DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Amendments
2. The claim amendments filed Nov 24, 2025 have been entered. Claims 1-3, 8, 11, 17 and 20 have been amended. Claims 12-13 were cancelled. Claim 21 was newly added.
Withdrawal of Objections and Rejections
3. The following rejections have been withdrawn in view of applicants amendments:
A) The scope of enablement rejection of claims 1-11 and 14-20 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph;
B) The rejection claims 1, 3, 8, 11, 17 and 20 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph; and
C) The objection claims 1-9, 11 and 14-20.
Maintained Grounds of Rejection
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
4. Claims 1-11 and 14-21 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Rahman et al., (WO2016086205 published June 2, 206; priority to Nov. 25, 2014).
The claims are drawn to a method for treating antibiotic resistant Enterobacteriaceae in the microbiome of an animal wherein said method comprises administering to said animal a therapeutically effective amount of a bacterium selected from the group consisting of Klebsiella oxytoca, K. michiganensis, K. grimontii, and K. aerogenes wherein said bacterium outcompetes said Enterobacteriaceae for use of beta-glucosidic sugars.
Rahman et al., describe Probiotic compositions containing non-pathogenic microbial entities, e.g., bacterial entities, are described herein. The probiotic compositions may optionally contain or be used in conjunction with one or more prebiotics. Uses of the probiotic compositions to treat or prevent disorders of the local or systemic microbiome in a subject are also provided [abstract]. Disclosed are therapeutic compositions containing probiotic, nonpathogenic bacterial populations and networks thereof, for the prevention, control, and treatment of diseases, disorders and conditions, in particular diseases associated with dysbiosis, e.g., dysbiosis distal to the gastrointestinal tract, and for general nutritional health [para 008]. Numerous genera of bacteria harbor species that are developing resistance to antibiotics. These include but are not limited to Vancomycin Resistant Enterococcus (VRE) and Carbapenem resistant Klebsiella (CRKp) Klebsiella pneumoniae and Escherichia coli strains are becoming resistant to carbapenems and require the use of old antibiotics characterized by high toxicity, such as colistin [para 06]. Pathogens include, but are not limited to Klebsiella pneumonia [para 937].Thus teaching claim 13 and 21. Bacterial-based therapeutics would provide a new tool for decolonization, with a key benefit of not promoting antibiotic resistance as antibiotic therapies do [para 006]. Thereby teaching claim 2. In some embodiments, the mammalian subject suffers from a colonization with a pathogen or pathobiont, or infection with a drug-resistant pathogen or pathobiont [para 74]. The mammalian subject is suffering from a gastrointestinal disease, disorder or condition selected from the group consisting of Clostridium difficile-induced diarrhea, irritable bowel syndrome (IBS), colonization with a pathogen or pathobiont, infection with a drug-resistant pathogen or pathobiont, colitis, and Crohn's Disease [para 94 and 99].
Without being limited to a specific mechanism, it is thought that such compositions inhibit the growth of pathogens such as C. difficile, Salmonella spp., enteropathogenic E. coli, Fusobacterium spp., Klebsiella spp. and vancomycin-resistant Enterococcus spp., so that a healthy, diverse and protective microbiota can be maintained or, in the case of pathogenic bacterial infections, repopulate the intestinal lumen to reestablish ecological control over potential pathogens [para 660]. In one embodiment, the bacterial entity, e.g., species or strain, useful in the compositions and methods of the invention is Klebsiella oxytoca [para 669]. See also para 921, 922, 1003, 1029, 1004, 1115]. Preferred bacterial species are provided in Table 1, Table 1B, and Table 1E [para 1114]. See Table 1, and Tables 1B and Table 1E both entitled “Exemplary Bacteria Useful in the Present Invention” reciting K. oxytoca. Table 1 recites Enterobacter aerogenes which is now known as K. aerogenes. Thereby teaching claims 1, 3 and 21. A microbial network in a given niche may comprise diverse microbes that all accomplish one or more of the same functions, or may instead comprise diverse microbes that all individually contribute to accomplish one or more functions. In another example, microbes in a given niche may compete with one another for nutrients or space [para 564].
