`
`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
`
`Application No.: 11/505,591
`
`Art Unit: 1626
`
`Filed: August 16, 2006
`
`RESPONSE TO OFFICE ACTION
`
`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
`
`following amendments and remarks.
`
`Amendments to the Claims are reflected in the listing of claims which begins on page 2 of this
`paper.
`
`Remarks/ Arguments begin on page 7 of this paper.
`
`Page 1of12
`
`CFAD Exhibit 1015
`
`
`
`Appl. No. 11/505,591
`Response to Office Action dated January 27, 2009
`Response dated May 14, 2009
`
`PATENT
`
`Amendments to the Claims:
`
`This listing of claims will replace all prior versions, and listings of claims in the application.
`
`Listing of Claims:
`
`1.-120. (Cancelled)
`
`1
`
`2
`
`3
`
`4
`
`5
`
`1
`
`2
`
`1
`
`2
`
`2
`
`3
`
`4
`
`5
`
`1
`
`2
`
`121.
`
`(Previously presented) A pharmaceutical formulation, comprising:
`
`(a) 1,3-dihydro-5-fluoro-l-hydroxy-2, 1-benzoxaborole, or a salt thereof; and
`
`(b) a pharmaceutically acceptable excipient
`
`wherein said pharmaceutical formulation is for topical administration to an animal
`
`suffering from an infection by a microorganism.
`
`122. - 192. (Cancelled).
`
`193. (Previously presented) The formulation of claim 121, wherein said
`
`formulation is a member selected from a lacquer, lotion, cream, gel, ointment and spray.
`
`194. (Previously presented) The formulation of claim 121, wherein said
`
`formulation is a lacquer.
`
`195. (Previously presented) The fotmulation of claim 121, wherein said
`
`formulation further comprises one or more members selected from an emulsifier, emollient,
`
`antioxidant, perservative, chelating agent, neutralizing agent, viscosity increasing agent, nail
`
`penetration enhancer, anti-inflammatory agent, vitamin, anti-aging agent, sunscreen and acne-
`
`treating agent.
`
`196. (Previously presented) The formulation of claim 121, wherein said
`
`formulation comprises one or more members selected from ethanol and propylene glycol.
`
`Page 2of12
`
`
`
`Appl. No. 11/505,591
`Response to Office Action dated January 27, 2009
`Response dated May 14, 2009
`
`PATENT
`
`1
`
`2
`
`3
`
`2
`
`3
`
`1
`
`2
`
`3
`
`1
`
`2
`
`3
`
`1
`
`2
`
`3
`
`197. (Previously presented) The formulation of claim 121, comprising: about
`
`propylene glycol:ethanol in a ratio of about 1 :4, and about 1: 10 wt/ volume of said 1,3-dihydro-
`
`5-fluoro-1-hydroxy-2, 1-benzoxaborole.
`
`198. (Previously presented) The formulation of claim 121, comprising: about
`
`70% ethanol; about 20% poly(vinyl methyl ether-alt-maleic acid monobutyl ester) and about
`
`10% of said 1,3-dihydro-5-fluoro-1-hydroxy-2, 1-benzoxaborole.
`
`199. (Previously presented) The formulation of claim 121, comprising: about
`
`56% ethanol; about 14% water; about 15% poly(2-hydroxyethyl methacrylate); about 5% dibutyl
`
`sebacate and about 10% of said 1,3-dihydro-5-fluoro-1-hydroxy-2, 1-benzoxaborole.
`
`200. (Previously presented) The formulation of claim 121, comprising: about
`
`55% ethanol; about 15% ethyl acetate; about 15% poly(vinyl acetate); about 5% dibutyl sebacate
`
`and about 10% 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole.
`
`201. (Previously presented) The formulation of claim 121, wherein said 1,3-
`
`dihydro-5-fluoro-1-hydroxy-2, 1-benzoxaborole is present in said formulation in a concentration
`
`from about 0.5% to about 15% w/v.
`
`202. (Previously presented) The formulation of claim 121, wherein said 1,3-
`
`2
`
`dihydro-5-fluoro-1-hydroxy-2, 1-benzoxaborole, or salt thereof, is present in a form which is a
`
`3 member selected from a hydrate with water, a solvate with an alcohol, an adduct with an amino
`
`4
`
`1
`
`2
`
`2
`
`3
`
`compound, and an adduct with an acid.
