CERTIFICATE OF ELECTRONIC TRANSMISSION
`
`I hereby certify that this correspondence, including listed enclosures is
`being electronically transmitted in Portable Document Form (PDF) through
`EFS-Web via Hyper Text Transfer Protocol to the United States Patent and
`
`Attorney Docket No.: 064507-5014-USOl
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re application of:
`
`Confirmation No.: 5739
`
`Stephen J. BAKER, et al.
`
`Examiner: SHIAO, Rei Tsang
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`Application No.: 11/505,591
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`Art Unit: 1626
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`Filed: August 16, 2006
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`RESPONSE TO OFFICE ACTION
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`For: BORON-CONTAINING SMALL
`MOLECULES
`
`Customer No.: 43850
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Madam:
`
`In response to the Office Action dated January 27, 2009, please enter the
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`following amendments and remarks.
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`Amendments to the Claims are reflected in the listing of claims which begins on page 2 of this
`paper.
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`Remarks/ Arguments begin on page 7 of this paper.
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`Page 1of12
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`CFAD Exhibit 1015
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`

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`Appl. No. 11/505,591
`Response to Office Action dated January 27, 2009
`Response dated May 14, 2009
`
`PATENT
`
`Amendments to the Claims:
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`This listing of claims will replace all prior versions, and listings of claims in the application.
`
`Listing of Claims:
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`1.-120. (Cancelled)
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`1
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`2
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`3
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`4
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`5
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`1
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`2
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`1
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`2
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`2
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`5
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`1
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`2
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`121.
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`(Previously presented) A pharmaceutical formulation, comprising:
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`(a) 1,3-dihydro-5-fluoro-l-hydroxy-2, 1-benzoxaborole, or a salt thereof; and
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`(b) a pharmaceutically acceptable excipient
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`wherein said pharmaceutical formulation is for topical administration to an animal
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`suffering from an infection by a microorganism.
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`122. - 192. (Cancelled).
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`193. (Previously presented) The formulation of claim 121, wherein said
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`formulation is a member selected from a lacquer, lotion, cream, gel, ointment and spray.
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`194. (Previously presented) The formulation of claim 121, wherein said
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`formulation is a lacquer.
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`195. (Previously presented) The fotmulation of claim 121, wherein said
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`formulation further comprises one or more members selected from an emulsifier, emollient,
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`antioxidant, perservative, chelating agent, neutralizing agent, viscosity increasing agent, nail
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`penetration enhancer, anti-inflammatory agent, vitamin, anti-aging agent, sunscreen and acne-
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`treating agent.
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`196. (Previously presented) The formulation of claim 121, wherein said
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`formulation comprises one or more members selected from ethanol and propylene glycol.
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`Page 2of12
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`

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`Appl. No. 11/505,591
`Response to Office Action dated January 27, 2009
`Response dated May 14, 2009
`
`PATENT
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`1
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`2
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`3
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`2
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`3
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`1
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`2
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`3
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`1
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`2
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`3
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`1
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`2
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`3
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`197. (Previously presented) The formulation of claim 121, comprising: about
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`propylene glycol:ethanol in a ratio of about 1 :4, and about 1: 10 wt/ volume of said 1,3-dihydro-
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`5-fluoro-1-hydroxy-2, 1-benzoxaborole.
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`198. (Previously presented) The formulation of claim 121, comprising: about
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`70% ethanol; about 20% poly(vinyl methyl ether-alt-maleic acid monobutyl ester) and about
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`10% of said 1,3-dihydro-5-fluoro-1-hydroxy-2, 1-benzoxaborole.
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`199. (Previously presented) The formulation of claim 121, comprising: about
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`56% ethanol; about 14% water; about 15% poly(2-hydroxyethyl methacrylate); about 5% dibutyl
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`sebacate and about 10% of said 1,3-dihydro-5-fluoro-1-hydroxy-2, 1-benzoxaborole.
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`200. (Previously presented) The formulation of claim 121, comprising: about
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`55% ethanol; about 15% ethyl acetate; about 15% poly(vinyl acetate); about 5% dibutyl sebacate
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`and about 10% 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole.
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`201. (Previously presented) The formulation of claim 121, wherein said 1,3-
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`dihydro-5-fluoro-1-hydroxy-2, 1-benzoxaborole is present in said formulation in a concentration
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`from about 0.5% to about 15% w/v.
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`202. (Previously presented) The formulation of claim 121, wherein said 1,3-
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`2
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`dihydro-5-fluoro-1-hydroxy-2, 1-benzoxaborole, or salt thereof, is present in a form which is a
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`3 member selected from a hydrate with water, a solvate with an alcohol, an adduct with an amino
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`4
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`1
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`2
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`2
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`3
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`compound, and an adduct with an acid.
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`203. (Previously presented) The formulation of claim 121, wherein said
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`formulation is in a cosmetically effective amount.
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`204. (Previously presented) The formulation of claim 121, wherein a site of said
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`topical administration is skin or nail or hair or skin surrounding the nail or skin surrounding the
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`hair.
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`Page 3of12
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`

