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 .
Continued Examination Under 37 CFR 1.114
2. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 May 28, 2026 has been entered.
Claim Amendments
3. The claim amendments filed May 28, 2026 have been entered. Claims 1, 16 and 21 have been amended. Claims 12-13 and 15 were cancelled. Claims 1-4, 6-11, 14, and 16-21 are under consideration in this Office Action.
New Grounds of Rejection Necessitated By Applicants Amendments
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 1-4, 6-11, 14, and 16-21 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) as evidenced by Osbelt et al., (Cell Host & Microbe. Volume 29, Issue 11, 10 November 2021, Pages 1663-1679.e7).
The claims are drawn to a method for treating antibiotic resistant Enterobacteriaceae in the microbiome located in the gut 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 sucrose and/or cellobiose wherein the Enterobacteriaceae is Klebsiella pneumoniae.
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 multi-drug resistant bacteria such as Klebsiella [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. The methods further comprise administering a prebiotic to the subject such as sucrose and/or cellobiose [para 27].
The bacterial composition provides a protective or therapeutic effect against infection by one or more GI pathogens of interest [para 929]. These pathogens include Klebsiella pneumoniae [para 931]. In order to characterize those antagonistic relationships between gut commensals that are relevant to the dynamics of the mammalian gut habitat, provided are assays that demonstrate the efficacy of those bacterial compositions, including the ability to inhibit (or antagonize) the growth of a bacterial pathogen or pathobiont, typically a gastrointestinal microorganism [para 933]. These methods provide novel combinations of gut microbiota species that are able to restore or enhance ecological control over important pathogens or pathobionts in vivo [para 934]. The bacterial compositions are provided with the ability to exclude, reduce or downmodulate pathogenic bacteria. Exemplary bacterial compositions are demonstrated to reduce or downmodulate the growth rate of a pathogen or pathobiont, wherein the ability of the bacterial compositions is demonstrated by assessing the antagonism activity of the given pathogen [para 935]. In preferred embodiments, the mammalian subject suffers from or is at risk of developing dysbiosis, e.g., gastrointestinal dysbiosis, or a gastrointestinal disease, disorder or condition. The prebiotic component of the invention favors the growth of an administered or endogenous microbe, wherein the growth of the administered or endogenous microbe and/or the fermentation of the administered prebiotic by the administered or endogenous microbe slows or reduces the growth of a pathogen or pathobiont [para 937]. The K. oxytoca and/or K. aerogenes compositions for modulating a distal microbiome may optionally be administered in conjunction with a prebiotic. For example, a prebiotic can be selected which augments the growth of the anti-inflammatory bacterial population present in the probiotic composition. Exemplary prebiotics are provided in Table 7. Exemplary prebiotics which may augment the growth of exemplary bacterial species are provided in Figure 29. In one embodiment, the prebiotic is sucrose or sugars such as sucrose and/or cellobiose and combinations thereof [para 1012].
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 a disorder, ii) isolating one or more bacterial entities from the fecal material [para 253]. The methods may be carried out on a subject or subjects with particular profiles. For example, 16S sequencing may be performed for a given subject to identify the bacteria present in his or her microbiota. The sequencing may either profile the subject's entire microbiome using 16S sequencing (to the family, genera, or species level), a portion of the subject' s microbiome using 16S sequencing, or it may be used to detect the presence or absence of specific candidate bacteria that are biomarkers for health or a particular disease state, such as markers of multi-drug resistant organisms or specific genera of concern such as Escherichia [para 960]. 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.
Thus, Rahman et al., teach method for treating antibiotic resistant Enterobacteriaceae, such as Klebsiella pneumoniae commonly known to be located in the gut of an animal and causes gastrointestinal dybiosis in the gut; wherein said method comprises administering to said animal a therapeutically effective amount of Klebsiella oxytoca and/or K. aerogenes where inherently Klebsiella oxytoca and/or K. aerogenes outcompetes Klebsiella pneumoniae for use of sucrose and/or cellobiose.
Thus, Rahman et al., anticipates the rejected claims.
Osbelt et al., teach gut colonization with multidrug-resistant enterobacteria increases risk of bloodstream infections. Osbelt et al. characterize the ability of human stools to inhibit growth of multidrug-resistant Klebsiella pneumoniae. Commensal Klebsiella oxytoca strains were identified in protected human donors, which in cooperation with other commensals outcompete K. pneumoniae through beta-glucoside utilization in mice [In Brief]. K. oxytoca strains reduce gut colonization of MDR K. pneumoniae strains in antibiotic-treated and gnotobiotic mouse models [Summary]. In addition to direct competition between K. oxytoca and K. pneumoniae, cooperation with additional commensals is required to reestablish full colonization resistance and gut decolonization [Summary]. Finally, humanized microbiota mice generated from K. pneumoniae-susceptible donors are protected by K. oxytoca administration, demonstrating the potential of commensal K. oxytoca strains as next-generation probiotics [Summary]. Protective K. oxytoca strains outcompete K. pneumoniae for different beta-glycosides in vitro. Focusing on sugars that could be utilized by K. pneumoniae MDR1 and protective strains, differences between the panel of protective (n = 4) and nonprotective (n = 2) strains in the utilization capacity of various disaccharides (cellobiose and sucrose), could be identified (Table S4; Figure 5F). Osbelt et al., teach indicating that beta-glucoside utilization may contribute to the interspecies competition of Klebsiella strains [page 1670]. To test whether these K. oxytoca strains could indeed outcompete K. pneumoniae for beta-glucosides utilization, both species were cocultured in a 1:1 ratio in minimal medium supplemented with sucrose, cellobiose, salicin, or arbutin as sole carbon sources for 24 h under anaerobic conditions, see (Figures 5G, -5H, S5C, and S5D). Thus, Osbelt et al., teach the CasA gene enables K. oxytoca to outcompete K. pneumoniae for beta-glucosides in vivo. Therefore, Osbelt et al., evidence Klebsiella oxytoca will naturally outcompetes Klebsiella pneumoniae for use of sucrose and/or cellobiose in the gut.