`
`203. (Previously presented) The formulation of claim 121, wherein said
`
`formulation is in a cosmetically effective amount.
`
`204. (Previously presented) The formulation of claim 121, wherein a site of said
`
`topical administration is skin or nail or hair or skin surrounding the nail or skin surrounding the
`
`hair.
`
`Page 3of12
`
`
`
`Appl. No. 11/505,591
`Response to Office Action dated January 27, 2009
`Response dated May 14, 2009
`
`PATENT
`
`205. (Previously presented) The formulation of claim 121, wherein the
`
`2 microorganism is a fungus or a yeast.
`
`1
`
`2
`
`3
`
`206. (Previously presented) The formulation of claim 205, wherein said fungus
`
`or yeast is a member selected from Candida species, Trichophyton species, Microsporium
`
`species, Aspergillus species, Cryptococcus species, Blastomyces species, Cocciodiodes species,
`
`4 Histoplasma species, Paracoccidiodes species, Phycomycetes species, Malassezia species,
`
`5
`
`6
`
`7
`
`1
`
`2
`
`3
`
`4
`
`Fusarium species, Epidermophyton species, Scytalidium species, Scopulariopsis species,
`
`Alternaria species, Penicillium species, Phialophora species, Rhizopus species, Scedosporium
`
`species and Zygomycetes species.
`
`207. (Previously presented) The formulation of claim 205, wherein said fungus
`
`or yeast is a member selected from Aspergilus fumigatus, Blastomyces dermatitidis, Candida
`
`albicans, Candida glabrata, Candida krusei, Cryptococcus neoformans, Candida parapsilosis,
`
`Candida tropicalis, Cocciodiodes immitis, Epidermophyton floccosum, Fusarium solani,
`
`5 Histoplasma capsulatum, Malasseziafurfur, Malassezia pachydermatis, Malassezia sympodialis,
`
`6 Microsporum audouinii, Microsporum canis, Microsporum gypseum, Paracoccidiodes
`
`7
`
`brasiliensis, Trichophyton mentagrophytes, Trichophyton rubrum and Trichophyton tonsurans.
`
`1
`
`2
`
`3
`
`4
`
`5
`
`2
`
`1
`
`2
`
`208. (Previously presented) The formulation of claim 205, wherein said fungus
`
`or yeast is a member selected from Trichophyton concentricum, Trichophyton violaceum,
`
`Trichophyton schoenleinii, Trichophyton verrucosum, Trichophyton soudanense, Microsporum
`
`gypseum, Microsporum equinum, Candida guilliermondii, Malassezia globosa, Malassezia
`
`obtuse, Malassezia restricta, Malassezia sloojjiae and Aspergillusflavus.
`
`209. (Previously presented) The formulation of claim 205, wherein said fungus
`
`or yeast is a dermatophyte.
`
`210. (Previously presented) The formulation of claim 205, wherein said fungus
`
`or yeast is a member selected from Tinea unguium, Trichophyton rubrum and Trichophyton
`
`3 mentagrophytes.
`
`Page 4of12
`
`
`
`Appl. No. 111505,591
`Response to Office Action dated January 27, 2009
`Response dated May 14, 2009
`
`PATENT
`
`1
`
`2
`
`2
`
`1
`
`2
`
`1
`
`2
`
`211. (Previously presented) The formulation of claim 121, wherein the infection
`
`is a cutaneous infection.
`
`212. (Previously presented) The formulation of claim 121, wherein the infection
`
`is a member selected from an ungual, periungual and subungual infection.
`
`213. (Previously presented) The formulation of claim 121, wherein the infection
`
`is onychomycosis.
`
`214. (Previously presented) The formulation of claim 121, wherein the animal is
`
`a human.
`
`Page 5of12
`
`
`
`Appl. No. 11/505,591
`Response to Office Action dated January 27, 2009
`Response dated May 14, 2009
`
`PATENT
`
`REMARKS/ARGUMENTS
`
`I. Status ofthe Claims
`
`Claims 121and193-214 are pending.
`
`II. Response to the Rejections
`
`3 5 USC§ 112, first paragraph
`
`Claim 195 is rejected under 35 USC § 112, first paragraph, because the Examiner alleges
`
`that while the specification enables an anti-aging agent selected from niacinamide and an acne(cid:173)
`
`treating agent selected from salicylic acid, the specification does not reasonably provide
`
`enablement for any anti-aging agent or acne-treating agent.
