Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Withdrawn Rejections:
Applicant's amendments and arguments filed on 12/18/2025 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or objection not specifically addressed below is herein withdrawn.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
Claims 1-5 and 14-15 are pending and under examination.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Walsh et al. (US7517852) as evidenced by Flynn et al. (WO2014164280).
Determination of the scope and content of the prior art
(MPEP 2141.01)
Walsh et al. teaches compositions (e.g., comprising a lantibiotic and mupirocin or gentamicin) and methods of treating (e.g., killing or inhibiting growth of) bacteria (abstract). Walsh et al. a method for treating or preventing infection comprising exposing a surface of a subject (including skin surface) to a topical pharmaceutical formulation comprising a lantibiotic and mupirocin (column 3, line 33-50). In some embodiments, the invention provides a pharmaceutical composition containing (a) a composition comprising mupirocin and a lantibiotic (e.g., nisin); and (b) one or more other agents (e.g., an antibiotic). Examples of other types of antibiotics include bacitracin and colistimethate (column 12 line 57 to column 13, line 10). Currently, BACTROBAN (2% mupirocin ointment: SmithKline Beecham, Bristol, Tenn.) is the most widely prescribed and effective antibacterial agent for treatment of S. aureus skin infections (column 8, line 54-57). Topical Ointment: 74 g of PEG 400 and 24 g of PEG 3350 were added to a 250 mL. glassbeaker and heated until all of the PEG 3350 was melted. The Solution was stirred well and allowed to cool to room temperature, which resulted in a Smooth, opaque ointment. Powdered nisin and bacitracin were added to the ointment on a w/w basis and stirred until homogenously mixed. For formulations containing mupirocin, 1 g of Bactroban Ointment was weighed into a container and powdered nisin added to 2% or 6% (w/w) and mixed well (column 15, line 40-50). In some embodiments, the composition is from 0.01 to 15% (e.g., 0.1-10%, 0.5-5%. 1-3%, 2%) by weight lantibiotic (e.g., nisin) and/or mupirocin (column 14, line 35-50).
Flynn et al. teaches Colistimethate sodium is a white to slightly yellow hygroscopic powder. It is commercially supplied at a particle size of 100-200 μιη mass median diameter. The powder is highly soluble in water, slightly soluble in ethanol (96%) and is used for parenteral administration by dissolving in water. As a powder, colistin sulphomethate sodium must be stored in air-tight containers, preferably protected from light (page 1, line 29 to page 2, line 1).
Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02)
The difference between the instant application and Walsh et al. is that Walsh et al. does not teach all the limitation in one embodiment.
Finding of prima facie obviousness
Rational and Motivation (MPEP 2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce the instant invention.
Walsh et al. teaches a method of for treating or preventing infection comprising exposing a skin surface (obvious the infected surface or suspected infected surface) of a subject to a topical pharmaceutical formulation comprising a lantibiotic, mupirocin and colistimethate.
Walsh et al. does not expressly teach the combining powder colistimethate and 2% mupirocin ointment, Walsh et al. teaches powdered nisin and bacitracin were added to the ointment, and powdered nisin to Bactroban (2% mupirocin ointment) Ointment for formulation comprising mupirocin. As evidenced by that Flynn et al. that Colistimethate sodium is a powder, as suggested by Walsh et al. that Colistimethate sodium is additional antibiotics (alternative to bacitracin), it is obvious to add powdered nisin and powdered Colistimethate to Bactroban (2% mupirocin ointment) Ointment and produce instant claimed invention with reasonable expectation of success.
In arguendo that it is not obvious to combine powdered Colistimethate and 2% mupirocin ointment, it is argued that all these ingredients need combined and admixed with ointment, and Selection of any order of mixing ingredients is prima facie obvious. MPEP 2144.04 IV C.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 2-5 and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Walsh et al. (US7517852) as evidenced by Flynn et al. (WO2014164280), as applied for the above 103 rejection for claim 1, further in view of Jesnig (US2569720), Hong (US20100209404), Melhus et al. (US20070141129), Cottarel et al. (US20100028334) and Parenti et al. (“Mupirocin: a topical antibiotic with a unique structure and mechanism of action”, Clin Pharm. 1987 Oct; 6(10):761-70)
Determination of the scope and content of the prior art
(MPEP 2141.01)
Walsh et al. and Flynn et al. teaching have already been discussed in the above 103 rejection and are incorporated herein by reference.
