DETAILED ACTION
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 .
Status of the Claims
Claims 1-19, filed 8/27/24 are under consideration.
Claim Objections
Claims 1 and 2 objected to because of the following informalities: “administrating” should be amended to “administering”. Appropriate correction is required.
Claim 1 is objected to because of the following informalities: the claim should be amended to “A method for enhancing the efficacy of polymyxin against bacterial infections in a subject in need thereof, the method comprising administering a C-Jum N-terminal kinase inhibitor, SU3327 in combination with a polymyxin to the subject” or the like. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2 and 11 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 2 is indefinite because the limitation “…enhancing the efficacy against bacterial infection in a subject…” is unclear. It is unclear what efficacy is being enhanced by the claim. The claim does not specify whether the recited enhancement refers to the efficacy of Su3327 or polymyxin or the combination of both. The scope of the claim is unclear because “efficacy” lacks an object or reference for what its to enhance.
Claim 11 is indefinite because the limitation “wherein a final therapeutic dose of the Polymyxin E and the SU3327 is 10mg/kg body weight” is unclear. It is unclear if the recited dose of 10 mg/kg refers to the dose of polymyxin E, the dose of SU3327, the dose of each polymyxin E and SU3327 or the combined dose of polymyxin E and SU3327. The metes and bounds of the claim is unclear.
Claims 9-10 and 12-19 are rejected for depending on rejected claim 2.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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, 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 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.
Claims 1-10, 12 and 14-19 are rejected under 35 U.S.C. 103 as being unpatentable over Collins et al. (WO2021/050473) in view of Doolin et al. (Nature Commun. 2020 Aug 4; 11:3888).
Collins et al. teach halicin (SU3327) as an effective antimicrobial agent (bottom of p. 1). Collins et al. teach that halicin dissipates the ΔpH component of the proton motive force (PMF) (p. 18, Fig. 4). Fig. 4D of Collins et al. evaluates both polymyxin B and halicin in connection with bacterial cytoplasmic membrane. Collins et al. teach while halicin produces a distinct effect involving dissipation of the ΔpH component of the proton motive force, polymyxin B disrupts the cytoplasmic membrane (Fig. 4 and 1st para of p. 72). Collins et al. therefore teach the effect of polymyxin B and halicin have distinct effects on bacterial membranes. Collins et al. further teaches halicin has broad spectrum bactericidal activity (Fig. 3) and teaches a pharmaceutical composition for treatment of microbial infections. In particular, Collins et al. teach the pharmaceutical compositions for treating a subject having or at risk of developing a bacterial infection, particularly an antibiotic resistant and/or antibiotic tolerant bacterial infection (top of p. 2).
Collins et al. does not teach enhancing the effect of polymyxin against a bacterial infection comprising administering halicin, however the teachings of Doolin et al. cure this deficiency.
Doolin et al. teach treatment with H2A and the pore-forming antibiotic polymyxin B completely eradicates bacterial growth (Abstract).Therefore, Doolin teach that an additional agent administered with polymyxin B amplified their antimicrobial activities (Abstract). Doolin discloses treatment of E. coli with polymyxin B alone only slightly inhibited bacterial growth in contrast to treatment of H2A with polymyxin B resulted in complete eradication of bacterial growth (Fig. 7).
With respect to claims 1 and 2, a person of ordinary skill in the art would have been motivated to administer halicin and polymyxin B in order to enhance the antibacterial effect because Collins et al. teach each agent has a distinct antimicrobial effect and Doolin et al. teach that the antimicrobial effect of polymyxin B can be enhanced by supplementing with an additional antimicrobial agent. A person of ordinary skill in the art would look to the teachings of Doolin, wherein polymyxin B alone had little activity against E. coli, while combination with an additional antimicrobial agent resulted in complete eradication of bacterial growth. Therefore, a skilled artisan would have a clear motivation to administer halicin and polymyxin B to a subject for increasing efficacy against a bacterial infection. There is a reasonable expectation of success given that Collins et al. independently establishes halicin impairs bacterial viability through disruption of the proton motive force, while Doolin et al. teach polymyxin B has membrane pore forming effects.
With respect to claim 3, Collins et al. and Doolin et al. teach polymyxin B.
With respect to claims 4, 7, 14 and 17, Collins et al. teach halicin was tested against E. coli strains harboring resistance genes against polymyxins (MCR1) (p. 70).
With respect to claims 5, 6 and 15, Collins et al. teach halicin has eradicated conventionally antibiotic tolerant cells and retained activity in the presence of some of the most clinically problematic antibiotic resistant Gram negative pathogens ( p. 37, top p. 70). Importantly, E. coli and K. pneumoniae are gram negative.
With respect to claims 8, 16 and 18, Collins et al. teach treatment of microbial infections including E. coli and Klebsiella pneumoniae (p. 2, last para.).
With respect to claim 9, Doolin et al. teach administering polymyxin B with an additional antimicrobial agent at a mass ratio of 10:1 (Fig. 7C, 10µg/ml H2A and 1µg/ml polymyxin B), which falls within the claimed ratio. It would have been obvious to a person of ordinary skill in the art to use the claimed halicin and polymyxin in the claimed mass ratio as the ratio is explicitly taught in the art. There is a reasonable expectation of success given that the mass ratio was sufficient to completely eradicate bacterial growth.
With respect to claim 10, Collins et al. teach ways to administer the composition or pharmaceutically active ingredient to a subject include tablets, capsule, solution, powder or the like (top of p. 13).
With respect to claim 12, Collins et al. teach polymyxin B (Fig. 4) and Doolin et al. teach polymyxin B (Abstract and Fig. 7).