`
`Applicants traverse. The test for enablement is whether one reasonably skilled in the art
`
`could make or use the invention from the disclosures in the application coupled with information
`
`known in the art without undue experimentation. See MPEP 2164.01 (citing United States v.
`
`Telectronics, Inc., 857 F.2d 778, 785 (Fed. Cir. 1988)). In determining whether experimentation
`
`would be undue, the Examiner must consider a number of factors set forth by the Federal Circuit
`
`in In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988). Here, the Examiner has improperly
`
`analyzed a number of the Wands factors and thus has failed to establish a basis for concluding
`
`that the experimentation needed to make and use the invention is undue.
`
`The state o[the prior art
`
`The Examiner on page 4 of the instant office action states that "the state of the prior art is
`
`Austin et al. US 5,880, 188 ("Austin"), it discloses similar compositions or formulation, see
`
`column 28." Austin, however, states that "The present invention relates to the use of oxaboroles
`
`and salts thereof as industrial biocides ... " Col. 1, lines 6-8. A previous citation in the literature
`
`(FR 73293 70) "discloses that an oxaborole is ... useful in inhibiting the growth of micro
`
`organisms in aviation fuels." Col. 1, lines 39-45. Austin suggests that the disclosed compounds
`
`"containing an oxaborole ring are particularly effective against ... fungi, especially fungi which
`
`cause degradation of plastics materials." Col. I, lines 46-50.
`
`Austin contemplates using oxaboroles for "the protection of a medium susceptible to
`
`microbial attack." Col. I, lines 54 & 55. Examples of a "medium" according to Austin include
`
`Page 6of12
`
`
`
`Appl. No. 11/505,591
`Response to Office Action dated January 27, 2009
`Response dated May 14, 2009
`
`PATENT
`
`"solvent-based paint", col. 5, line 8; "a plastics material", col. 5, line 11; "an aqueous medium"
`
`col. 5, line 15. Austin suggests use of oxaboroles in systems such as
`
`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[.]
`
`Col. 8, lines 1-10. Further, 5-fluoro substituted benzoxaboroles are taught to provide
`
`"particularly useful effects ... in plastics materials and paint films." Col. 4, lines 50-54.
`
`Column 28 of Austin, to which the Examiner has pointed specifically, discloses compositions
`
`comprising an oxaborole and a carrier exemplified by a paint film, a plastics material, plasticized
`
`PVC or polyurethane and a stabilizer or plasticizer for a plastics material. Thus, in the state of
`
`art according to Austin, oxaboroles were recognized as useful in industry. In contrast, claim 195
`
`is directed to a pharmaceutical formulation comprising in part a pharmaceutically acceptable
`
`excipient.
`
`The amount of direction or guidance present
`
`The Examiner on page 5 of the instant office action states that "the only direction or
`
`guidance present in the instant specification is that anti-aging agent selected from niacinamide
`
`and acne-treating agent is selected from salicylic acid, see page 168 of the specification." This
`
`characterization of the specification is incorrect. The specification, page 168, paragraph 406,
`
`states that "anti-aging agents include, but are not limited to, niacinamide, retinol and retinoid
`
`derivatives, AHA, Ascorbic acid, lipoic acid, coenzyme Q 10, beta hydroxy acids, salicylic acid,
`
`copper binding peptides, dimethylaminoethyl (DAEA), and the like." The specification, page
`
`168, paragraph 408, states that "acne-treating agents include, but are not limited to, salicylic
`
`acid, benzoyl peroxide, coal tar, selenium sulfide, zinc oxide, pyrithione (zinc and/or sodium),
`
`tazarotene, calcipotriene, tretinoin, adapalene and the like." Thus, the specification provides at
`
`least 11 examples of anti-aging agents and at least 10 types of acne-treating agents. It is
`
`therefore inaccurate to assert that an anti-aging agent is exemplified by only niacinamide and an
`
`acne-treating agent is exemplified by only salicylic acid in the specification.
`
`Page 7of12
`
`
`
`Appl. No. 111505,591
`Response to Office Action dated January 27, 2009
`Response dated May 14, 2009
`
`The presence or absence of working examples
`
`PATENT
`
`The Examiner states that "there is no data present in the instant anti-aging agent and
`
`acne-treating agent, which is not limited." Applicants note, however, that "[w]hen considering
`
`the factors relating to a determination of non-enablement, if all the other factors point toward
`
`enablement, then the absence of working examples will not by itself render the invention non(cid:173)
`
`enabled." MPEP 2164.02. As discussed herein, claim 195 is fully enabled by the specification
`
`coupled with knowledge in the art, and the Examiner has not established a factual basis for
`
`concluding otherwise.
