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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/10/2025 has been entered.
Withdrawal of Rejections
The response and amendments filed on 12/10/2025 are acknowledged. Any previously applied minor objections and/or minor rejections (i.e., formal matters), not explicitly restated here for brevity, have been withdrawn necessitated by Applicant’s formality correction and/or amendments. For the purposes of clarity of the record, the reasons for the Examiner’s withdrawal, and/or maintaining, if applicable, of the substantive or essential claim rejections are detailed directly below and/or in the Examiner’s Response to Arguments section.
Briefly, the previous rejections under 35 U.S.C. 112(b) for indefiniteness have been withdrawn necessitated by Applicant’s amendments.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/10/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 103, Obviousness
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Interpretation: For claims 176, 195, and 198, the Examiner has interpreted the wherein clause reciting “…wherein the purified bacterial mixture does not comprise…” to mean that (i), or (ii), or (iii) are required due to the “and/or” linking phrase. Therefore, for the purposes of applying prior art, the prior art only needs to teach either (i), or (ii), or (iii).
Claims 176, 182-184, 190-192, and 198-199 are rejected under 35 U.S.C. 103 as being unpatentable over Berry (US 2016/0193258; Date of Publication: July 7, 2016 – previously cited) in view of Bengoechea (Klebsiella pneumoniae infection biology: living to counteract host defences; 2019 – previously cited), Henn (US 2017/0151291; Date of Publication: June 1, 2017 – previously cited), and Fathi (Isolation, Detection, and Characterization of Enterotoxigenic Bacteroides fragilis in Clinical Samples; 2016 – previously cited).
Berry’s general disclosure relates to probiotic, non-pathogenic bacterial populations for the prevention, control, and treatment of disorders and conditions, in particular diseases associated with graft versus host disease (see, e.g., Berry, [0004]).
Regarding claims 176 and 198 pertaining to the purified bacterial composition, Berry teaches a purified bacterial composition containing combinations of commensal bacteria of human gut microbiota with the capacity to meaningfully provide functions of a healthy microbiota when administered to a mammalian subject, wherein the composition inhibits the growth of a pathogen 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 (see, e.g., Berry, [0199], [0348]-[0349]). The bacterial compositions can comprise 15 or more bacterial species, wherein those bacterial strain can belong to the species of Bacteroides ovatus, Bacteroides vulgatus, Bifidobacterium longum, Blautia coccoides, Clostridium citroniae, Clostridium clostridioforme, Clostridium innocuum, Dorea longicatena, Erysipelatoclostridium ramosum, Blautia obeum, Alistripes putredinis, Collinsella aerofaciens, Phasocolarctobacterium faecium, Fusobacterium mortiferum, and Escherichia coli (see, e.g., Berry, [0206]-[0207] & Table 1). Therefore, Berry teaches a purified bacterial composition comprising at least 15 bacterial species wherein the species can be those listed above and a method of administering the composition to a subject to inhibit the replication and/or survival of a pathogenic organism thereby suppressing the colonization of a pathogenic organism.
Regarding claims 182-183 pertaining to the pathobiont, Berry teaches that the pathogenic organism is a pathobiont that is in the intestine of the subject or part of the gut microbiota of the subject (see, e.g., Berry, [0199], [0329]).
Regarding claims 184 and 198 pertaining to the Th1 responses, Berry teaches that the bacterial composition can be used for treatment of dysbiosis (or pathobiont imbalance in the gut microbiota), wherein the pathogenic organism is capable of altering a proportion of the immune subpopulations, e.g., T cell subpopulations, in the subject (see, e.g., Berry, [0496]). In particular, the bacterial composition is capable of reducing Th1 cells (see, e.g., Berry, [0497]-[0499]). Therefore, it is obvious that the pathobiont is inducing a Th1 response in the subject that is being treated by the bacterial composition.
Regarding claims 190-192 pertaining to the pharmaceutical composition, Berry teaches that the pharmaceutical bacterial composition is formulated for delivery to the GI tract or intestines by an oral route (see, e.g., Berry, [0262], [0362]). Berry teaches the composition can be formulated to be pH sensitive and can be formulated to have an enteric-coated capsule or tablet or with a buffering or protective composition (see, e.g., Berry, [0262]).
