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 .
DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 1/22/2026 has been entered.
The office acknowledges Applicants filing of the amendments and arguments on 1/22/2026. Claim 1 has been amended. For the sake of compact prosecution, allowable subject matter was discussed with attorney April Barnard. Attorney Barnard on 4/24/2026 advised that an office action be issued. Applicants arguments have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. Arguments, which are directed to withdrawn rejections, are thus rendered moot. The arguments in regards to the reiterated rejections/references from the previous office action are addressed below. Further search and consideration necessitated the rejections in this action . The action is made non-final. Claims 1-9 are pending and are examined based on the merits herein.
Response to Applicants Arguments
Applicants argue that the cited references Wright, Garey and Binda, whether considered alone or in any combination, fail to teach or suggest the eradication of C. difficile with concurrent restoration of the microbiome (Actinobacteria/Firmicutes) and favorable shifts in bile acids independent of the dysbiosis typically caused by antibiotics.
Wright is to a therapeutic aimed at pathogen killing-not microbiome restoration. Garey is a Phase 1 healthy volunteer study designed to evaluate safety, PK, and microbiome changes. The cited art lacks a reasoned motivation to administer ibezapolstat for the specific purpose of regenerating Actinobacteria in a depleted microbiome and shifting bile acids to reduce recurrence risk.
In response, Wright teach treating C. difficile associated diseases with compounds including ibezapolstat. Garey is explicit in teaching the effects of ibezapolstat in healthy subjects and teaches the dosage amounts safe for administration as 300 mg, 450 mg. Further Garey is explicit in teaching that diversity changes were characterized as an increase in the Actinobacteria phylum in subjects that received ibezapolstat and an increase in Proteobacteria in subjects given vancomycin. Amrane is explicit in teaching that dysbiosis is associated with C. difficile infection and firmicutes and actinobacteria were less common in the CDI group. Hence from the combined teachings of the prior art a person skilled in the art would have been motivated to administer an effective amount of ibezapolstat in subjects with C. difficile infection, e.g. dysbiosis subjects to treat the disorder. Hence administration of the same agent, ibezapolstat to subjects with C. difficile/dysbiosis would result on increase in actinobacteria and improvement in the health of a gut microbiome in such subject or a subject in need thereof, e.g. C. difficile infected subjects. The cited art need not explicitly teach the mechanism or the properties of the agent when administered to the same set of subjects as instantly claimed.
In regards to hindsight arguments, no hindsight reasoning was employed in rejecting the claims over the prior art because it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. Wright, Garey and Amrane teachings has been relied upon for the reasons above. As stated above, it would have been obvious to a person skilled in the art to administer an effective amount of ibezapolstat to subjects with C. difficile infection (CDI) (e.g. dysbiosis). Amrane is explicit in teaching that firmicutes and actinobacteria were less common in the CDI group compared to control group. Hence administration of the same agent to CDI subjects will result in increase in actinobacteria and increase/decrease in the ratio of primary and secondary bile acids.
Applicants argue that the cited art lacks a reasoned motivation to administer ibezapolstat for the specific purpose of regenerating Actinobacteria in a depleted microbiome and shifting bile acids to reduce recurrence risk.
In response, a person of ordinary skill in the art is not limited to the same motivation that may have motivated the applicants. The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve different problem. It is not necessary that the prior art suggest the combination or modification to achieve the same advantage or result discovered by applicant. In re Linter, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972). In the instant case a person skilled in the art would have been motivated to administer ibezapolstat in c. difficile infected subjects for therapeutic response.
Applicants argue that the specification documents surprising and clinically meaningful microbiome and bile acid outcomes with ibezapolstat including microbiome restoration without Proteobacteria bloom. Compared to baseline, ibezapolstat decreased primary bile acids and increased (or preserved) secondary bile acids, improving the secondary: primary ratio-a biochemical signature linked to resistance to C. difficile recurrence.