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`Appl. No. 11/505,591
`Response to Office Action dated January 27, 2009
`Response dated May 14, 2009
`
`PATENT
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`205. (Previously presented) The formulation of claim 121, wherein the
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`2 microorganism is a fungus or a yeast.
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`1
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`2
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`3
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`206. (Previously presented) The formulation of claim 205, wherein said fungus
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`or yeast is a member selected from Candida species, Trichophyton species, Microsporium
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`species, Aspergillus species, Cryptococcus species, Blastomyces species, Cocciodiodes species,
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`4 Histoplasma species, Paracoccidiodes species, Phycomycetes species, Malassezia species,
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`5
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`6
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`7
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`1
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`2
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`3
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`4
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`Fusarium species, Epidermophyton species, Scytalidium species, Scopulariopsis species,
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`Alternaria species, Penicillium species, Phialophora species, Rhizopus species, Scedosporium
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`species and Zygomycetes species.
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`207. (Previously presented) The formulation of claim 205, wherein said fungus
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`or yeast is a member selected from Aspergilus fumigatus, Blastomyces dermatitidis, Candida
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`albicans, Candida glabrata, Candida krusei, Cryptococcus neoformans, Candida parapsilosis,
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`Candida tropicalis, Cocciodiodes immitis, Epidermophyton floccosum, Fusarium solani,
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`5 Histoplasma capsulatum, Malasseziafurfur, Malassezia pachydermatis, Malassezia sympodialis,
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`6 Microsporum audouinii, Microsporum canis, Microsporum gypseum, Paracoccidiodes
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`7
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`brasiliensis, Trichophyton mentagrophytes, Trichophyton rubrum and Trichophyton tonsurans.
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`1
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`2
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`3
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`4
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`5
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`2
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`1
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`2
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`208. (Previously presented) The formulation of claim 205, wherein said fungus
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`or yeast is a member selected from Trichophyton concentricum, Trichophyton violaceum,
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`Trichophyton schoenleinii, Trichophyton verrucosum, Trichophyton soudanense, Microsporum
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`gypseum, Microsporum equinum, Candida guilliermondii, Malassezia globosa, Malassezia
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`obtuse, Malassezia restricta, Malassezia sloojjiae and Aspergillusflavus.
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`209. (Previously presented) The formulation of claim 205, wherein said fungus
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`or yeast is a dermatophyte.
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`210. (Previously presented) The formulation of claim 205, wherein said fungus
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`or yeast is a member selected from Tinea unguium, Trichophyton rubrum and Trichophyton
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`3 mentagrophytes.
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`Page 4of12
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`

