`
`By: Philip D. Segrest, Jr.
`HUSCH BLACKWELL LLP
`120 South Riverside Plaza, Suite 2200
`Chicago, Illinois 60606
`Philip.Segrest@HuschBlackwell.com
`Tel. (312) 655-1500
`Fax. (312) 655-1501
`
`
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`FlatWing Pharmaceuticals, LLC,
`
`Petitioner,
`
`v.
`
`Anacor Pharmaceuticals, Inc.,
`
`Patent Owner.
`
`Case No.: 2018-00168
`
`Patent No. 9,549,938
`
`DECLARATION OF STEPHEN KAHL PH.D. IN SUPPORT OF PETITION
`FOR INTER PARTES REVIEW OF PATENT NO. 9,549,938
`
`MYLAN - Ex. 1003, p. 1
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,549,938
`
`TABLE OF CONTENTS
`
`TABLE OF CONTENTS ........................................................................................ I
`
`DECLARATION ...................................................................................................... 1
`
`I.
`
`INTRODUCTION ............................................................................................. 1
`
`II. BACKGROUND AND EXPERIENCE ............................................................ 1
`
`III. COMPENSATION AND RELATIONSHIP TO THE PARTIES .................... 3
`
`IV. MATERIALS CONSIDERED .......................................................................... 4
`
`V. LEGAL STANDARDS ..................................................................................... 7
`
`VI. LEVEL OF ORDINARY SKILL IN THE ART ............................................... 8
`
`VII. THE ’938 PATENT AND RELEVANT PROSECUTION HISTORY ............ 9
`
`VIII. OPINIONS ....................................................................................................... 12
`
`IX. CONCLUSION ................................................................................................ 18
`
`
`
`
`– i –
`
`MYLAN - Ex. 1003, p. 2
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,549,938
`
`DECLARATION
`
`I, Stephen Kahl, Ph.D., hereby state the following:
`
`I.
`
`INTRODUCTION
`
`1.
`
`In this declaration, I am providing my expert opinions in support of the
`
`above-captioned petition for inter partes review (“IPR”) of U.S. Patent
`
`No. 9,549,938 (“the ’938 Patent”) filed by petitioner (FlatWing Pharmaceuticals,
`
`LLC), which challenges the patentability of claims 1–6 of the ’938 Patent.
`
`2.
`
`3.
`
`This Declaration sets forth the bases and reasons for my opinions.
`
`This Declaration is based on information currently available to me. I
`
`reserve the right to continue my investigation and analysis, which may include a
`
`review of documents and information not yet produced. I further reserve the right
`
`to expand or otherwise modify my opinions and conclusions as my investigation
`
`and study continues, and to supplement my opinions and conclusions in response
`
`to any additional information that becomes available to me.
`
`II. BACKGROUND AND EXPERIENCE
`
`4.
`
`I received a B.S. in Chemistry from Duke University (1964-68) and a
`
`Ph.D. in Chemistry from Indiana University (1968-72).
`
`5.
`
`From 1972 until 1974, I was a Postdoctoral Fellow at the University of
`
`California, Berkeley in the Departments of Chemistry and Physics. From 1975
`
`until 1982, I was an Assistant Professor at Wellesley College in the Department of
`
`
`
`– 1 –
`
`MYLAN - Ex. 1003, p. 3
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,549,938
`
`Chemistry. From 1982 until the present, I have held the following positions in the
`
`Department of Pharmaceutical Chemistry at the University of California, San
`
`Francisco: Visiting Assistant Professor (1982–1985); Assistant Professor In
`
`Residence (1985-1990); Associate Professor In Residence (1990–1995); Professor
`
`in Residence (1995-2011); and Professor In Residence Emeritus (2011–Present). I
`
`also served as Vice Chair of the UCSF Department of Pharmaceutical Chemistry
`
`from 1993 to 2013. From 1983 to 2015, I held the title of Visiting Professor
`
`(Lecturer) in the Department of Chemistry at Stanford University.
`
`6.
`
`I have received numerous honors and awards, including the Dean’s
`
`Recognition for Excellence in Teaching, University of California School of
`
`Pharmacy on nine different occasions since its inception in 2005.
`
`7.
`
`I have also served as an Ad Hoc Reviewer for twenty journals including:
`
`Journal of Medicinal Chemistry (1985–Present); Journal of Organic Chemistry
`
`(1991–Present); Cancer Research (1989–Present); Proceedings of the National
`
`Academy of Sciences, USA (1990–Present); and Journal of American Chemical
`
`Society (1986–Present).
