Filed on behalf of Petitioner FLATWING PHARMACEUTICALS, LLC
`
`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.: 2018-00169
`
`Patent No. 9,566,289
`
`DECLARATION OF STEPHEN KAHL PH.D. IN SUPPORT OF PETITION
`FOR INTER PARTES REVIEW OF PATENT NO. 9,566,289
`
`FlatWing Ex. 1003, p. 1
`
`
`
`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.: 2018-00169
`
`Patent No. 9,566,289
`
`DECLARATION OF STEPHEN KAHL PH.D. IN SUPPORT OF PETITION
`FOR INTER PARTES REVIEW OF PATENT NO. 9,566,289
`
`FlatWing Ex. 1003, p. 1
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,566,289
`
`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 ’289 PATENT AND RELEVANT PROSECUTION HISTORY .......... 10
`
`VIII. OPINIONS ....................................................................................................... 12
`
`IX. CONCLUSION ................................................................................................ 18
`
`
`
`
`– i –
`
`FlatWing Ex. 1003, p. 2
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,566,289
`
`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. 9,566,289 (“the ’289 Patent”) filed by petitioner (FlatWing Pharmaceuticals,
`
`LLC), which challenges the patentability of claims 1–15 of the ’289 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 –
`
`FlatWing Ex. 1003, p. 3
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,566,289
`
`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 –
`
`FlatWing Ex. 1003, p. 4
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,566,289
`
`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 ’289 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 –
`
`FlatWing Ex. 1003, p. 5
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,566,289
`
`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. 9,566,289
`
`SHORT FORM
`
`‘289 Patent
`
`Ex. 1002 Prosecution History of the ‘289 Patent
`
`
`
`Ex. 1007 Austin et al., PCT Pub. No. WO 1995/033754
`
`Austin ‘574
`
`Ex. 1008 Brehove, U.S. Patent Pub. No. 2002/0165121
`
`Brehove ‘121
`
`Ex. 1009 Freeman et al., PCT Pub. No. WO 2003/009689
`
`Freeman ‘689
`
`Ex. 1010 Samour et al., U.S. Patent No. 6,224,887
`Ex. 1011 Handbook of Pharmaceutical Excipients (Arthur H.
`Kibbe ed., 3d ed. 2000)
`Ex. 1012 U.S. Patent No. 7,582,621
`
`Samour ‘887
`Excipients
`Handbook
`‘621 Patent
`
`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”)
`
`
`
`
`
`‘657 Patent
`
`
`
`– 4 –
`
`FlatWing Ex. 1003, p. 6
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,566,289
`
`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
`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. 1023 Remington: The Science and Practice of Pharmacy
`(Lippincott Williams & Wilkins eds., 21st ed. 2005)
`Ex. 1024 Hawley’s Condensed Chemical Dictionary (John
`Wiley & Sons, Inc., 13th ed. 1997)
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=6440876, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/64408
`76 (retrieved on May 26, 2017)
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=3198, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/3198
`(retrieved on May 26, 2017)
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=11499245, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/11499
`245 (retrieved on May 26, 2017)
`
`Ex. 1025
`
`Ex. 1026
`
`Ex. 1027
`
`
`
`– 5 –
`
`
`
`
`
`
`
`‘894 Patent
`
`Murdan 2002
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`FlatWing Ex. 1003, p. 7
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,566,289
`
`Ex. 1028
`
`Ex. 1029
`
`Ex. 1030
`
`Meds. & Healthcare Prods. Regulatory Agency,
`Curanail 5% Nail Lacquer (Amorolfine
`Hydrochloride) PL 10590/0049, UK Public
`Assessment Report (approved July 4, 2006)
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=22497760, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/22497
`760 (retrieved on May 26, 2017)
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=61764, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/61764
`(retrieved on May 26, 2017)
`Mertin, Dirk, and Lippold, Bernhard C. “In-vitro
`permeability of the human nail and of a keratin
`membrane from bovine hooves: Prediction of the
`penetration rate of antimycotics through the nail
`plate and their efficacy.” Journal of pharmacy and
`pharmacology 49, no. 9 (1997): 866-872
`Groziak, Michael P. “Boron therapeutics on the
`horizon,” American journal of therapeutics 8, no. 5
`(2001): 321-328
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=66827, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/66827
`(retrieved on May 26, 2017)
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=2775922, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/27759
`22 (retrieved on May 26, 2017)
`Ex. 1035 Aldrich Handbook of Fine Chemicals and
`Laboratory Equipment (Sigma-Aldrich, 2004)
`
`Ex. 1031
`
`Ex. 1032
`
`Ex. 1033
`
`Ex. 1034
`
`
`
`
`
`
`
`Mertin 1997
`
`Groziak 2001
`
`
`
`
`
`Ex. 1035
`
`
`
`– 6 –
`
`FlatWing Ex. 1003, p. 8
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,566,289
`
`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.