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`Appl. No. 111505,591
`Response to Office Action dated January 27, 2009
`Response dated May 14, 2009
`
`PATENT
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`1
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`2
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`2
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`1
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`2
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`1
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`2
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`211. (Previously presented) The formulation of claim 121, wherein the infection
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`is a cutaneous infection.
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`212. (Previously presented) The formulation of claim 121, wherein the infection
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`is a member selected from an ungual, periungual and subungual infection.
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`213. (Previously presented) The formulation of claim 121, wherein the infection
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`is onychomycosis.
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`214. (Previously presented) The formulation of claim 121, wherein the animal is
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`a human.
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`Page 5of12
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`

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`Appl. No. 11/505,591
`Response to Office Action dated January 27, 2009
`Response dated May 14, 2009
`
`PATENT
`
`REMARKS/ARGUMENTS
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`I. Status ofthe Claims
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`Claims 121and193-214 are pending.
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`II. Response to the Rejections
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`3 5 USC§ 112, first paragraph
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`Claim 195 is rejected under 35 USC § 112, first paragraph, because the Examiner alleges
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`that while the specification enables an anti-aging agent selected from niacinamide and an acne(cid:173)
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`treating agent selected from salicylic acid, the specification does not reasonably provide
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`enablement for any anti-aging agent or acne-treating agent.
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`Applicants traverse. The test for enablement is whether one reasonably skilled in the art
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`could make or use the invention from the disclosures in the application coupled with information
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`known in the art without undue experimentation. See MPEP 2164.01 (citing United States v.
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`Telectronics, Inc., 857 F.2d 778, 785 (Fed. Cir. 1988)). In determining whether experimentation
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`would be undue, the Examiner must consider a number of factors set forth by the Federal Circuit
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`in In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988). Here, the Examiner has improperly
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`analyzed a number of the Wands factors and thus has failed to establish a basis for concluding
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`that the experimentation needed to make and use the invention is undue.
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`The state o[the prior art
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`The Examiner on page 4 of the instant office action states that "the state of the prior art is
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`Austin et al. US 5,880, 188 ("Austin"), it discloses similar compositions or formulation, see
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`column 28." Austin, however, states that "The present invention relates to the use of oxaboroles
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`and salts thereof as industrial biocides ... " Col. 1, lines 6-8. A previous citation in the literature
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`(FR 73293 70) "discloses that an oxaborole is ... useful in inhibiting the growth of micro
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`organisms in aviation fuels." Col. 1, lines 39-45. Austin suggests that the disclosed compounds
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`"containing an oxaborole ring are particularly effective against ... fungi, especially fungi which
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`cause degradation of plastics materials." Col. I, lines 46-50.
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`Austin contemplates using oxaboroles for "the protection of a medium susceptible to
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`microbial attack." Col. I, lines 54 & 55. Examples of a "medium" according to Austin include
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`Page 6of12
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`