The compositions inhibit the growth, proliferation, and/or colonization of one or a plurality of pathogenic bacteria in the dysbiotic microbiotal niche, so that a healthy, diverse and protective microbiota colonizes and populates the intestinal lumen (and microbiotal niches distal to the intestinal lumen) to establish or reestablish ecological control over pathogens or potential pathogens (e.g., some bacteria are pathogenic bacteria only when present in a dysbiotic environment). Inhibition of pathogens includes those pathogens such as C. difficile, Salmonella spp., enteropathogenic E coli, multi-drug resistant bacteria such as Klebsiella, and E. coli, Carbapenem-resistant Enterobacteriaceae (CRE), extended spectrum beta-lactam resistant Enterococci (ESBL), and vancomycin-resistant Enterococci (VRE) [para 927].
The distal dysbiosis is associated with increased susceptibility to graft versus host disease (GVHD) in the subject. In one embodiment of the foregoing aspect, the subject is a subject receiving a transplant. In one embodiment of the foregoing aspect, the transplant is a hematopoietic stem cell transplant, a bone marrow transplant, or a solid organ transplant [para 25]. Thereby teaching claim 8. For example, a bacterial composition can be cultivated to a concentration of 1010 CFU/mL [para 712]. Thus teaching claim 10. In some embodiments of the foregoing aspect, the population comprises a single bacterial preparation or a combination of bacterial preparations, wherein each bacterial preparation is purified from a fecal material obtained from a single mammalian donor subject. In some embodiments, the population comprises a single bacterial preparation or a combination of bacterial preparations wherein each bacterial preparation is purified from a fecal material obtained from a mammalian donor subject [para 92]. The bacterial composition comprises a synergistic combination of two or more bacterial entities. In some embodiments, the synergistic combination comprises an interaction network. In some embodiments, at least one of the two or more bacterial entities comprises a keystone bacterial entity [para 181]. In one embodiment, the bacterial entity, e.g., species or strain, useful in the compositions and methods of the invention is Enterococcus faecalis. therapeutic compositions comprise, or in the alternative modulate the colonization and/or engraftment, of the following exemplary bacterial entities: Lactobacillus reuteri, Enterococcus faecalis, Clostridium clostridioforme, Blautia producta, and Clostridium sp. ID5 [para 938]. Thus teaching claims 11, 19 and 20.
These compositions are advantageous in being suitable for safe administration to humans and other mammalian subjects and are efficacious in numerous dysbiotic diseases, disorders and conditions and in general nutritional health [para 8]. Thus teaching claim 14. In some embodiments of the foregoing aspects, the composition remains within the gut for more than three hours. In some embodiments, the composition is effective for sustaining a modulated gut microbiome for at least 24 hours [para 155]. Thus teaching claim 5. Rahman et al., provide a method of obtaining a microbiome profile, comprising the steps of: i) providing a fecal material obtained from a human subject suitable for an allogeneic transplant procedure and/or at risk of developing an autoimmune disorder, ii) isolating one or more bacterial entities from the fecal material [para 253]. Thereby teaching claim 9. Solid dosage forms for oral administration include capsules, tablets, caplets, pills, troches, lozenges, powders, and granules. A capsule typically comprises a core material comprising a bacterial composition and a shell wall that encapsulates the core material [para 860]. Suitable polymers include, but are not limited to: cellulosic polymers such as those formed from acrylic acid, methacrylic acid, methyl acrylate, ammonio methylacrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate (e.g., those copolymers sold under the trade name "Eudragit")[para 860]. Thereby teaching claims 17-18.
It is noted that upon administer of Klebsiella oxytoca and/or K. aerogenes, will inherently outcompete the Enterobacteriaceae for use of beta-glucosidic sugars, sucrose and/or cellobiose.
Thus, Rahman et al., anticipates the rejected claims.