`
`8. My research interests over my career have related to the development of
`
`organic synthetic methodologies and separation techniques for the preparation of
`
`bioactive boron molecules specifically targeted to biological systems, e.g. cancer
`
`cells, atherosclerotic plaques, and viral and parasitic vectors, and the application of
`
`
`
`– 2 –
`
`MYLAN - Ex. 1003, p. 4
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,549,938
`
`methods to assess the toxicology and gross and subcellular biodistribution of these
`
`molecules. To date, my research has resulted in over 65 publications in books and
`
`peer reviewed journals; and over 30 invited presentations.
`
`9. My CV, which lists in further detail my relevant professional experience,
`
`is attached as Exhibit 1004.
`
`10.
`
`I am informed that in proceedings on patents in the same patent family
`
`claiming priority to the same disclosure, the Board determined that I was “qualified
`
`to testify as to the knowledge of a person of ordinary skill in the art in this
`
`proceeding.” Coalition for Affordable Drugs X LLC v. Anacor Pharmaceuticals,
`
`Inc., IPR2015-01780, Paper 70 at 11 (P.T.A.B. Feb. 23, 2017).
`
`III. COMPENSATION AND RELATIONSHIP TO THE PARTIES
`
`11.
`
`I am being compensated at my standard consulting rate of $500 per hour
`
`for the time I spend studying materials and issues associated with this matter and
`
`$750 per hour for the time I spend providing testimony. My compensation is not
`
`contingent upon the outcome of this matter. I expect to be reimbursed for
`
`reasonable expenses associated with travel, including lodging, transportation, and
`
`other expenses incurred in connection with this matter.
`
`12.
`
`It is my understanding that Anacor Pharmaceuticals Inc. (“Anacor”) is
`
`the assignee of the ’938 Patent. Prior to this matter, I have not worked for Anacor
`
`or had any vested interest in the Petitioner or its related entities. I own no stock or
`
`
`
`– 3 –
`
`MYLAN - Ex. 1003, p. 5
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,549,938
`
`ownership interest in Anacor or the Petitioner or its related entities and I am aware
`
`of no other financial interest I have with those companies.
`
`IV. MATERIALS CONSIDERED
`
`13. All the exhibits I have considered and relied on in this proceeding are the
`
`kinds of documents I typically rely on when forming opinions, including the
`
`opinions I have offered in this proceeding.
`
`14.
`
`I reviewed the following documents and information:
`
`DESCRIPTION
`EXHIBIT
`Ex. 1001 U.S. Patent No. 9,549,938
`
`SHORT FORM
`
`‘938 Patent
`
`Ex. 1002 Prosecution History of the ‘938 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
`
`Ex. 1016 Prosecution History of the ‘657 Patent
`
`Samour ‘887
`
`‘621 Patent
`
`
`
`
`
`‘657 Patent
`
`
`
`
`
`– 4 –
`
`MYLAN - Ex. 1003, p. 6
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,549,938
`
`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
`following 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
`Hydrochloride) PL 10590/0049, UK Public
`Assessment Report (approved July 4, 2006)
`
`
`
`– 5 –
`
`
`
`
`
`‘894 Patent
`
`Murdan 2002
`
`
`
`
`
`
`
`
`
`
`
`
`
`MYLAN - Ex. 1003, p. 7
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,549,938
`
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=22497760, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/22497
`760 (retrieved on May 26, 2017)
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=61764, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/61764
`(retrieved on May 26, 2017)
`Mertin, Dirk, and Lippold, Bernhard C. “In-vitro
`permeability of the human nail and of a keratin
`membrane from bovine hooves: Prediction of the
`penetration rate of antimycotics through the nail
`plate and their efficacy.” Journal of pharmacy and
`pharmacology 49, no. 9 (1997): 866-872
`Groziak, Michael P. “Boron therapeutics on the
`horizon,” American journal of therapeutics 8, no. 5
`(2001): 321-328
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=66827, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/66827
`(retrieved on May 26, 2017)
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=2775922, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/27759
`22 (retrieved on May 26, 2017)
`
`Ex. 1029
`
`Ex. 1030
`
`Ex. 1031
`
`Ex. 1032
`
`Ex. 1033
`
`Ex. 1034
`
`
`
`
`
`
`
`Mertin 1997
`
`Groziak 2001
`
`
`
`
`
`15.