`
`The breadth ofthe claims
`
`The Examiner states that "the instant breadth of the rejected claims is broader than the
`
`disclosure, specifically, the instant claims include any anti-aging agent and acne-treating agent,
`
`which are not limited." Applicants disagree. In paragraphs 404-409, the specification describes
`
`commercially available additional active agents that may find use in the claimed invention.
`
`Particularly, anti-aging agents and acne-treating agents are exemplified by no fewer than 10
`
`different types of each of those agents. Thus, while the terms "anti-aging agent" and "acne(cid:173)
`
`treating agent" are generic terms embracing a number of compounds, many examples of those
`
`compounds are provided in the specification. The disclosure fully supports the use of these
`
`terms in the claims.
`
`Quantity or experimentation needed and the level of skill in the art
`
`As stated by the Examiner, the level of skill in the chemical arts is high. In view of this
`
`finding, Applicants submit that the specification, coupled with the knowledge generally known
`
`in the art, is sufficient to enable practice of the full scope of the rejected claim. Claim 195
`
`encompasses a pharmaceutical formulation comprising 1,3-dihydro-5-fluoro-1-hydroxy-2, 1-
`
`benzoxaborole ("C 1 O") or a salt thereof, a pharmaceutically acceptable excipient and at least one
`
`of the members recited in the claim. Methods of making ClO are described in Examples 5-7, and
`
`characterization data are provided in paragraph 457. Figures 2-7 show the effectiveness of C 10
`
`in inhibiting the growth of numerous microorganisms. Numerous formulations of C 10 are
`
`described in paragraphs 211-213 and 346-402 and exemplified in paragraph 514, 551 and 556.
`
`Other formulations may be made based on excipients, additives and methods known in the art.
`
`See, e.g., Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams &
`
`Page 8of12
`
`
`
`Appl. No. 11/505,591
`Response to Office Action dated January 27, 2009
`Response dated May 14, 2009
`
`PATENT
`
`Wilkins (2005), incorporated by reference in paragraph 72. Formulations comprising an
`
`additional active agent such as those listed in claim 195 can be made by one of skill in the art.
`
`Specific additional active agents such as anti-aging agents and acne-treating agents are known
`
`according to the teachings of the present specification. See paragraph 406 ("Anti-aging agents
`
`include, but are not limited to, niacinamide, retinol and retinoid derivatives, AHA, Ascorbic acid,
`
`lipoic acid, coenzyme Q 10, beta hydroxy acids, salicylic acid, copper binding peptides,
`
`dimethylaminoethyl (DAEA), and the like.") and paragraph 408 ("acne-treating agents include,
`
`but are not limited to, salicylic acid, benzoyl peroxide, coal tar, selenium sulfide, zinc oxide,
`
`pyrithione (zinc and/or sodium), tazarotene, calcipotriene, tretinoin, adapalene and the like.")).
`
`These and many other anti-aging and acne-treating agents, as well as methods of formulating
`
`them for pharmaceutical use, are well-known in the art. See, e.g, US Patent Application
`
`Publication Nos. 2006/0083777 ("Treatment of acne"); 2006/0008537 ("Method of treating
`
`acne"); 2004/0092482 ("Hydroxy acids based delivery systems for skin resurfacing and anti(cid:173)
`
`aging compositions"); 2004/0067890 ("Ascorbic acid salts of organic bases with enhanced
`
`bioavailability for synergi[ s ]tic anti-aging and skin protective cosmetic compositions"); and
`
`2004/0001897 ("Skin vitalizing composition for external use anti-aging preparation"). In view
`
`of the specification and the teachings of the art, claim 195, which recites a pharmaceutical
`
`formulation that may comprise at least one anti-aging agent and/or acne-treating agent, can be
`
`practiced without undue experimentation by one of ordinary skill in the art.
`
`The Examiner has failed to establish a sufficient factual basis under the Wands factors to
`
`conclude that the claims are not enabled in view of the specification and the art. Withdrawal of
`
`the rejection is therefore respectfully requested.