In response, clinically meaningful microbiome and bile acid are the outcomes of the administration of an effective amount of ibezapolstat to the same set of subjects, e.g. C. difficile infected subjects (e.g. dysbiosis). In other words it is the pharmacological activity of the agent when administered to C. difficile subjects. The primary reference Wright is explicit in teaching the use of ibezapolstat in treating C. difficile infections in the subject. The unexpected results that are observed by the applicant would have been obvious from the teachings of the prior art. Moreover, “when unexpected results are used as evidence of nonobviousness, the results must be shown to be unexpected compared with the closest prior art.” In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991). While Applicants argue that the results presented show unexpected results, there is no clear or specific comparative data or evidence supporting that argument. For the reasons cited in the rejections below the claimed methods would have been obvious from the teachings of the prior art.
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, 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-9 are rejected under 35 U.S.C. 103 as being unpatentable over Acrux Pharmaceuticals (IDS: Acurx announces positive Phase 2A Clinical Trial Results for Ibezapolstat in C. difficile Infection at Prominent International Conference, Nov 19 2020) and Amrane et al. (Scientific Reports, www.nature.com/scientificreports, 2019).
Acurx teach ibezapolstat, is the first of a new class of antibiotics with a novel mechanism of action, a DNA polymerase me inhibitor, to enter clinical efficacy trials. 10 of 10 patients (100%) enrolled in a Ph2A trial met the study's primary and secondary efficacy endpoints of Clinical Cure at end of treatment and Sustained Clinical Cure of no recurrence of CDI at the 28 day follow up visit. The compelling evidence of efficacy and safety allowed early termination of Segment 2A and advancement to Segment 2B. Favorable microbiome signature relative to vancomycin as evidenced by enhanced proportion of actinobacteria without proteobacteria overgrowth (See p 1, para 1-4). These results also represent the first-ever clinical validation of DNA polymerase IIIC as a therapeutically relevant antibacterial target (p 2, lines 24-25). In Segment 2A of this trial, 10 subjects with diarrhea caused by C. difficile were treated with ibezapolstat 450 mg orally for 10 days and evaluated for clinical cure. All cured subjects were followed for sustained clinical cure at 28 ± 2 days (See p 2, para 4). It is noted that the reference is explicit in teaching that the results of the study was presented at a prominent international conference and was featured in a poster (See last para of p 1 and p 2, lines 3-4).
Amrane is explicit in teaching that gut dysbiosis is the triggering factor of C. difficile infection (CDI) (See p 1, lines 3-4). Amrane teach that phyla repartition between CDI and control group was different (Fig. 2C). Proteobacteria were more common in the CDI group (23.2%) compared to the control group (2.2%). Firmicutes and Actinobacteria were less common in the CDI group (respectively 33.5% and 1.4%) compared to the control group (respectively 55.2% and 14.3%) (p 3, para 6).
From the above prior art teachings a person skilled in the art before the effective filing date of the invention would have found it obvious to arrive at the claimed method of promoting the growth of actinobacteria in a subject with C. difficile/dysbiosis with an effective amount of ibezapolstat because (i) Acurx teach the clinical cure effects of ibezapolstat in CDI subjects (450 mg orally for 10 days) and enhanced proportion of actinobacteria without proteobacteria overgrowth during the treatment (ii) Amrane is explicit in teaching that gut dysbiosis is the triggering factor of C. difficile infection (CDI). and actinobacteria and firmicutes was less common in the CDI group. A person skilled in the art would have been motivated to arrive at claim 1 with a reasonable expectation of success and to derive therapeutic effects in treating C. difficile infection in dysbiosis subjects. Further administration of the same agent herein ibezapolstat in effective amount(s) to the same set of subjects, herein CDI/dysbiosis thus addressing the claim limitations of exhibiting the reduced abundance of actinobacteria such that reduced abundance of Actinobacteria is sufficient to indicate dysbiosis and this would result in promoting the actinobacteria as claimed.
As to claim 2, a skilled artisan, e.g. a physician would have found it obvious to continue ibezapolstat administration until the subject has achieved a specific regrowth of Actinobacteria for patient's long term health, until recurrence of infection is reduced and healthy gut microbiome is achieved. As to claim 3, a skilled artisan, e.g. a physician would have found it obvious to terminate the treatment ibezapolstat administration once the patient has achieved specific regrowth of Actinobacteria in the gut microbiome.