Jesnig teaches the medicinal powder such as penicillin, streptomycin or mixtures of the same, or any other suitable medicinal powder, is preferably placed in a standard gelatine cup-like medicinal capsule half of the telescoping type, which can be filled by a standard filling machine. Any other light container of comparable size may be used, such as an aluminum capsule half or cup. Most of the medicinal powders of the types which will be employed are hygroscopic, and therefore the closed capsules or other containers will preferably be kept in a bottle or other air tight container prior to use (column 2, line 4-18).
Hong teaches “Pluronic™ F68” is an example of a difunctional block copolymer surfactant terminating in primary hydroxyl groups. Specifically, Pluronic™ F68 is a nonionic polyoxyethylene-polyoxypropylene block co-polymer with the general formula HO(C2H4O)a(—C3H6O)b(C2H4O)aH. It is available in different grades which vary from liquids to solids. It is commonly used as an emulsifying agent, solubilising agent, surfactant, and wetting agent for antibiotics. Poloxamer is also used in ointment and suppository bases and as a tablet binder or coater. (Martindale The Extra Pharmacopoeia, 31st ed) ([0040]).
Melhus et al. teaches Wound care product, comprising a substance which
inhibits the growth of bacteria in wounds, characterized in that the substance is xylitol and the said wound care product comprises an ointment which contains xylitol (claims 1-2).
Cottarel et al. teaches A pharmaceutical composition comprising an antimicrobial agent and an enhancer of an antimicrobial agent, wherein the
enhancer of an antimicrobial agent is an inhibitor of gene, that by inactivating the gene product potentiates the effectiveness of the antimicrobial agent. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the antimicrobial agent is an antimicrobial peptide such as a polymyxin, for example but not limited to colistin. In some embodiments of the present invention provides methods to treat and/or prevent infection of a Subject with a microorganism by administering a pharmaceutical composition comprising an antimicrobial agent and an enhancer of an antimicrobial agent. In some embodiments, the present invention provides methods to inhibit growth of a microorganism by administering a pharmaceutical composition comprising an antimicrobial agent and an enhancer of an antimicrobial agent (abstract). In one embodiment, the antimicrobial peptide comprises colistin methanesulphonate (colistimethate) and/or colistin Sulphate (page 10, [0105]); page 12, [0117]. As Such, antimicrobial agents and enhancers of anti
microbial agents herein may be used to treat infections, for example bacterial infections and other conditions such as urinary tract infections, ear infections, sinus infections, bacterial infections of the skin, bacterial infections of the lungs, sexually transmitted diseases, tuberculosis, pneumonia, lymedisease, and Legionnaire's disease. Thus any of the above conditions and other conditions resulting microorganism
infections, for example bacterial infections may be prevented or treated by the compositions of the invention herein (page 21, [0186]). In some embodiments, an effective amount of an active agent (e.g., an antimicrobial agent and an enhancer of antimicrobial agent or additional therapeutic agent(s)) is from about 0.0001 mg to about 500 mg active agent per kilogram body weight of a patient, in Some embodiments from about 0.001 to about 250 mg active agent per kilogram body weight of the patient, in further embodiments from about 0.01 mg to about 100 mg active agent per kilogram body weight of the patient, yet still more embodiments from about 0.5 mg to about 50 mg active agent per kilogram body weight of the patient, and in another embodiment from about 1 mg to about 15 mg active agent per kilogram body weight of the patient. In terms of weight percentage, a pharmaceutical formulation of an active agent (e.g., an antimicrobial agent and an enhancer of antimicrobial agent or additional therapeutic agent(s)) can, in some embodiments, comprises of an amount from about 0.0001 wt.% to about 10 wt.%, and in alternative embodiments, from about 0.001 wt. % to about 1 wt.%, and in further embodiments from about 0.01 wt.% to about 0.5 wt.%. In any of the formulations herein antimicrobial agents and enhancers of antimicrobial agents can be formulated as a salt, a prodrug, or a metabolite. Such formulations can also include additional therapeutic agent(s) such as, for example, antibiotics, antiviral agents, antifungal agents, and/or antiprotozoan agents including. for example, aminoglycosides, carbapenems, cephalosporins, cephems, glycopeptides, fluoroquinolones/quino
lones, oxazolidinones, penicillins, streptogramins, Sulfonamides, and tetracyclines.