`
`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
`
`
`
`– 7 –
`
`FlatWing Ex. 1003, p. 9
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,566,289
`
`analysis. I understand there may be a number of rationales that may support a
`
`reasonable expectation of success, including:
`
`• 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 ’289 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 ’289 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
`
`’289 Patent, February 16, 2005.
`
`22.
`
`I believe a POSITA at the time U.S. application to which the ’289 patent
`
`claims priority was filed would have had an advanced degree (Master’s or Ph.D.)
`
`
`
`– 8 –
`
`FlatWing Ex. 1003, p. 10
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,566,289
`
`or equivalent experience in chemistry, pharmacology, or biochemistry, and at least
`
`two years of experience with the research, development, or production of
`
`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 prior art
`
`cited therein, which included all prior art relied upon in the current Petition, was
`
`“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 ’289 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).
`
`
`
`– 9 –
`
`FlatWing Ex. 1003, p. 11
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,566,289
`
`VII. THE ’289 PATENT AND RELEVANT PROSECUTION HISTORY
`
`24.
`
`I understand the ’289 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.)
`
`25.
`
`I further understand the ’289 Patent specifically claims a pharmaceutical
`
`formulation including 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole. (Id. at
`
`Cols. 323-24.) 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole has the
`
`following structure:
`
`
`I understand that during the prosecution of the application leading to U.S.
`
`26.
`
`Patent No. 7,582,621 (the “’621 Patent”), from which the ’289 Patent claims
`
`priority, that the Examiner rejected the pending claims over Austin WO ’574and
`
`the definition of “fungicide” from Answers.com. (Ex. 1013 at 53-55.) Specifically,
`
`the Examiner appears to have recognized that Austin WO ’574 discloses 1,3-
`
`
`
`– 10 –
`
`FlatWing Ex. 1003, p. 12
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,566,289
`
`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 p. 55.)
`
`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
`
`
`
`– 11 –
`
`FlatWing Ex. 1003, p. 13
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,566,289
`
`which the application that issued as the ’289 patent claimed priority and thus are
`
`part of the prosecution history of the ’289 patent. (Ex.1001.)
`
`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
`
`
`
`– 12 –
`
`FlatWing Ex. 1003, p. 14
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,566,289
`
`trialkylboranes and a POSITA would recognize that the boron-containing
`
`compounds of Austin WO ’574 are generally considered safe.
`
`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 –
`
`FlatWing Ex. 1003, p. 15
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,566,289
`
`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 ’289 Patent.
`
`36. Austin WO ’574 discloses “5- and 6-fluoro or bromo-1,3 dihydro-
`
`1hydroxy-2,1-benzoxaborole” as “[p]referred compounds” on the front page of the
`
`patent application publication. (Ex. 1007 at [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. (Id. 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 –
`
`FlatWing Ex. 1003, p. 16
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,566,289
`
`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 –
`
`FlatWing Ex. 1003, p. 17
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,566,289
`
`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 –
`
`FlatWing Ex. 1003, p. 18
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,566,289
`
`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 1–15 of the ’289
`
`– 17 –
`
`FlatWing Ex. 1003, p. 19
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,566,289
`
`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 –
`
`FlatWing Ex. 1003, p. 20
`
`
`
`Declaration of Stephen Kahl, Ph.D. in support of
`Petition for Inter Partes Review of U.S. Patent No. 9,566,289
`
`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
`
`FlatWing Ex. 1003, p. 21
`
`
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