As to claim 5, Acurx is explicit in teaching an increase in the Actinobacteria phylum in CDI subjects that received an effective amount of ibezapolstat (450 mg).
As to claims 4, 6 it is noted that Acurx is explicit in teaching an increase in the Actinobacteria phylum in CDI subjects that received an effective amount of ibezapolstat (450 mg) and favorable microbiome signature relative to vancomycin as evidenced by enhanced proportion of actinobacteria without proteobacteria overgrowth. Amrane is explicit in teaching that gut dysbiosis is the triggering factor of C. difficile infection (CDI) and actinobacteria and firmicutes was less common in the CDI group. A skilled person in the art would have been motived from the prior art teachings and arrive at method(s) of claims 4 and 6 to improve the health of a gut microbiome of subjects with CDI and adjust the level to a healthier balance with an effective amount of ibezapolstat to maintain a healthier gut and thus maintain gut homeostasis.
As to claims 7-9 wherein the administration of ibezapolstat results in an increase in the ratio of primary to secondary bile acids or decrease in primary bile acids or increase in secondary bile acids administration of an effective amount of ibezapolstat to the same set of subjects (e.g. C. difficile infected) as claimed would substantially result in the same pharmacological effects as claimed.
Claim(s) 1-9 are rejected under 35 U.S.C. 103 as being unpatentable over Wright et al. (WO 2011031935 A1) in view of Garey et al. (J Antimicrob Chemother 2020, 75, 3635-43) and Amrane et al. (www.nature.com/ scientificreports, Scientific Reports, 2019).
Wright teaches a method of treating or reducing the likelihood of developing a Clostridium difficile associated disease said method comprising administering to an animal in need thereof a therapeutically effective amount of a compound having the formula:
PNG
media_image1.png
114
500
media_image1.png
Greyscale
and the compound include, 7-[2-( morpholinyl)ethyl-2-(3,4-dichlorobenzylamino)-6-oxopurine (compound 362E, see p 10, line 26). Clostridium difficile associated disease include Clostridium difficile-associated diarrhea or Clostridium difficile-associated colitis. Wright teach general dose ranges are from about 0.01 mg/kg to about 1 g/kg of body weight per day (p 15, last two lines). Table 4 teaches minimum inhibitory concentrations and activity against C. diff strains for compound 362E. Wright teach selective anti-bacterials for treating clostridium difficile infections (see Title, abstract). The reference teaches antibacterial compounds that are selective active against Clostridium difficile in vitro and in vivo, and more particularly to 7-substituted 2-benzylamino-6- oxopurines and salts thereof.
Wright is not explicit in teaching the actinobacteria growth is promoted in a subject exhibiting reduced abundance of actinobacterium (indicating dysbiosis) compared to a healthy gut microbiome or improving the health of a gut microbiome.
Garey teach Ibezapolstat (ACX362E) is a DNA polymerase IIIC inhibitor with
potent activity against C. difficile (see p 3636, col. 1, para 1, lines 1-2). Garey teach multiple ascending dose Phase 1 study to determine the safety, pharmacokinetics and food and faecal microbiome effects of ibezapolstat administered orally to healthy subjects with doses of 300 mg and 450 mg (Table 1). The reference teaches that at Day 10 of dosing, differential abundance analysis and b-diversity demonstrated a distinct difference between the microbiome in subjects given vancomycin compared with either dose of ibezapolstat (P= 0.006). Diversity changes were characterized as an increase in the Actinobacteria phylum in subjects that received ibezapolstat and an increase in Proteobacteria in subjects given vancomycin (See p 3635, Results, Fig. 6). Garey teach in page 3636, col. 1, para 1 that DNA polymerase IIIC enzyme is essential for replication of low G+C content Gram-positive bacteria and thus should be selective for Firmicutes, such as C. difficile yet inactive against other host microbiota such as Actinobacteria or Bacteroidetes.