`
`35USC§103
`
`Claims 121 and 193-214 are rejected under 35 USC § 103 as allegedly being
`
`unpatentable over Austin et al., US Patent No. 5,880,188 ("Austin I") in view of Austin et al.,
`
`CAPLUS Document No. 124:234024 ("Austin II").
`
`To establish aprimafacie case of obviousness, the Examiner is required to perform a
`
`factual analysis according to the Graham factors and to provide some articulated reasoning with
`
`some rational underpinning to support the legal conclusion of obviousenss. See KSR Int'/. Co. v.
`
`Teleflex Inc., 127 S.Ct. 1727, 1734, 1741 (2007).
`
`Page 9of12
`
`
`
`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
`
`as inhibiting bacterial or fungal growth in aviation fuels, plastics materials, cooling water liquors,
`
`paper mill liquors, metal working fluids, geological drilling lubricants, polymer emulsions,
`
`surface coating compositions such as paints, varnishes and lacquers, and solid materials such as
`
`wood, plastics materials, leather, and plastics materials such as plasticized PVC and urethanes.
`
`Austin II discloses 1,3-dihydro-5-fluoro- l-hydroxy-2, 1-benzoxaborole. However, Austin
`
`II also suggests that the oxaboroles disclosed therein are useful in industrial settings. See Austin
`
`II, page 1, second to the last line, which discloses "oxaboroles and salts and their use as biocides
`
`for plastics". Furthermore, Austin II is a chemical database record showing a number of patent
`
`applications that claim priority to PCT Application No. GB1995/01206 ("Austin PCT
`
`Application"), filed May 26, 1995. One such application is Austin I, which is the US national
`
`phase filing of the Austin PCT Application. Thus, in view of Austin I, Austin II does not appear
`
`to disclose any additional information relating to the use of oxaboroles outside of an industrial
`
`setting.
`
`The Examiner states that "the motivation to make the claimed compounds derived from
`
`the known compounds/compositions would possess similar activity (i.e., fungicide or treating
`
`fungal infection) to that which is claimed in the reference." However, the fact that Austin I and
`
`Austin II disclose industrial uses of oxaboroles does not suggest to one of skill in the art to use
`
`the claimed benzoxaboroles in a pharmaceutical formulation. Applicants submit that one of
`
`skill in the art would not presumptively consider a compound to be suitable for administration to
`
`an animal, especially a human, merely because a compound has been shown to have antifungal
`
`effects in paint or aviation fuel. In fact, a reference ("Answers.com", attached as Exhibit A)
`
`cited by the Examiner against the parent of this case (Application No. 11/357,687) teaches away
`
`from presuming that any antifungal compound can be administered to an animal. For example,
`
`Answers.com, page 3, states that
`
`Page 10of12
`
`
`
`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.
`
`Answers.com, page 4 teaches that "some fungicides are dangerous to human health, such as
`
`vinclozolin, which has now been removed from use [citation to Hrelia et al., The genetic and
`
`non-genetic toxicity of the fungicide Vinclozolin. Mutagenesis 1996, 11: 445-453]." Certain
`
`fungicides, such as captafol, pentachlorophenol, pentachlorophenate sodium, fentin,
`
`cycloheximide, chlorobenzilate, and copper arsenate hydroxide, are banned in Thailand because
`
`of their adverse effects on humans. See http://thailand.ipm(cid:173)
`
`info.org/pesticides/pesticides_banned.htm. Thus, the art teaches that compounds that are useful
`
`for killing or inhibiting fungi may also harm animals, and thus teaches away from assuming that
`
`any fungicide can be used in a pharmaceutical formulation as claimed. Austin I and II, cited by
`
`the Examiner, teaches the use of oxaboroles in treating plastics and materials and in other
`
`industrial settings, and there is no reason why, in view of Answers.com, one of skill in the art
`
`would extrapolate such use for treating animals given the potential harm that may occur.
`
`The Examiner has not provided any valid reasoning why one of skill in the art would find
`
`the claimed invention obvious in view of the cited references. Without this reasoning, the
`
`Examiner has not established a prima facie case of obviousness. Withdrawal of the rejection is
`
`therefore respectfully requested.
`
`Page 11 of 12
`
`
`
`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
`
`Application are in condition for allowance. The issuance of a formal Notice of Allowance at an
`
`early date is respectfully requested.
`
`If the Examiner believes a telephone conference would expedite prosecution of
`
`this application, please telephone the undersigned at 415-442-1000.
`
`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