`
`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.
`
`
`
`– 6 –
`
`MYLAN - Ex. 1003, p. 8
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,549,938
`
`16.
`
`I reserve the right to supplement my opinions to address any information
`
`obtained, or positions taken, based on any new information that comes to light
`
`throughout this proceeding.
`
`V.
`
`LEGAL STANDARDS
`
`17.
`
`18.
`
`I am not an attorney. I do not offer any opinions on the law.
`
`It is my understanding 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.
`
`19.
`
`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
`
`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.
`
`20.
`
`I further understand that whether there is a reasonable expectation of
`
`success from combining references in a particular way is also relevant to the
`
`analysis. I understand there may be a number of rationales that may support a
`
`reasonable expectation of success, including:
`
`
`
`– 7 –
`
`MYLAN - Ex. 1003, p. 9
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,549,938
`
`• combining prior art elements according to known methods to yield
`
`predictable results;
`
`• substitution of one known element for another to obtain predictable
`
`results;
`
`• use of known technique to improve similar devices (methods, or
`
`products) in the same way;
`
`• applying a known technique to a known device (method, or product)
`
`ready for improvement to yield predictable results; and
`
`• “obvious to try” – choosing from a finite number of identified,
`
`predictable solutions, with a reasonable expectation of success.
`
`VI. LEVEL OF ORDINARY SKILL IN THE ART
`
`21.
`
`It is my understanding that the ’938 Patent is to be interpreted based on
`
`how it would have been read by a POSITA at the time of the effective filing date of
`
`the earliest application to which the ’938 Patent claims priority. I was familiar with
`
`the technology at issue and the state of the art as of the earliest priority date of the
`
`’938 Patent, February 16, 2005.
`
`22.
`
`I believe a POSITA at the time U.S. application to which the ’938 patent
`
`claims priority was filed would have had an advanced degree (Master’s or Ph.D.)
`
`or equivalent experience in chemistry, pharmacology, or biochemistry, and at least
`
`two years of experience with the research, development, or production of
`
`
`
`– 8 –
`
`MYLAN - Ex. 1003, p. 10
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,549,938
`
`pharmaceuticals. I am informed that in proceedings on patents in the same patent
`
`family claiming priority to the same disclosure, the Board has held that “the cited
`
`prior art is representative of the level of ordinary skill in the art” and “consistent
`
`with Petitioner’s broader description of the level or ordinary skill in the art.”
`
`IPR2015-01780, Paper 70 at 8.
`
`23.
`
`I consider myself to have had at least such ordinary skill in the art with
`
`respect to the subject matter of the ’938 Patent at the time the patent was filed. I
`
`am informed that in proceedings on patents in the same patent family claiming
`
`priority to the same disclosure, the Board has determined:
`
`Dr. Kahl has a Ph.D. in chemistry, is a professor in the
`department of pharmaceutical chemistry at the University of
`California, San Francisco, has served as an ad hoc reviewer for 20
`journals, and has conducted research related to bioactive boron
`molecules that are specifically targeted to biological systems, which
`has resulted in over 65 publications in books and peer-reviewed
`journals. Ex. 1009 ¶¶ 4–8; Ex. 1010. Based on the facts in this record,
`we determine that Drs. Murthy and Kahl are qualified to testify as to
`the knowledge of a person of ordinary skill in the art in this
`proceeding.
`
`IPR2015-01780, Paper 70 at 11 (emphasis added).
`
`VII. THE ’938 PATENT AND RELEVANT PROSECUTION HISTORY
`
`24.
`
`I understand the ’938 Patent describes treating fungal infections,
`
`including onychomycosis, via topical application of boron-containing small
`
`molecules to the nail or skin of a human. (Ex. 1001, [57] Abstract.)
`
`
`
`– 9 –
`
`MYLAN - Ex. 1003, p. 11
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,549,938
`
`25.
`
`I further understand the ’938 Patent specifically claims a method of
`
`treating a Tinea unguium infection of a human toenail including a step of topically
`
`administering a pharmaceutical composition including 1,3-dihydro-5-fluoro-1-
`
`hydroxy-2,1-benzoxaborole. (Id. at Cols. 319–20.) 1,3-dihydro-5-fluoro-1-
`
`hydroxy-2,1-benzoxaborole has the following structure:
`
`
`I understand during the prosecution of the application leading to U.S.
`
`26.