Amrane is explicit in teaching that gut dysbiosis is the triggering factor of C. difficile infection (CDI) (See p 1, lines 3-4). Amrane teach that phyla repartition between CDI and control group was different (Fig. 2C). Proteobacteria were more common in the CDI group (23.2%) compared to the control group (2.2%). Firmicutes and Actinobacteria were less common in the CDI group (respectively 33.5% and 1.4%) compared to the control group (respectively 55.2% and 14.3%) (p 3, para 6).
A person skilled in the art from the teachings of the prior art would have found it obvious to promote the growth of actinobacterium or increase the amount of actinobacterium in a gut microbiome in a subject with C. difficile and dysbiosis by administering an effective amount of ibezapolstat from the prior art teachings because (i) Wright teach an effective amount of compound 362E (which is ibezapolstat) is useful in treating C. difficile associated colitis (ii) Garey teach that actinobacterium growth is increased in healthy subjects with ibezapolstat (iii) Amrane is explicit in teaching that gut dysbiosis is the triggering factor of C. difficile infection (CDI) and actinobacteria and firmicutes was less common in the CDI group. A skilled artisan would have been motivated to promote or increase the growth of actinobacterium in a subject suffering from c. difficile infection or a subject in need thereof (e.g. c. difficile dysbiosis) with an effective amount of ibezapolstat to provide therapeutic benefits. Administration of an effective amount of ibezapolstat from the combined teachings of the prior art to a C. difficile subject would result in the promotion of the growth of actinobacteria in those subjects. As to the limitation of wherein the amount of Actinobacteria in the subject’s gut microbiome is increased or the proportion of Actinobacteria compared to Proteobacteria is increased or wherein the amount of Actinobacteria is higher in the gut microbiome compared to amount of Actinobacteria in the gut microbiome prior to the administration of the ibezapolstat, it is noted that administration of an effective amount of ibezapolstat to the same subject for treating the same condition (e.g. C. difficile dysbiosis) as claimed would result in such effects. Further administration of the same agent herein ibezapolstat in effective amount(s) to the same set of subjects, herein CDI/dysbiosis thus addressing the claim limitations of exhibiting the reduced abundance of actinobacteria such that reduced abundance of Actinobacteria is sufficient to indicate dysbiosis and this would result in promoting the actinobacteria as claimed. Thus claim 1 would have been obvious over the combined prior art teachings. As to the limitation of the administration results in an increase in the ratio of primary to secondary bile acids, it is noted that administration of an effective amount of ibezapolstat to the same subject for treating the same condition (e.g. C. difficile colitis) as claimed would result in such pharmacological effects. Thus claim 5 is addressed.
As to claim 2, a skilled artisan, e.g. a physician would have found it obvious to continue ibezapolstat administration until the subject has achieved a specific regrowth of Actinobacteria for patient's long term health, until recurrence of infection is reduced and healthy gut microbiome is achieved. As to claim 3, a skilled artisan, e.g. a physician would have found it obvious to terminate the treatment ibezapolstat administration once the patient has achieved specific regrowth of Actinobacteria in the gut microbiome.
As to claims 4, 6 it is noted that Garey is explicit in teaching an increase in the Actinobacteria phylum in healthy subjects that received ibezapolstat. Amrane is explicit in teaching that gut dysbiosis is the triggering factor of C. difficile infection (CDI) and actinobacteria and firmicutes was less common in the CDI group. A skilled person in the art would have been motived from Garey and Amrane to arrive at method claims 4 and 6 to improve the health of a gut microbiome of subjects with CDI and adjust the level to a healthier balance with an effective amount of ibezapolstat to maintain a healthier gut and thus maintain gut homeostasis.
As to claims 7-9 wherein the administration of ibezapolstat results in an increase in the ratio of primary to secondary bile acids or decrease in primary bile acids or increase in secondary bile acids administration of an effective amount of ibezapolstat to the same set of subjects (e.g. C. difficile infected) as claimed would substantially result in the same pharmacological effects as claimed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to UMAMAHESWARI RAMACHANDRAN whose telephone number is (571)272-9926. The examiner can normally be reached M-F- 8:30-5:00 PM (PST).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Kortney Klinkel can be reached at 5712705239. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/ docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Umamaheswari Ramachandran/Primary Examiner, Art Unit 1627
Prosecution Insights