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`Appl. No. 11/505,591
`Response to Office Action dated January 27, 2009
`Response dated May 14, 2009
`
`PATENT
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`"solvent-based paint", col. 5, line 8; "a plastics material", col. 5, line 11; "an aqueous medium"
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`col. 5, line 15. Austin suggests use of oxaboroles in systems such as
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`liquid, particularly aqueous, systems such as cooling water liquors, paper
`mill liquors, metal working fluids, geological drilling lubricants, polymer
`emulsions and especially surface coating compositions such as paints,
`varnishes and lacquers and more especially solid materials such as wood,
`plastics materials[,] leather[, and] plastics materials such as plasticised
`PVC and urethanes[.]
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`Col. 8, lines 1-10. Further, 5-fluoro substituted benzoxaboroles are taught to provide
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`"particularly useful effects ... in plastics materials and paint films." Col. 4, lines 50-54.
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`Column 28 of Austin, to which the Examiner has pointed specifically, discloses compositions
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`comprising an oxaborole and a carrier exemplified by a paint film, a plastics material, plasticized
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`PVC or polyurethane and a stabilizer or plasticizer for a plastics material. Thus, in the state of
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`art according to Austin, oxaboroles were recognized as useful in industry. In contrast, claim 195
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`is directed to a pharmaceutical formulation comprising in part a pharmaceutically acceptable
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`excipient.
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`The amount of direction or guidance present
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`The Examiner on page 5 of the instant office action states that "the only direction or
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`guidance present in the instant specification is that anti-aging agent selected from niacinamide
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`and acne-treating agent is selected from salicylic acid, see page 168 of the specification." This
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`characterization of the specification is incorrect. The specification, page 168, paragraph 406,
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`states that "anti-aging agents include, but are not limited to, niacinamide, retinol and retinoid
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`derivatives, AHA, Ascorbic acid, lipoic acid, coenzyme Q 10, beta hydroxy acids, salicylic acid,
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`copper binding peptides, dimethylaminoethyl (DAEA), and the like." The specification, page
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`168, paragraph 408, states that "acne-treating agents include, but are not limited to, salicylic
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`acid, benzoyl peroxide, coal tar, selenium sulfide, zinc oxide, pyrithione (zinc and/or sodium),
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`tazarotene, calcipotriene, tretinoin, adapalene and the like." Thus, the specification provides at
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`least 11 examples of anti-aging agents and at least 10 types of acne-treating agents. It is
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`therefore inaccurate to assert that an anti-aging agent is exemplified by only niacinamide and an
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`acne-treating agent is exemplified by only salicylic acid in the specification.
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`Page 7of12
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`

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`Appl. No. 111505,591
`Response to Office Action dated January 27, 2009
`Response dated May 14, 2009
`
`The presence or absence of working examples
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`PATENT
`
`The Examiner states that "there is no data present in the instant anti-aging agent and
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`acne-treating agent, which is not limited." Applicants note, however, that "[w]hen considering
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`the factors relating to a determination of non-enablement, if all the other factors point toward
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`enablement, then the absence of working examples will not by itself render the invention non(cid:173)
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`enabled." MPEP 2164.02. As discussed herein, claim 195 is fully enabled by the specification
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`coupled with knowledge in the art, and the Examiner has not established a factual basis for
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`concluding otherwise.
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`The breadth ofthe claims
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`The Examiner states that "the instant breadth of the rejected claims is broader than the
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`disclosure, specifically, the instant claims include any anti-aging agent and acne-treating agent,
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`which are not limited." Applicants disagree. In paragraphs 404-409, the specification describes
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`commercially available additional active agents that may find use in the claimed invention.
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`Particularly, anti-aging agents and acne-treating agents are exemplified by no fewer than 10
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`different types of each of those agents. Thus, while the terms "anti-aging agent" and "acne(cid:173)
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`treating agent" are generic terms embracing a number of compounds, many examples of those
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`compounds are provided in the specification. The disclosure fully supports the use of these
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`terms in the claims.
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`Quantity or experimentation needed and the level of skill in the art
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`As stated by the Examiner, the level of skill in the chemical arts is high. In view of this
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`finding, Applicants submit that the specification, coupled with the knowledge generally known
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`in the art, is sufficient to enable practice of the full scope of the rejected claim. Claim 195
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`encompasses a pharmaceutical formulation comprising 1,3-dihydro-5-fluoro-1-hydroxy-2, 1-
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`benzoxaborole ("C 1 O") or a salt thereof, a pharmaceutically acceptable excipient and at least one
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`of the members recited in the claim. Methods of making ClO are described in Examples 5-7, and
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`characterization data are provided in paragraph 457. Figures 2-7 show the effectiveness of C 10
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`in inhibiting the growth of numerous microorganisms. Numerous formulations of C 10 are
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`described in paragraphs 211-213 and 346-402 and exemplified in paragraph 514, 551 and 556.
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`Other formulations may be made based on excipients, additives and methods known in the art.
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`See, e.g., Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams &
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`Page 8of12
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`

