxaborole) is:
`
`OH
`B
`
`O
`
`
`
`F
`
`41.
`
`In addition to referring to 1,3-dihydro-5-fluoro-1-hydroxy-2,1-
`
`benzoxaborole as C10, the ’621 Patent also refers to his compound as “compound
`
`I.” (See, e.g., Ex. 1001 at Col. 32:10-25.)
`
`42. The ’621 Patent discloses methods of treating ungual and periungual
`
`infections, and more specifically, onychomycosis. (Id. at Cols. 28:5 – 29:19.)
`
`The ’621 Patent recognizes that “[o]nychomycosis is a disease of the nail caused
`
`by yeast, dermatophytes, or other molds, and represents approximately 50% of all
`
`nail disorders.” (Id. at Col. 28:18-20.) The ’621 Patent alleges that “anti-fungal
`11
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`

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`Declaration of S. Narasimha Murthy, Ph.D.
`Inter Partes Review of Patent No. 7,582,621
`
`drugs cannot readily penetrate the nail plate to reach the infection sites under the
`
`nail.” (Id. at Col. 28:46-49.) I disagree because both Brehove and Freeman
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`disclose anti-fungal drugs capable of treating onychomycosis through topical
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`application to the nail and surrounding skin of a human.
`
`43. The ’621 Patent also discloses methods for determining the anti-
`
`fungal activity of compounds and the keratin binding properties of compounds.
`
`(Id. at Cols. 59:15 – 60:42.) The ’621 Patent admits these methods were well
`
`known in the prior art. (Id. at Col. 59:16-18 (“All MIC testing followed the
`
`National Committee for Clinical Laboratory Standards (NCCLS) guidelines for
`
`anti-microbial testing of yeasts and filamentous fungi”); id. at Col. 59:34-37 (“The
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`affinities of the compounds for keratin powder was determined by a method
`
`described in Tatsumi, Antimicrobial Agents and Chemotherapy, 46(12): 3797-3801
`
`(2002).”).) I agree. Determining the anti-fungal activity of compounds and the
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`keratin binding properties of compounds was well known in the art before
`
`February 16, 2005 and is nothing more than routine experimentation.
`
`44. The ’621 Patent further discloses the determination of solubility,
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`stability, and log P values for compounds, specifically, 1,3-dihydro-5-fluoro-1-
`
`hydroxy-2,1-benzoxaborole. (Id. at Cols. 60:45 – 62:30.) The determination of
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`solubility, stability, and log P values for a compound under consideration for
`
`topical application was standard practice before February 16, 2005 and is nothing
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`
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`12
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`Declaration of S. Narasimha Murthy, Ph.D.
`Inter Partes Review of Patent No. 7,582,621
`
`more than routine experimentation.
`
`45. The ’621 Patent further discloses methods for determining the
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`efficacy of nail penetration by anti-fungal compounds. (Id. at Cols. 30:20 – 33:4;
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`Cols. 62:34 – 67:24.) The ’621 Patent admits these methods were well known in
`
`the prior art. (Id. at Col. 62:36-49 (“Two nail penetration studies were performed
`
`based on the protocol in Hui et al., Journal of Pharmaceutical Sciences, 91(1):
`
`189-195 (2002).”).) I agree. Determining the efficacy of nail penetration by
`
`compounds, including anti-fungal compounds, was well known in the art before
`
`February 16, 2005 and is nothing more than routine experimentation.
`
`46.
`
`Independent claim 1 of the ’621 Patent recites a “method of treating
`
`an infection in an animal, said method comprising administering to the animal a
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`therapeutically effective amount of 1,3-dihydro-5-fluoro-1-hydroxy-2,1-
`
`benzoxaborole, or a pharmaceutically acceptable salt thereof, sufficient to treat
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`said infection.” (Id. at Col. 67.) A short name for 1,3-dihydro-5-fluoro-1-hydroxy-
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`2,1-benzoxaborole is 5-fluoro benzoxaborole.
`
`47. Claim 2 depends from claim 1 and narrows the method of claim 1 to
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`“wherein said infection is a member selected from a systemic infection, a
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`cutaneous infection, and an ungual or periungual infection.” (Id.) A “cutaneous
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`infection” is a skin infection and an “ungual” infection is an infection of an
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`animal’s nail, hoof, or claw.
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`13
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`Declaration of S. Narasimha Murthy, Ph.D.
`Inter Partes Review of Patent No. 7,582,621
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`
`48. Claim 3 depends from claim 1 and narrows the method of claim 1 to
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`“wherein said infection is a member selected from a” long list of diseases,
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`including “dermatological diseases” and “Tinea pedis.” (Id. at Cols. 67-68.)
`
`“[D]ermatological diseases” is a broad term that includes onychomycosis. “Tinea
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`pedis” is commonly known as athlete’s foot, which is often caused by fungus of
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`the trichophyton genus, including trichophyton rubrum.
`
`49. Claim 4 depends from claim 1 and narrows the method of claim 1 to
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`“wherein said infection is onychomycosis.” (Id. at Col. 68.) “[O]nychomycosis” is
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`a fungal infection of the nail that is often caused by three types of fungi:
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`dermatophytes, yeast, and non-dermatophyte molds. Dermatophytes refer to the
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`following three fungi genre: Microsporum, Epidermophyton, and Trichophyton.
`
`Trichophyton rubrum is the most common dermatophyte involved in
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`onychomycosis. Candida is a genus of yeast and Candida albicans is the most
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`commonly isolated species associated with onychomycosis.
`
`50. Claim 5 depends from claim 1 and narrows the method of claim 1 to
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`“wherein said animal is a member selected from a human, cattle, goat, pig, sheep,
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`horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, chicken and turkey. (Id.)
`
`51. Claim 6 depends from claim 4 and narrows the method of claim 1 to
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`“wherein said onychomycosis is tinea unguium.” (Id.) Tinea unguium is another
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`term for a type of onychomycosis.
`
`
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`14
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`Declaration of S. Narasimha Murthy, Ph.D.
`Inter Partes Review of Patent No. 7,582,621
`
`
`52. Claim 7 depends from claim 1 and narrows the method of claim 1 to
`
`“wherein said animal is a human.” (Id.)
`
`53. Claim 8 depends from claim 1 and narrows the method of claim 1 to
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`“wherein the administering is at a site which is a member selected from the skin,
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`nail, hair, hoof and claw.” (Id.)
`
`54. Claim 9 depends from claim 8 and narrows the method of claim 1 to
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`“wherein said skin is the skin surrounding the nail, hair, hoof or claw.” (Id.)
`
`55. Claim 10 depends from claim 1 and narrows the method of claim 1 to
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`“wherein said infection is a fungal infection.” (Id.)
`
`56.
`
`Independent claim 11 of the ’621 Patent recites a “method of treating
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`onychomycosis in a human, said method comprising administering to the human a
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`therapeutically effective amount of 1,3-dihydro-5-fluoro-1-hydroxy-2,1-
`
`benzoxaborole, or a pharmaceutically acceptable salt thereof, sufficient to treat
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`said onychomycosis.” (Id.)
`
`57.
`
` Independent claim 12 of the ’621 Patent recites a “method of
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`inhibiting the growth of a fungus in a human, said method comprising
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`administering to the human a therapeutically effective amount of 1,3-dihydro-5-
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`fluoro-1-hydroxy-2,1-benzoxaborole, or a pharmaceutically acceptable salt
`
`thereof.” (Id.)
`
`
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`
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`15
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`Declaration of S. Narasimha Murthy, Ph.D.
`Inter Partes Review of Patent No. 7,582,621
`
`
`C.
`
`Prosecution History Of The ’621 Patent
`
`58.
`
`I understand that U.S. Patent Appl. No. 11/357,687, which became the
`
`’621 Patent, was filed on February 16, 2006. I understand the first substantive
`
`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. 1012 at pp. 10-12.) The Examiner appears to argue 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 Answers.com discloses that a fungicide can be used
`
`for agriculture or the pharmaceutical industry. (Id. at p. 12.) I agree.
`
`59. To overcome this rejection, I understand that the Patent Owner argued
`
`that a POSITA would not choose an industrial fungicide for the 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 . . . Asnwers.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 pp. 6-7.) 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 pp. 5-7.) I disagree with the Patent Owner’s argument.
`
`
`
`16
`
`