`
`Patent No. 7,582,621 (the “’621 Patent”), from which the ’938 Patent claims
`
`priority, that the Examiner rejected the pending claims over Austin WO ’574 and
`
`the definition of “fungicide” from Answers.com. (Ex. 1013 at 53-55.) Specifically,
`
`the Examiner appears to have recognized that Austin ’574 discloses 1,3-dihydro-5-
`
`fluoro-1-hydroxy-2,1-benzoxaborole for use as an industrial fungicide. (Id.) And
`
`that the definition of fungicide from Answers.com discloses that a fungicide can be
`
`used for agriculture or the pharmaceutical industry. (Id. at 55.)
`
`
`
`– 10 –
`
`MYLAN - Ex. 1003, p. 12
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,549,938
`
`27.
`
`I further understand that in order to overcome this rejection that the
`
`Patent Owner argued that a POSITA would not choose an industrial fungicide for
`
`human use because some fungicides are dangerous to humans. I understand the
`
`Patent Owner argued: “the art teaches that compounds that are useful for killing or
`
`inhibiting fungi may also harm animals” and “Answers.com thus does not provide
`
`a motivation to modify the teachings of Austin WO ’574 to use any particular
`
`oxaborole to treat an animal, and in fact teaches away from such modification.”
`
`(Id. at 18-19.)
`
`28.
`
`I understand that the Examiner relied on the Patent Owner’s argument in
`
`deciding to allow the pending claims which ultimately issued as claims 1–12 the
`
`’621 Patent. (Id. at 6-7.)
`
`29. Also, I understand the Patent Owner relied on the same argument during
`
`prosecution of the application leading to U.S. Patent No. 7,767,657 (“the ‘657
`
`Patent”), which the ‘823 Patent claims priority to, and the Examiner relied on the
`
`Patent Owner’s argument in deciding to allow the pending claims. (Ex. 1016 at 24-
`
`25, 6-7.) Finally, I understand the arguments made above were in applications to
`
`which the application that issued as the ’938 patent claimed priority and thus are
`
`part of the prosecution history of the ’938 patent. (Ex. 1001.)
`
`
`
`– 11 –
`
`MYLAN - Ex. 1003, p. 13
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,549,938
`
`VIII. OPINIONS
`
`30. Boron-containing compounds were well known to a POSITA before
`
`February 16, 2005. I have been personally studying boron-containing compounds
`
`as therapeutic agents for over forty-five years, including the administration of
`
`boron-containing compounds to humans for the treatment of cancer.
`
`31. Groziak 2001 published a review of the then-current state of research and
`
`development concerning boron-based therapeutics for use in humans. (Ex. 1032 at
`
`Abstract.) In particular, Groziak 2001 recognized that it was “not at all surprising
`
`to find that most of the boron-based therapeutics currently on the horizon are either
`
`boronic acids themselves or boron heterocycles that are simply internally
`
`complexed versions of boronic acids.” (Id. at p. 322, left col.) In my opinion, to a
`
`reasonable degree of scientific certainty, that statement in Groziak 2001 is correct,
`
`because boronic acids and boron heterocycles often share similar functional
`
`properties based on the unique chemical properties of boron itself.
`
`32. Boron-containing compounds are generally considered safe. One notable
`
`exception is triakylboranes, which are compounds with the general formula BR3
`
`where R is an alkyl group. Trialkylboranes can spontaneously combust under
`
`certain conditions. The oxaboroles disclosed by Austin WO ’574 are not
`
`trialkylboranes and a POSITA would recognize that the boron-containing
`
`compounds of Austin WO ’574 are generally considered safe.
`
`
`
`– 12 –
`
`MYLAN - Ex. 1003, p. 14
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,549,938
`
`33. Based on my experience working with boron-containing molecules, I am
`
`not aware of any reason why a POSITA would be discouraged from selecting an
`
`oxaborole as disclosed by Austin WO ’574 for consideration as a topical
`
`therapeutic in humans. In fact, for the reasons discussed below, based on Austin’s
`
`disclosure of 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole (referred to in
`
`Austin WO ’574 as 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole, which is
`
`the same compound) as one of three preferred anti-fungal compounds for the
`
`treatment of Candida albicans, a POSITA would consider the compound as
`
`obvious to try as a starting point for developing a topical composition to treat
`
`fungal infections, and that a POSITA would have a reasonable expectation of
`
`success in doing so.