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`Appl. No. 11/505,591
`Response to Office Action dated January 27, 2009
`Response dated May 14, 2009
`
`PATENT
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`Wilkins (2005), incorporated by reference in paragraph 72. Formulations comprising an
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`additional active agent such as those listed in claim 195 can be made by one of skill in the art.
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`Specific additional active agents such as anti-aging agents and acne-treating agents are known
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`according to the teachings of the present specification. See paragraph 406 ("Anti-aging agents
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`include, but are not limited to, niacinamide, retinol and retinoid derivatives, AHA, Ascorbic acid,
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`lipoic acid, coenzyme Q 10, beta hydroxy acids, salicylic acid, copper binding peptides,
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`dimethylaminoethyl (DAEA), and the like.") and paragraph 408 ("acne-treating agents include,
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`but are not limited to, salicylic acid, benzoyl peroxide, coal tar, selenium sulfide, zinc oxide,
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`pyrithione (zinc and/or sodium), tazarotene, calcipotriene, tretinoin, adapalene and the like.")).
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`These and many other anti-aging and acne-treating agents, as well as methods of formulating
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`them for pharmaceutical use, are well-known in the art. See, e.g, US Patent Application
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`Publication Nos. 2006/0083777 ("Treatment of acne"); 2006/0008537 ("Method of treating
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`acne"); 2004/0092482 ("Hydroxy acids based delivery systems for skin resurfacing and anti(cid:173)
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`aging compositions"); 2004/0067890 ("Ascorbic acid salts of organic bases with enhanced
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`bioavailability for synergi[ s ]tic anti-aging and skin protective cosmetic compositions"); and
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`2004/0001897 ("Skin vitalizing composition for external use anti-aging preparation"). In view
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`of the specification and the teachings of the art, claim 195, which recites a pharmaceutical
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`formulation that may comprise at least one anti-aging agent and/or acne-treating agent, can be
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`practiced without undue experimentation by one of ordinary skill in the art.
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`The Examiner has failed to establish a sufficient factual basis under the Wands factors to
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`conclude that the claims are not enabled in view of the specification and the art. Withdrawal of
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`the rejection is therefore respectfully requested.
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`35USC§103
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`Claims 121 and 193-214 are rejected under 35 USC § 103 as allegedly being
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`unpatentable over Austin et al., US Patent No. 5,880,188 ("Austin I") in view of Austin et al.,
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`CAPLUS Document No. 124:234024 ("Austin II").
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`To establish aprimafacie case of obviousness, the Examiner is required to perform a
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`factual analysis according to the Graham factors and to provide some articulated reasoning with
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`some rational underpinning to support the legal conclusion of obviousenss. See KSR Int'/. Co. v.
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`Teleflex Inc., 127 S.Ct. 1727, 1734, 1741 (2007).
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`Page 9of12
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`

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`Appl. No. 11/505,591
`Response to Office Action dated January 27, 2009
`Response dated May 14, 2009
`
`PATENT
`
`As discussed above, Austin I is directed to uses of oxaboroles in industrial settings, such
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`as inhibiting bacterial or fungal growth in aviation fuels, plastics materials, cooling water liquors,
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`paper mill liquors, metal working fluids, geological drilling lubricants, polymer emulsions,
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`surface coating compositions such as paints, varnishes and lacquers, and solid materials such as
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`wood, plastics materials, leather, and plastics materials such as plasticized PVC and urethanes.
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`Austin II discloses 1,3-dihydro-5-fluoro- l-hydroxy-2, 1-benzoxaborole. However, Austin
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`II also suggests that the oxaboroles disclosed therein are useful in industrial settings. See Austin
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`II, page 1, second to the last line, which discloses "oxaboroles and salts and their use as biocides
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`for plastics". Furthermore, Austin II is a chemical database record showing a number of patent
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`applications that claim priority to PCT Application No. GB1995/01206 ("Austin PCT
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`Application"), filed May 26, 1995. One such application is Austin I, which is the US national
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`phase filing of the Austin PCT Application. Thus, in view of Austin I, Austin II does not appear
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`to disclose any additional information relating to the use of oxaboroles outside of an industrial
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`setting.
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`The Examiner states that "the motivation to make the claimed compounds derived from
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`the known compounds/compositions would possess similar activity (i.e., fungicide or treating
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`fungal infection) to that which is claimed in the reference." However, the fact that Austin I and
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`Austin II disclose industrial uses of oxaboroles does not suggest to one of skill in the art to use
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`the claimed benzoxaboroles in a pharmaceutical formulation. Applicants submit that one of
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`skill in the art would not presumptively consider a compound to be suitable for administration to
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`an animal, especially a human, merely because a compound has been shown to have antifungal
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`effects in paint or aviation fuel. In fact, a reference ("Answers.com", attached as Exhibit A)
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`cited by the Examiner against the parent of this case (Application No. 11/357,687) teaches away
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`from presuming that any antifungal compound can be administered to an animal. For example,
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`Answers.com, page 3, states that
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`Page 10of12
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`