`
`Declaration of S. Narasimha Murthy, Ph.D.
`Inter Partes Review of Patent No. 7,582,621
`
`
`60. 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. 1014 at
`
`p. 2.)
`
`D. Background And Overview Of The Prior Art
`
`61.
`
`1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole (hereinafter, “5-
`
`fluoro benzoxaborole”) was not a novel compound in February of 2005 as the ’621
`
`Patent claims. In fact, 5-fluoro benzoxaborole was not only known, but was
`
`disclosed as a “preferred” fungicide. Austin discloses 5-fluoro benzoxaborole (5-
`
`fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole) as a preferred fungicide. (Ex.
`
`1002, Abstract.) Austin discloses that compounds containing an “oxaborole ring”
`
`are “particularly effective” as fungicides. (Id. at p. 1, ll. 35-40.) Austin’s
`
`“preferred” oxaborole ring compounds are “5- and 6-fluoro or bromo- 1,3-dihydro-
`
`1-hydroxy-2,1-benzoxaborole.” (Id. at Abstract.) 5-fluoro-1,3-dihydro-1-hydroxy-
`
`2,1-benzoxaborole is the compound recited in claims 1-12 of the ’621 Patent,
`
`which I refer to as 5-fluoro benzoxaborole.
`
`62. Austin discloses how to prepare various benzoxaborole derivatives
`
`which includes the compound of claims 1-12 of the ‘621 Patent. (Id. at p. 22, ll. 1-
`
`15.) Austin discloses the preparation of benzoxaborole derivatives having the
`
`following general structure where R8 represents one or more substituents in the
`
`phenyl ring:
`
`
`
`17
`
`