Response to Arguments
5. Applicant's arguments filed Nov. 24, 2025 have been fully considered but they are not persuasive.
Applicants argue that Rahman et al., only provides working examples using Blautia. Applicants attention is directed to MPEP section 2123 teaches that patents are relevant as prior art for all they contain, “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). See also Celeritas Technologies Ltd. v. Rockwell International Corp., 150 F.3d 1354, 1361, 47 USPQ2d 1516, 1522-23 (Fed. Cir.1998) (The court held that the prior art anticipated the claims even though it taught away from the claimed invention. “The fact that a modem with a single carrier data signal is shown to be less than optimal does not vitiate the fact that it is disclosed.”). Therefore applicant’s argument is not persuasive because the teaching of Rahman et al., is not limited to particular working examples. Instead Rahman et al., is relevant for all it clearly describes. In this case, Rahman et al., clearly and repeated states K. oxytoca is a useful species for administration to treat and inhibit pathogens such as C. difficile, Salmonella spp., enteropathogenic E coli, multi-drug resistant bacteria such as Klebsiella, and E. coli, Carbapenem-resistant Enterobacteriaceae (CRE), extended spectrum beta-lactam resistant Enterococci (ESBL), and vancomycin-resistant Enterococci (VRE). All of the bacteria are antibiotic resistant species within the Enterobacteriaceae family. Furthermore, the instantly recited K. pneumoniae is encompassed and taught by multi-drug resistant bacteria Klebsiella, and Carbapenem-resistant Enterobacteriaceae. Therefore Rahman et al., clearly and specifically describe treatment. Reduction to practice is not the only way for the prior art to describe their disclosure. The Rahman et al., reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art.
Applicants argue that Rahman teach the bacterial entity is useful in the composition and methods is E. coli. And E coli cannot decolonize and clear K pneumoniae MDR2. Contrary to Applicants arguments, Rahman et al., repeatedly states the bacterial entity, e.g., species or strain, useful in the compositions and methods of treatment is Klebsiella oxytoca. Therefore, Rahman et al., is not limited to only administration of E. coli; Instead Rahman et al., clearly teach the administration of K. oxytoca. Moreover, Rahman et al., specifically disclose treating antibiotic resistant Enterobacteriaceae infection. Thus Applicants argument is not persuasive.
Applicants assert that Rahman et al., do not enable a method for treating antibiotic resistant Enterobacteriaceae, such as K pneumoniae in the microbiome of an animal wherein said method comprises administering to said animal a therapeutically effective amount of a bacterium selected from the group consisting of Klebsiella oxytoca, K. michiganensis, K. grimontii, and K. aerogenes. Contrary to Applicants assertion, Rahman et al., clearly describe a method for treating antibiotic resistant Enterobacteriaceae, such as multi-drug resistant Klebsiella and E. coli, Carbapenem-resistant Enterobacteriaceae (CRE), extended spectrum beta-lactam resistant Enterococci (ESBL), and vancomycin-resistant Enterococci (VRE); in the microbiome of an animal wherein said method comprises administering to said animal a therapeutically effective amount of Klebsiella oxytoca and/or K. aerogenes wherein said bacterium has the inherent and natural ability to outcompetes said Enterobacteriaceae for use of beta-glucosidic sugars. Therefore, none of Applicants arguments are found persuasive and the rejection is maintained.
Claim Rejections - 35 USC § 102
6. Claims 1-5, 7, 9-10 and 16 under 35 U.S.C. 102(a)(1) as being anticipated by Oliveira et al.
The claims are drawn to a method for treating antibiotic resistant Enterobacteriaceae in the microbiome of an animal wherein said method comprises administering to said animal a therapeutically effective amount of a bacterium selected from the group consisting of Klebsiella oxytoca, K. michiganensis, K. grimontii, and K. aerogenes wherein said bacterium outcompetes said Enterobacteriaceae for use of beta-glucosidic sugars.