`
`34. Not all boron-based compounds are bioactive. If there is a known
`
`molecule that is bioactive against a fungus, such as Candida albicans, which is a
`
`cause of onychomycosis, a POSITA would consider that molecule as obvious to try
`
`for therapeutic use in humans. This is particularly true in light of the other known
`
`prior art, Brehove ’121 and Freeman ‘689, demonstrating that boron-based
`
`compounds are effective against the pathogens that cause onychomycosis,
`
`including Candida albicans and dermatophytes.
`
`
`
`– 13 –
`
`MYLAN - Ex. 1003, p. 15
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,549,938
`
`35. Austin WO ’574 discloses such bioactivity with its three preferred
`
`compounds, in particular 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole,
`
`which is the exact same compound claimed for use in the ’938 Patent.
`
`36. Austin WO ’574 discloses “5- and 6-fluoro or bromo-1,3 dihydro-1-
`
`hydroxy-2,1-benzoxaborole” as “[p]referred compounds” on the front page of the
`
`patent application publication. (Ex. 1007 [57] Abstract.) In Table 9, it reports the
`
`bioactivity of the 5-fluoro (Example 64), 5-bromo (Example 68), and 6-fluoro
`
`(Example 70) compounds. Of the preferred compounds, 5-fluoro-1,3-dihydro-1-
`
`hydroxy-2,1-benzoxaborole demonstrated the lowest Minimum Inhibitory
`
`Concentration (“MIC”) values against several pathogens, including Candida
`
`albicans. (Ex. 1007 at p. 39, Table 9.) In other words, of the three preferred
`
`compounds tested, 5-fluoro-1,3-dihydro- 1-hydroxy-2,1-benzoxaborole inhibited
`
`the visible growth of Candida albicans (after a period of incubation) at the lowest
`
`level of concentration. (Id.)
`
`37. Brehove ’121 and Freeman ‘689 are patent application publications that
`
`disclose the use of boron-containing compounds as anti-fungal agents to treat
`
`onychomycosis in humans at least one year before February 16, 2005.
`
`38. Brehove ’121 disclosed the effective use of the following boron-
`
`containing compounds to treat onychomycosis in humans:
`
`– 14 –
`
`MYLAN - Ex. 1003, p. 16
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,549,938
`
`39. Brehove ’121 states that “[o]nychomycosis is a nail disease of the toes
`
`and fingers typically caused by the organisms Candida albicans, Tricophyton
`
`mentagrophytes, Tricophyton rubrum, or Epidermpophyton floccusum.” (Ex. 1008
`
`at ¶ [0005].). Brehove ’121 then specifically discloses that these boron-based
`
`compounds are effective in vitro against Candida albicans, which is a cause of
`
`onychomycosis: “This invention also comprises a method of treating
`
`onychomycosis by topical application of a composition containing, as an active
`
`ingredient, at least one member selected from the group consisting of 2,2’-(1-
`
`methyltrimethylenedioxy) bis-(4-methyl-1,3,2-dioxaborinane) and 2,2’-oxybis
`
`(4,4,6-trimethyl-1,3,2-dioxaborinane).” (Id. at ¶ [0017]; see also id. at ¶¶ [0032]-
`
`[0033], Table 1.)
`
`40. Brehove ’121 prepared topical compositions containing these boron-
`
`based compounds to successfully treat humans suffering from onychomycosis.
`
`(See, e.g., id. at ¶¶ [0030] – [0038].) This is the same pathogen inhibited in Austin
`
`with a boron-based compound. Not only did Brehove ’121 successfully treat
`
`humans with this boron-based compound, the compound was commercially sold as
`
`– 15 –
`
`MYLAN - Ex. 1003, p. 17
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,549,938
`
`an industrial biocide for fuel under the trade name Biobor® JF. (Exs. 1021–1022.)
`
`Thus, Brehove ’121 successfully used a boron-based industrial fungicide to treat
`
`humans. This is real world proof that a POSITA would not be discouraged, and
`
`would in fact select a boron-based industrial fungicide for use in humans to treat
`
`onychomycosis.
`
`41.
`
`Freeman ‘689 disclosed the effective use of the boron-containing
`
`compounds to treat onychomycosis in humans, including the following disclosed
`
`compounds:
`
`(Ex. 1009 at ¶ [0062].)
`
`42.