`
`Declaration of S. Narasimha Murthy, Ph.D.
`Inter Partes Review of Patent No. 7,582,621
`
`
`R8
`
`OH
`B
`
`O
`
`R9
`
`
`
`(Id. at p. 22, ll. 1-15; id. at p. 36, ll. 15-26.) Example 64 of Austin is 5-fluoro
`
`benzoxaborole, namely, where R9 is hydrogen and R8 is a single fluorine at the 5
`
`position of the phenyl ring. For example, Austin discloses the analysis of 5-fluoro
`
`benzoxaborole in Table 5 at Example 64. (Id. at p. 23, Table 5.)
`
`63.
`
`Importantly, Austin teaches that 5-fluoro benzoxaborole, the
`
`compound of claims 1-12 in the ’621 Patent, has strong anti-fungal activity. (Id. at
`
`p. 37, Table 9.) For example, the anti-fungal activity of 5-fluoro benzoxaborole is
`
`disclosed in Table 9 at Example 64. (Id.) Table 9 discloses that 5-fluoro
`
`benzoxaborole is an effective anti-fungal 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 pp. 36-
`
`37.) 5-fluoro benzoxaborole is effective at a concentration as low as five (5) parts
`
`per million (PPM) which was the lowest concentration tested by Austin. (Id. at p.
`
`33, ll. 33-35; id. at p. 37, Table 9.)
`
`64. Austin further discloses that 5-fluoro benzoxaborole is effective
`
`against Candida albicans. (Id. at p. 37, Table 9.) Candida albicans is a fungus that
`
`
`
`18
`
`

`
`Declaration of S. Narasimha Murthy, Ph.D.
`Inter Partes Review of Patent No. 7,582,621
`
`causes onychomycosis, sometimes in conjunction with dermatophytes.
`
`65. Austin discloses 5-fluoro benzoxaborole, which is the compound of
`
`claims 1-12, as a preferred fungicide to effectively inhibit Candida albicans, which
`
`is one of the fungi responsible for onychomycosis.
`
`66. Not only was 5-fluoro benzoxaborole a known fungicide by February
`
`16, 2005 but the use of boron-based compounds to safely and effectively inhibit
`
`onychomycosis in humans was also known.
`
`67. Brehove discloses the topical application of boron-based compounds
`
`to “treat and prevent the spread of nail infections or onychomycosis caused by
`
`bacteria, fungi and other pathogens.” (Ex. 1003 at Abstract, ¶ [0003].) Brehove
`
`acknowledges that boron-based compounds “have long been known to exhibit
`
`biocidal activity.” (Id. at ¶ [0007].) Brehove, consistent with Austin, recognizes
`
`that formulations containing boron-based compounds have “powerful potency
`
`against Candida albicans . . . effectively kill[ing] the most common pathogen
`
`causing onychomycosis.” (Id. at ¶ [0018].)
`
`68.
`
`I understand that the topical compositions for treating onychomycosis
`
`in Brehove include the following compounds: 2,2’-(1-methyltrimethylene dioxy)
`
`bis (4-methyl-1,3, 2-dioxaborinane) and/or 2,2’-oxybis (4, 4, 6-trimethyl-1, 3, 2-
`
`dioxaborinane). (Id. at ¶¶ [0022], [0030].) These two compounds have the
`
`following structures:
`
`
`
`19
`
`

`
`O
`
`OB
`
`O
`
`OB
`
`O
`
`2,2'-oxybis (4, 4, 6-trimethyl-
`1, 3, 2-dioxaborinane)
`
`
`
`
`
`Declaration of S. Narasimha Murthy, Ph.D.
`Inter Partes Review of Patent No. 7,582,621
`
`
`O B
`
`O B
`
`O
`O
`O
`O
`2,2'-(1-methyltrimethylene dioxy)
`bis (4-methyl-1, 3, 2-dioxaborinane)
`
`69. These compounds were previously disclosed as anti-fungal additives
`
`for leaded motor fuel in order to improve its combustion efficiency. (Id. at ¶¶
`
`[0015], [0023] (citing U.S. Patent No. 2,741,548).) For example, these compounds
`
`have been used under the trade name BioborJF® as an antifungal fuel additive
`
`since 1965. (Exs. 1024-25.) The current BioborJF® specification sheet explains:
`
`(Ex. 1024.) BioborJF® is a recognized anti-fungal for industrial applications.
`
`
`
`(Id.) The material safety datasheet for BioborJF® from January 1, 2004 discloses
`
`its active ingredients as 2,2’-(1-methyltrimethylene dioxy) bis (4-methyl-1,3, 2-
`
`
`
`
`
`20
`
`