The additional therapeutic agent includes streptomycin (page 21, [0192-0195]).
Cephalosporins and cephems are also used to treat otitis media, Some skin infections, bronchitis, lower respiratory infections (pneumonia), and bone infection (certain;
members), and are a preferred antibiotic for Surgical prophylaxis. Examples of Cephalosporins include cefixime, cefpodoxime, ceftibuten, cefdinir, cefaclor, cefprozil, loracarbef, cefadroxil, cephalexin, and cephradineze. Examples of cephems include cefepime, cefpirome, cefataxidime pentahydrate, ceftazidime, ceftriaxone, ceftazidime, cefotaxime, cefteram, cefotiam, cefuroxime, cefamandole, cefuroxime axetil, cefotetan, cefazolin Sodium, cefazolin, cefalexin (page 22, [0198]). Examples of pharmaceutically acceptable carriers for topical formulations include: ointments, cream, suspensions, lotions, powder, Solutions, pastes, gels, spray, aerosolor oil (page 23, [0210]).
Parenti et al. teaches Mupirocin (Bactroban, Beecham Laboratories) is currently formulated as a 2% ointment in a water-miscible polyethylene glycol base (abstract).
Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02)
The difference between the instant application and Walsh et al. is that Walsh et al. do not expressly teach a capsule comprising Colistimethate, additional active nisin, xylitol and poloxamer, as well as amount of Colistimethate. This deficiency in Walsh et al. is cured by the teachings of Jesnig, Hong, Melhus et al. and Cottarel et al.
Finding of prima facie obviousness
Rational and Motivation (MPEP 2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the invention of Walsh et al., as suggested by Jesnig, Hong, Melhus et al. and Cottarel et al., and produce the instant invention.
One of ordinary skill in the art would have been motivated to open a capsule comprising Colistimethate to release Colistimethate powder for combining with Mupirocin 2% ointment because hygroscopic medical is stored in the closed capsules or other containers as suggested by Jesnig. As evidenced by Flynn et al., that Colistimethate is sodium hygroscopic powder that must be stored in air-tight containers, it is advantage to store Colistimethate powder in capsule before use to avoid Colistimethate powder absorbing moisture, and it is obvious for one of ordinary skill in the art to open a capsule comprising Colistimethate powder to release Colistimethate powder for combining with Mupirocin 2% ointment and produce instant claimed invention with reasonable expectation of success.
One of ordinary skill in the art would have been motivated to include xylitol and poloxamer because they are suitable ingredient in anti-infective ointment. MPEP 2144.07. Under guidance from Hong teaching Poloxamer as emulsifying agent, solubilizing agent, surfactant, and wetting agent for antibiotics in ointment, Melhus et al. teaching ointment comprising xylitol inhibiting the growth of bacteria in wounds, thus, it is advantage to have poloxamer solubilizing antibiotic and have xylitol inhibiting the growth of bacteria in wounds. Therefore, it is obvious for one of ordinary skill in the art to include xylitol and poloxamer and produce instant claimed invention with reasonable expectation of success.