Oliveira et al., disclose gut microbiota transmission prevents antibiotic-induced stochastic loss of colonization resistance. The intestinal microbiota contains beneficial microorganisms that protect against pathogen colonization. Antibiotics can disrupt the microbiota and compromise colonization resistance. Here, we determine how the exchange of microbes between hosts impacts the resilience of the gut microbiota to resist colonization after antibiotic-induced dysbiosis. We assess the functional consequences of dysbiosis using a mouse model of colonization resistance against an invading Escherichia coli. Antibiotics caused the stochastic loss of microbiota members, but the microbiotas of co-housed animals remained more similar to each other than those among singly houses animals [abstract]. This competition poses a challenge for invading species, since unutilized niches are unlikely to exist. Dietary fiber and mucus polysaccharides are mostly degraded by strict anaerobes, and the released di and mono-saccharides are rapidly taken up by other commensals, including Enterobacteriaceae species [Introduction]. One such Enterobacteriaceae species, Escherichia coli, efficiently consumes simple sugars present in the mucus layer, such as fucose, mannose, and arabinose. On average, five different commensal E. coli strains are able to co-exist in the gut, with subtle differences in their sugar utilization repertoires. These commensals are important to successfully ensure colonization resistance to pathogenic E. coli [Introduction].
The ability to retain or share a particular commensal, Klebsiella michiganensis, a related member of the same family Enterobacteriaceae, was sufficient for colonization resistance after antibiotic-induced dysbiosis. K. michiganensis generally outcompeted E. coli in vitro, but in vivo administration of galactitol to bi-colonized gnotobiotic mice, a nutrient that supports only E. coli growth in vitro, abolished the colonization resistance capacity of K. michiganensis against E. coli, supporting nutrient competition as the primary mechanism for their interaction. K. michiganensis also hampered colonization of the enteric Enterobacteriaceae pathogen Salmonella typhimurium and prolonged host survival [abstract].
Oliveira et al., describe the K. michiganensis was isolated from a mouse faecal sample during the study [Bacterial strains and strain construction]. Mice were administered 108 CFUs of K. michiganensis , then mice were administered 108 CFU of K. michiganensis [Colonization-resistance experiment]. Oliveira et al., determined colonization levels of E.coli and the loads of K. michiganensis [Colonization-resistance experiment]. Next Oliveira et al., performed E.coli colonization challenged with K. michiganensis. Oliveira et al., also determined the ability of K. michiganensis to provide colonization resistance against S. Typhimurium where mice were administered 108 CFU of K. michiganensis.
It is noted that upon administer of Klebsiella oxytoca, the Klebsiella oxytoca will inherently outcompete the Enterobacteriaceae for use of beta-glucosidic sugars, sucrose and/or cellobiose. Therefore, Oliveira et al., anticipates the rejected claims.
Response to Arguments
7. Applicant's arguments filed Nov. 24, 2025 have been fully considered but they are not persuasive.
Applicants argue that ARO112, the strain used by Oliveira et al., is not a K michiganensis species. The 1.132 Declaration of Dr.Strowig provides evidence of the genetic relationship of ARO112. It is the position of the Office that ARO112 was previously identified as Klebsiella michiganensis but is often now referred to as Klebsiella sp. ARO112. Thus, the Office agrees that ARO112 of Oliveira et al., do not meet the requirements to be considered K. michiganensis. However, Genomic analysis indicates that K. grimontii is the closest tested relative to ARO112, though predicted pathogenic traits often hint at a close relationship with K. michiganensis. See Cabral et al., Nature Communications. 