`
`Declaration of S. Narasimha Murthy, Ph.D.
`Inter Partes Review of Patent No. 7,582,621
`
`dioxaborinane) and/or 2,2’-oxybis (4, 4, 6-trimethyl-1, 3, 2-dioxaborinane), the
`
`very same compounds used to treat onychomycosis in humans by Brehove.
`
`
`
`(Ex. 1025.)
`
`70. Brehove specifically discloses that topical composition including
`
`these boron-based compounds are “highly effective in suppressing the growth of
`
`Candida albicans in vitro” at every concentration tested. (Ex. 1003 at ¶¶ [0032]-
`
`[0033].) In vivo, topical compositions including the same two boron-based
`
`compounds successfully treated onychomycosis in humans. (Id. at ¶¶ [0034]-
`
`[0038].)
`
`71. Brehove specifically applied topical compositions containing the
`
`active ingredient in BioborJF® to five volunteers who presented with
`
`onychomycosis. (Id.) In all five examples, the topical application of the
`
`compositions directly to the infected nail or cuticles surrounding the infected nail
`
`effectively treated the onychomycosis with “[n]o skin irritation . . . and no
`
`[evidence of] side effects. (Id. at ¶¶ [0022], [0030], [0034].)
`
`72. Brehove discloses the topical application of compositions including
`21
`
`
`
`

`
`Declaration of S. Narasimha Murthy, Ph.D.
`Inter Partes Review of Patent No. 7,582,621
`
`boron-based compounds, which were previously used as leaded fuel additives,
`
`directly to the nail and surrounding skin of humans with onychomycosis to
`
`effectively treat onychomycosis typically caused by the organisms Candida
`
`albicans, Trichophyton mentagrophytes, Trichophyton rubrum, or
`
`Epidermpophyton floccusum.
`
`73. Brehove was not the only disclosure of boron-based compounds for
`
`the treatment of onychomycosis in humans prior to February 16, 2005. Freeman
`
`also disclosed “methods and compositions for treating fungal infections, and more
`
`particularly, dermatophytoses or onchomycosis [sic] of the fingernail and the
`
`toenail” with phenyl boronic acid and derivatives thereof. (Ex. 1004 at ¶¶ [001],
`
`[0022].)
`
`74. Like Brehove, and consistent with the knowledge of a POSITA before
`
`February 16, 2005, Freeman disclosed that both “dermatophytes and non-
`
`dermatophytes, especially Candida Sp., have been identified as etiologic agents of
`
`onychomycosis.” (Id. at ¶ [008].) Therefore, Freeman links Candida Sp., also a
`
`common target of Austin and Brehove, to onychomycosis and further recognizes,
`
`consistent with the knowledge of a POSITA before February 16, 2005, that the
`
`“dermatophyte species that most often causes onychomycosis in North America”
`
`includes “T. rubrum.” (Id.)
`
`
`
`22
`
`

`
`Declaration of S. Narasimha Murthy, Ph.D.
`Inter Partes Review of Patent No. 7,582,621
`
`
`75. Freeman specifically discloses that “phenyl boronic acid and
`
`derivatives thereof as well as related boronic acid compounds have fungicidal
`
`properties . . . [which] have been found to be particularly useful in treating nail
`
`fungal infections.” (Id. at ¶ [0022].) Phenyl boronic acid (“PBA”) is a common
`
`compound and has the following structure:
`
`OH
`B
`
`OH
`
`Phenyl Boronic Acid
`
`
`
`(Id. at ¶¶ [0029]-[0034].) Along with PBA, Freeman discloses a pentafluoro
`
`phenyl boronic acid and a fluoro phenyl boronic acid, both derivatives of PBA,
`
`which have the following structures:
`
`F
`
`OH
`B
`
`OH
`
`F
`
`F
`
`F
`
`F
`Pentafluoro Phenyl
`Boronic Acid
`
`OH
`B
`
`OH
`
`F
`
`
`
`Fluoro Phenyl
`Boronic Acid
`
`
`
`(Id. at ¶ [0062] (“R1, R2, R3, R4, and R5” are all fluorine or “R3” is fluorine and the
`
`remaining substituents are hydrogen.))
`
`
`
`23
`
`

`
`Declaration of S. Narasimha Murthy, Ph.D.
`Inter Partes Review of Patent No. 7,582,621
`
`
`76.
`
`In vitro tests by Freeman disclose that PBA exhibits anti-fungal
`
`activity by inhibiting T. rubrum within a concentration range of 5-10 mg/ml. (Id. at
`
`¶¶ [0033] – [0037].) Like Brehov

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