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`Appl. No. 11/505,591
`Response to Office Action dated January 27, 2009
`Response dated May 14, 2009
`
`PATENT
`
`Most fungicides can cause acute toxicity, and some cause chronic toxicity
`as "':ell. Hexachlorobenzene, now banned or severely restricted in most
`parts of the world, has been associated with human poisoning from
`contaminated seed grain and poisoning of infants from misuse in laundry
`solutions. Metam sodium and other thiocarbanates are skin irritants that
`can cause reactive airway disease at low doses and severe toxicity and
`even death at high doses. The ethylene bis dithiocarbamates (EBCDs) are
`suspected human carcinogens and are tightly regulated in the United
`States.
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`Answers.com, page 4 teaches that "some fungicides are dangerous to human health, such as
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`vinclozolin, which has now been removed from use [citation to Hrelia et al., The genetic and
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`non-genetic toxicity of the fungicide Vinclozolin. Mutagenesis 1996, 11: 445-453]." Certain
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`fungicides, such as captafol, pentachlorophenol, pentachlorophenate sodium, fentin,
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`cycloheximide, chlorobenzilate, and copper arsenate hydroxide, are banned in Thailand because
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`of their adverse effects on humans. See http://thailand.ipm(cid:173)
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`info.org/pesticides/pesticides_banned.htm. Thus, the art teaches that compounds that are useful
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`for killing or inhibiting fungi may also harm animals, and thus teaches away from assuming that
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`any fungicide can be used in a pharmaceutical formulation as claimed. Austin I and II, cited by
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`the Examiner, teaches the use of oxaboroles in treating plastics and materials and in other
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`industrial settings, and there is no reason why, in view of Answers.com, one of skill in the art
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`would extrapolate such use for treating animals given the potential harm that may occur.
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`The Examiner has not provided any valid reasoning why one of skill in the art would find
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`the claimed invention obvious in view of the cited references. Without this reasoning, the
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`Examiner has not established a prima facie case of obviousness. Withdrawal of the rejection is
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`therefore respectfully requested.
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`Page 11 of 12
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`

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`Appl. No. 11/505,591
`Response to Office Action dated January 27, 2009
`Response dated May 14, 2009
`
`PATENT
`
`CONCLUSION
`
`In view of the foregoing, Applicants believe all claims now pending in this
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`Application are in condition for allowance. The issuance of a formal Notice of Allowance at an
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`early date is respectfully requested.
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`If the Examiner believes a telephone conference would expedite prosecution of
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`this application, please telephone the undersigned at 415-442-1000.
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`Respectfully submitted,
`
`MORGAN, LEWIS & BOCKIUS LLP
`One Market, Spear Street Tower
`San Francisco, CA 94105
`Tel: 415-442-1000
`Fax: 415-442-1001
`DB2/21111884.1
`
`Page 12of12