Response to Arguments
5. Applicant's arguments filed May 28, 2026 have been fully considered but they are not persuasive.
Applicants argue that Rahman et al., do not teach that the bacterium selected from Klebsiella oxytoca, K. michiganensis, K. grimontii, and K. aerogenes outcompetes the Klebsiella pneumoniae for use of sucrose and/or cellobiose as recited in claim 1, let alone outcompeting the MDR Klebsiella pneumoniae as recited in claim 21. As previously stated, administering to said animal a therapeutically effective amount of Klebsiella oxytoca and/or K. aerogenes will inherently Klebsiella oxytoca and/or K. aerogenes outcompetes Klebsiella pneumoniae for use of sucrose and/or cellobiose. In this case, the Office evidences that Osbelt et al., teach the CasA gene enables K. oxytoca to outcompete K. pneumoniae for use of sucrose and/or cellobiose in the gut. Therefore in relying upon the theory of inherency, the examiner provided a basis in fact and/or technical reasoning to reasonably support the determination that the allegedly inherent characteristic necessarily flows from the teachings of the applied prior art. See Ex parte Levy, 17 USPQ2d 1461, 1464 (Bd. Pat. App. & Inter. 1990) . In this case, Osbelt et al., clearly states K. oxytoca, because of the presence of the CasA gene will outcompete K. pneumoniae for use of sucrose and/or cellobiose in the gut. Therefore, Applicants argument is not found persuasive and the burden of proof shifts to Applicant.
Finally, applicants argue that Rahman do not disclose the presence of sucrose and/or cellobiose. However, Rahman et al., teach the prebiotic component of the invention favors the growth of an administered or endogenous microbe, wherein the growth of the administered or endogenous microbe and/or the fermentation of the administered prebiotic by the administered or endogenous microbe slows or reduces the growth of a pathogen or pathobiont [para 937]. The K. oxytoca and/or K. aerogenes compositions for modulating a distal microbiome may optionally be administered in conjunction with a prebiotic. Therefore, Rahman et al., does disclose making the sucrose and/or cellobiose will be present.
Therefore, none of Applicants arguments are found persuasive.
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., (Nat. Microbiol, 2020 Apr;5(4):630-641. Epub2020 Jan 20) as evidenced by Osbelt et al., (Cell Host & Microbe. Volume 29, Issue 11, 10 November 2021, Pages 1663-1679.e7).
The claims are drawn to a method for treating antibiotic resistant Enterobacteriaceae in the microbiome located in the gut 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 sucrose and/or cellobiose wherein the Enterobacteriaceae is Klebsiella pneumoniae.
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.
Thus, Oliveria et al., teach method for treating antibiotic resistant Enterobacteriaceae, such as Klebsiella pneumoniae commonly known to be located in the gut of an animal and causes gastrointestinal dybiosis in the gut; wherein said method comprises administering to said animal a therapeutically effective amount of Klebsiella oxytoca and/or K. aerogenes where inherently Klebsiella oxytoca and/or K. aerogenes outcompetes Klebsiella pneumoniae for use of sucrose and/or cellobiose.
Thus, Oliveria et al., anticipates the rejected claims.
Osbelt et al., teach a closely related species, K. michiganensis, has been shown to assist in protection against S. Typhimurium and E. coli (Oliveira et al., 2020). Notably, Oliveira and colleagues suggested that using indirect experiments that K. michiganensis mediates protection through sugar competition but did not identify a specific gene in K. michiganensis responsible for the effect.
It is noted that upon administer of Klebsiella michiganensis the Klebsiella michiganensis will inherently outcompete the Enterobacteriaceae for use of sucrose and/or cellobiose. Therefore, Oliveira et al., anticipates the rejected claims.
Response to Arguments
7. Applicant's arguments filed May 28, 2026 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
8. The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure.
Raghunand et al., 2003 The glucoside genes of Klebsiella aerogenes: conservation and divergence in relation to the cryptic Bgl genes of Escherichia coli. FEMS Microbiol. Lett., 223 (2003), pp. 267-274.
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.
Conclusion
9. No claims allowed.
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/JANA A HINES/Primary Examiner, Art Unit 1645
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