With respect to claim 19, Collins et al. teach inhibition of K. pneumoniae but do not explicitly teach that the K. pneumoniae is multiple drug resistant. However, Collins et al. is suggestive of the limitation. Collins et al. teach: “Overall, the results of the instant disclosure establish the utility in applying modem machine learning approaches to antibiotic discovery - further application of machine learning approaches, including the approaches disclosed herein, are contemplated as enabling an increase in the rate at which new molecular entities are discovered, while decreasing the resources required to identify these molecules, and also decreasing associated costs. Deep learning approaches are therefore contemplated as enabling drug discovery to outpace the emergence of multidrug-resistant pathogens, with global benefit. Collins et al. so teach multidrug resistant and polymyxin resistant E. coli. It would have been obvious to a person of ordinary skill in the art to treat K. pneumonia that is polymyxin or multidrug resistant with the composition made obvious by Collins et al. and Doolin et al. A person would have a motivation and reasonable expectation of success since the purpose of Collins et al. and halicin is to treatment microbials including multidrug resistant and polymyxin resistant pathogens.
Claims 1-19 are rejected under 35 U.S.C. 103 as being unpatentable over Collins et al. (WO2021/050473) in view of Xu et al. (Adv. Therap. 2020,32000084).
Collins et al. teach halicin (SU3327) as an effective antimicrobial agent (bottom of p. 1). Collins et al. teach that halicin dissipates the ΔpH component of the proton motive force (p. 18, Fig. 4). Fig. 4D of Collins et al. evaluates both polymyxin B and halicin in connection with bacterial cytoplasmic membrane. Collins et al. teach while halicin produces a distinct effect involving dissipation of the ΔpH component of the proton motive force, polymyxin B disrupts the cytoplasmic membrane (Fig. 4 and 1st para of p. 72). Collins et al. therefore teach the effect of polymyxin B and halicin have distinct effects on bacterial membranes. Collins et al. further teaches halicin has broad spectrum bactericidal activity (Fig. 3) and teaches a pharmaceutical composition for treatment of microbial infections. In particular, Collins et al. teach the pharmaceutical compositions for treating a subject having or at risk of developing a bacterial infection, particularly an antibiotic resistant and/or antibiotic tolerant bacterial infection (top of p. 2).
Collins et al. does not teach enhancing the effect of polymyxin against a bacterial infection comprising administering halicin, however the teachings of Xu et al. cure this deficiency.
Xu et al. teach econazole acts synergistically with colistin (polymyxin E) to effectively eradicate colistin resistant bacteria both in vitro and in a mouse infection model (Abstract, p. 5 para. 3.2). Xu et al. teach that econazole causes dissipation of transmembrane proton motive force and damage to the bacterial cell membrane (Abstract).
It would have been obvious to a person of ordinary skill in the art administer halicin of Collins et al. with polymyxin E as taught by Xu et al. because Xu et al. teach the efficacy of polymyxin E (colistin) is enhanced by administration with a PMF dissipating agent and Collins et al. teach that halicin is an antimicrobial agent that dissipates ΔpH component of the PMF. Therefore, based on Xu et al. demonstrated enhancement of colistin activity using a PMF disrupting agent and Collins et al. demonstrated PMF disrupting activity of halicin, one of ordinary skill in the art would have a reasonable expectation of success that halicin would have similar enhancement when administered with colistin.
With respect to claim 3, Collins et al. teach polymyxin B and Xu et al. teach polymyxin E.
With respect to claims 4, 7, 14 and 17, Collins et al. teach halicin was tested against E. coli strains harboring resistance genes against polymyxins (MCR1) (p. 70). Xu et al. teach treatment of colistin (polymyxin E) resistant K. pneumoniae strains (p. 5, para. 3.2).
With respect to claims 5, 6 and 15, Collins et al. teach halicin has eradicated conventionally antibiotic tolerant cells and retained activity in the presence of some of the most clinically problematic antibiotic resistant Gram negative pathogens (, p. 37, top p. 70). Importantly, E. coli and K. pneumoniae are gram negative.
With respect to claims 8, 16 and 18, Collins et al. teach treatment of microbial infections including E. coli and Klebsiella pneumoniae (p. 2, last para.). Xu et al. teach treatment of colistin (polymyxin E) resistant K. pneumoniae strains (p. 5, para. 3.2).
With respect to claim 9, Xu et al. teach administering 16µg/ml of econazole and 8µg/ml of colistin (p. 5, para. 5.2 and Fig. 2), which is a 2:1 ratio. The ratio of active ingredients in a composition is a result-effective variable and the determination of the optimum or workable ranges of said variable maybe characterized by routine experimentation (Please see MPEP 2144 II-Optimization of Ranges). It would have been obvious and routine experimentation to a person of ordinary skill in the art with a reasonable expectation of success to optimize relative amounts of the agents to obtain an effective antibacterial composition and to arrive at the dose ranges of claim 9.
With respect to claim 10, Collins et al. teach ways to administer the composition or pharmaceutically active ingredient to a subject include tablets, capsule, solution, powder or the like (top of p. 13).
With respect to claim 11, Collins et al. teach the normal dosage amount is 10 ng/kg up to about 100 mg/kg of an individual’s body weight (middle of p. 43).
With respect to claims 12 and 13, Collins et al. teach polymyxin B (Fig. 4) and Xu set al. teach polymyxin E (Abstract and Fig. 7).
With respect to claim 19, Xu et al. teach treatment of colistin (polymyxin E) resistant K. pneumoniae strains (p. 5, para. 3.2).
Conclusion
No claims are allowed.
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/TARA L MARTINEZ/Primary Examiner, Art Unit 1654
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