One of ordinary skill in the art would have been motivated to have the capsule comprising powdered nisin to release powdered nisin for combining with Mupirocin 2% ointment because hygroscopic medical is stored in the closed capsules or other containers as suggested by Jesnig. Since it is advantage to store powdered nisin in capsule before use to avoid powdered nisin absorbing moisture, and it is obvious for one of ordinary skill in the art to open a capsule comprising powdered nisin to release powdered nisin for combining with Mupirocin 2% ointment and produce instant claimed invention with reasonable expectation of success.
Regarding claims 3-5, it is advantage to include poloxamer, xylitol and colistimethate in capsule together with powdered nisin (additional active) to avoid absorbing moisture due to hygroscopic property before combining with Mupirocin 2% ointment. In arguendo that it is not obvious to have poloxamer, xylitol and colistimethate in capsule together with powdered nisin, it is argued that all these ingredients need combined and admixed with Mupirocin 2% ointment, and Selection of any order of mixing ingredients is prima facie obvious. MPEP 2144.04 IV C.
Regarding claim 14, Walsh et al. teaches 1-3% mupirocin, and one of ordinary skill in the art would have been motivated to have about 1% to about 9% of colistimethate because this is optimization under prior art condition or through routing experimentation. MPEP 2144.05. Under guidance from Cottarel et al. teaching about 0.0001% to 10% of colistimethate in topical composition, it is obvious to have about 1% to about 9% of colistimethate and produce instant claimed invention with reasonable expectation of success.
Regarding claim 15, as evidenced by Parenti et al. that Mupirocin (Bactroban, Beecham Laboratories) is currently formulated as a 2% ointment in a water-miscible polyethylene glycol base.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Argument:
Applicants argued that no teaching of colistimethate on the skin, All arguments are incorporated herein by reference.
In response to this argument: this is not persuasive. Applicants argued substantially the same as in the previous office action, let the examiner be clear that applicant’s arguments are not sufficient to overcome the 103 rejection at least for the following reasons. Firstly, as discussed in the above 103 rejections, Walsh et al. teaches topical pharmaceutical formulation containing (a) a composition comprising mupirocin and a lantibiotic (e.g., nisin); and (b) one or more other agents (e.g., an antibiotic) such as bacitracin and colistimethate. The co-administration of additional antibiotic is another embodiment, and all embodiment of prior art teaching can be relied on for 103 rejections. Secondly, although Flynn et al. teaches Colistimethate formulated in inhaled formulation, Flynn et al. does not teach Colistimethate can not be formulated in topical application. in the above 103 rejections, Flynn et al. is relied on for evidence that colistimethate is a powder. Kunin (US20100221245) is relied on for teaching teaches a topical skin care composition comprising Colistimethate (claim 12) that indicating Colistimethate properly being applied topically on skin surface, and the reciting other different antibacterial in the claims does not change the fact Colistimethate can be applied topically on skin. Therefore, it is obvious for one of ordinary skill in the art to formulate a composition comprising mupirocin and colistimethate in the form of topical composition and produce instant claimed invention with reasonable expectation of success.
Applicants argue that the invocation of MPEP 2144.04 IV C in the Office Action regarding the order of mixing ingredients as being prima facie obvious is also misplaced. This principle would apply only when all ingredients are already known to be compatible and effective in the final formulation. Here, the threshold question is not the order of combining colistimethate with mupirocin ointment, but whether colistimethate would be selected at all for topical use given the teachings of the art, which, as described above, it would not.
In response to this argument: this is not persuasive. As discussed in the above 103 rejections and response to argument, colistimethate can be properly applied in skin, thus, the 103 rejection is still proper.
MPEP 2141 III states: “The proper analysis is whether the claimed invention would have been obvious to one of ordinary skill in the art after consideration of all the facts.” Respectfully, after weighing all the evidence, the Examiner has reached a determination that the instant claims are not patentable in view of the preponderance of evidence and consideration of all the facts which is more convincing than the evidence which has been offered in opposition to it.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JIANFENG SONG. Ph.D. whose telephone number is (571)270-1978. The examiner can normally be reached M-F 8-5.
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/JIANFENG SONG/Primary Examiner, Art Unit 1613