16, Article number 10911 (2025). Cabral et al., state the non-pneumoniae Klebsiella clade shows ARO112 clustering with Klebsiella grimontii type strain and close to K. michiganensis type strain, and Klebsiella MBC022 mouse commensal strain clustering with the K. oxytoca DSM5175 type strain. This placement of ARO112 closer to K. grimontii than K. michiganensis was also recently shown by others (Osbelt et al., and Schluter et al.) , where phylogenetic analysis with new Klebsiella isolates placed ARO112 strain close, but not part of, the cluster containing three K. grimontii strains meaning that it should no longer be considered a K. michiganensis, as initially classified. Osbelt, L. et al. Klebsiella oxytoca causes colonization resistance against multidrug-resistant K. pneumoniae in the gut via cooperative carbohydrate competition. Cell Host Microbe 29, 1663–1679 (2021). Schluter, J. et al. The TaxUMAP atlas: efficient display of large clinical microbiome data reveals ecological competition in protection against bacteremia. Cell Host Microbe 31, 1126–1139 (2023). Therefore, even if Oliveira et al., misclassified ARO112 as K. michiganesis, one of ordinary skill in the art would believe ARO112, being K. grimontii because K. grimontii is closest strain, or one of skill in the art would classify ARO112 as a unique cluster from K. oxytoca. Therefore, regardless of which instantly recited Klebsiella strain, oxytoca, michiganesis or grimontii; ARO112 is still most closely identified as one of these three strains. Furthermore, Oliveira et al., clearly disclose a method for treating antibiotic resistant Enterobacteriaceae in the microbiome of an animal wherein said method comprises administering to said animal a therapeutically effective amount of a bacterium selected from the group consisting of Klebsiella oxytoca, K. michiganensis, and K. grimontii, wherein said bacterium outcompetes said Enterobacteriaceae for use of beta-glucosidic sugars. Thus the rejection is maintained because ARO112 is a bacterium selected from the group consisting of Klebsiella oxytoca, K. michiganensis, K. grimontii, known to be administered for treating antibiotic resistant Enterobacteriaceae in the microbiome of an animal, just as instantly required.
Pertinent Art
9. The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure.
Enterobacter aerogenes was officially reclassified to Klebsiella aerogenes based on whole-genome sequence-based phylogenetic analysis. The change reflects that the bacteria are more closely related to the Klebsiella genus than the Enterobacter genus. This pathogen is frequently associated with hospital-acquired infections and multi-drug resistance, such as carbapenem-resistant strains.
Klebsiella michiganensis and Klebsiella oxytoca are closely related bacteria, both belonging to the Klebsiella oxytoca complex where they share similarities and similar infection potential. K. michiganensis is one of nine species within this complex. Klebsiella oxytoca is actually a complex of nine species-Klebsiella grimontii, Klebsiella huaxiensis, Klebsiella michiganensis, K. oxytoca, Klebsiella pasteurii, Klebsiella spallanzanii, and three unnamed novel species. Phenotypic tests can assign isolates to the complex, but precise species identification requires genome-based analysis.
Eudragit is a family of polymethacrylate polymers used in drug delivery, particularly for enteric coatings, to protect medications from stomach acid and control their release in the intestines. These polymers are designed to be insoluble in the acidic environment of the stomach (low pH) but dissolve once they reach the more alkaline conditions of the intestines (higher pH). This allows for targeted drug delivery, protecting sensitive drugs from degradation in the stomach and ensuring they are released where they can be absorbed.
https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/eudragit
WO2019178490 Goodman et al. Provided herein are methods and compositions related to Klebsiella oxytoca bacteria useful as therapeutic agents.
WO2020139312 (published 2020-07-02; priority to 2019-12-27) Use in the method of at least 2 types of Klebsiella and 3 types of Proteus, including the 21st strain of bacteria, namely: Klebsiella pneumonia - 9, Klebsiella oxytoca - 3, Proteus vulgaris - 5, Proteus mirabilis - 3, Proteus peneri - 1 of different locations, isolated from various acute and chronic inflammatory diseases of bacterial etiology in children and adults, allows you to get a vaccine that has a high overall and local immunogenic effects and positive clinical responses after vaccination.
Faecal Microbiota Transplantation Eradicated Extended-Spectrum Beta-Lactamase-Producing Klebsiella pneumoniae from a Renal Transplant Recipient with Recurrent Urinary Tract Infections Anne Karmisholt Grosena (Case Rep Nephrol Dial 2019;9:102–107).
Conclusion
10. No claims allowed.
11. 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.
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JA-NA A HINES whose telephone number is (571)272-0859. The examiner can normally be reached Monday thru Thursday.
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/JANA A HINES/Primary Examiner, Art Unit 1645