`
`Freeman ‘689 states that “‘Onychomycosis’ has traditionally referred to a
`
`nondermatophytic infection of the nail. Onychomycosis is now used as a general
`
`term to denote any fungal nail infection. Tinea unguium specifically describes a
`
`dermatophytic invasion of the nail plate.” (Id. at ¶ [005].) In addition, Freeman
`
`‘689 recognizes that “[t]he dermatophyte species that most often causes
`
`onychomycosis in North America and parts of Europe are T. rubrum, T.
`
`metagrophytes, and Epidermophyton floccosum . . . Both dermatophytes and non-
`
`– 16 –
`
`MYLAN - Ex. 1003, p. 18
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,549,938
`
`dermatophytes, especially Candida Sp., have been identified as etiologic agents
`
`of onychomycosis.” (Id. at ¶ [008].)
`
`43.
`
`Freeman ‘689 discloses the treatment of onychomycosis using boron-
`
`based compounds: “[i]t has now been discovered that phenyl boronic acid and
`
`derivatives thereof as well as related boronic acid compounds have fungicidal
`
`properties, and that these compounds are particularly useful in treating fungal
`
`infections. These compounds have been found to be particularly useful in treating
`
`nail fungal infections.” (Id. at ¶ [022].)
`
`44.
`
`Freeman ‘689 then specifically discloses that certain boron-based
`
`compounds are effective in vitro against T. rubrum, which is a cause of
`
`onychomycosis: “[i]t can readily be seen from the above that the PBA exhibited
`
`fungicidal effects on T. rubrum within the concentration range of 5-10 mg/ml
`
`tested. (Id. at ¶¶ [0033] – [0037].) Freeman ‘689 then discloses “cosmetic and
`
`therapeutic vehicles” for application to the “skin or nails” of a human. (Id. at ¶¶
`
`[0064] – [0068]. Like Brehove, Freeman ‘689 is real-world proof that a POSITA
`
`would not be discouraged, and would in fact select a boron-based compound for
`
`use in humans to treat onychomycosis.
`
`45.
`
`In my opinion, to a reasonable degree of scientific certainty, as of
`
`February 16, 2005, a POSITA would consider the preferred compound of Austin
`
`WO ’574, which is the exact same compound recited in claims 1–6 of the ’938
`
`– 17 –
`
`MYLAN - Ex. 1003, p. 19
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,549,938
`
`Patent, obvious to try to successfully treat onychomycosis in humans based on its
`
`disclosed anti-fungal activity and structural similarities, e.g., boron-based cyclic
`
`compounds:
`
`IX. CONCLUSION
`
`
`
`46. Boron-containing compounds, like the oxaboroles disclosed by Austin
`
`WO ’574, are generally safe. A POSITA looking to develop a topical treatment for
`
`onychomycosis before February 16, 2005 would not be discouraged by the
`
`disclosures of oxaboroles in Austin WO ’574 for use as industrial fungicides. To
`
`the contrary, Austin WO ’574 in view of either Brehove ’121 or Freeman ‘689
`
`provides a reason as well as a direct teaching, suggestion, or motivation to try 1,3-
`
`dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole for use in humans. In my opinion,
`
`based on the success of Austin WO ’574 in inhibiting Candida albicans, and the
`
`success of Brehove ’121 and Freeman ‘689 in treating onychomycosis with boron-
`
`
`
`– 18 –
`
`MYLAN - Ex. 1003, p. 20
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,549,938
`
`based compounds, a POSITA would find it obvious to try 1,3-dihydro-5-fluoro-1-
`
`hydroxy-2,1-benzoxaborole disclosed in Austin WO ’574 for therapeutic use in
`
`animals and humans.
`
`47.
`
`In signing this Declaration, I understand that it will be filed as evidence
`
`in a contested case before the Patent Trial and Appeal Board of the USPTO. I
`
`acknowledge that I may be subject to cross-examination in the case and that cross-
`
`examination will take place within the United States. If cross-examination is
`
`required of me, I will appear for cross-examination within the United States during
`
`the time allotted for cross-examination.
`
`48.
`
`I hereby declare that all statements made herein of my own knowledge
`
`are true and that all statements made on information and belief are believed to be
`
`true; and that these statements were made with the knowledge that willful false
`
`statements and the like so made are punishable by fine or imprisonment or both.
`
`As provided in 28 U.S.C. § 1760, I declare under penalty of perjury that
`
`the foregoing is true and correct.
`
`Executed on ____________________
`
`_________________________
`
`– 19 –
`
`August 28, 2017
`
`MYLAN - Ex. 1003, p. 21
`
`