Regarding claims 198-199 pertaining to suppressing diseases and disorders, Berry teaches the disease or disorders to be treated by the bacterial compositions in the subject comprises dysbiosis, including, but not limited to, an infection due to a gastrointestinal pathogen or may be at risk of developing or transmitting to others an infection due to a gastrointestinal pathogen, and/or dysbiosis that contributes to or causes a condition classified as an autoimmune or inflammatory disease or inflammatory bowel disease (see, e.g., Berry, [0172]). Berry teaches a purified bacterial composition containing combinations of commensal bacteria of human gut microbiota with the capacity to meaningfully provide functions of a healthy microbiota when administered to a mammalian subject, wherein the composition inhibits the growth of a pathogen 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 (see, e.g., Berry, [0199], [0348]-[0349]). The bacterial compositions can comprise 15 or more bacterial species, wherein those bacterial strain can belong to the species of Bacteroides ovatus, Bacteroides vulgatus, Bifidobacterium longum, Blautia coccoides, Clostridium citroniae, Clostridium clostridioforme, Clostridium innocuum, Dorea longicatena, Erysipelatoclostridium ramosum, Blautia obeum, Alistripes putredinis, Collinsella aerofaciens, Phasocolarctobacterium faecium, Fusobacterium mortiferum, and Escherichia coli (see, e.g., Berry, [0206]-[0207] & Table 1). Berry teaches that the pathogenic organism is a pathobiont that is in the intestine of the subject or part of the gut microbiota of the subject (see, e.g., Berry, [0199], [0329]). Furthermore, Berry teaches “In another embodiment, a probiotic composition contains immunomodulatory bacteria that decrease the proportion of Th1 cells in a subject” (see, e.g., Berry, [0498]).
In addition, Examiner notes that Berry identifies that the disclosed compositions could be utilized to treat inflammatory bowel disease, NASH, primary sclerosing cholangitis, nonalcoholic fatty liver disease (see, e.g., Berry, [0507]-[0508], claim 95), and heart, autoimmune, and liver disease generally (see id. at [0361]), as well as alcoholism (see, e.g., Berry, [0840], treating a mouse model of alcoholism).
However, Berry does not teach: a pathogenic bacterium belonging to the species Klebsiella pneumoniae (claims 176 and 198); or wherein the purified bacterial mixture: (i) does not comprise a bacterial strain belonging to the species Bacteroides fragilis, (ii) does not comprise a bacterial strain belonging to the species Paraclostridium bifermentans, and/or (iii) does not comprise a bacterial strain belonging to the species Clostridium sordellii (claims 176 and 198).
Bengoechea’s general disclosure relates to understanding Klebsiella pneumoniae host-pathogen interactions, and K. pneumoniae immune invasion strategies, to develop new therapeutics for treating K. pneumoniae infection (see, e.g., Bengoechea, abstract). Moreover, Bengoechea discloses “Klebsiella species cause a wide range of diseases including pneumonia, urinary tract infections (UTIs), bloodstream infections and sepsis. These infections are particularly a problem among neonates, elderly and immunocompromised individuals” (see, e.g., Bengoechea, abstract). Furthermore, in regards to K. pneumoniae infections, Bengoechea discloses that that the “Defining features of these infections are the ability to metastatically spread and their significant morbidity and mortality” (see, e.g., Bengoechea, Introduction).
Regarding claims 176 and 198 pertaining to K. pneumoniae, Bengoechea teaches infections caused K. pneumoniae, wherein K. pneumoniae induces Th1 responses (see, e.g., Bengoechea, Introduction, pg. 123 & Contribution of Host Signaling in Defence Against K. pneumoniae Infections, pg. 127). Additionally, Bengoechea teaches that K. pneumoniae infections are primarily a problem among neonates, elderly, and immunocompromised individuals within the healthcare setting (see, e.g., Bengoechea, Introduction, pg. 123).
Henn’s general disclosure relates to bacterial mixture compositions, wherein the bacteria synergistically interact to inhibit a pathogenic bacterium, in order to prevent, treat, and reduce symptoms associated with a dysbiosis in a mammalian subject (see, e.g., Henn, abstract & [0008]).
Regarding claims 176 and 198 pertaining to the bacterial mixture not comprising certain bacteria, Henn teaches that in an embodiment, the bacterial composition does not comprise Bacteroides fragilis (see, e.g., Henn, [0132]). Moreover, Henn teaches that the compositions comprise an effective amount of a bacterial composition comprising bacteria that are inhibitor to a pathogenic bacterium, wherein the pathogenic bacterium can be Klebsiella (see, e.g., Henn, [0010]). Furthermore, Henn teaches the construction of assays to screen the bacterial compositions for inhibitor activity against Klebsiella pneumoniae (see, e.g., Henn, Example 10).
Fathi’s general disclosure relates to the isolation and characterization of Bacteroides fragilis in clinical samples (see, e.g., Fathi, abstract). Moreover, Fathi discloses that B. fragilis is an opportunistic pathogen that can cause abscess formation and bacteremia in humans (see, e.g., Fathi, abstract). Additionally, Fathi discloses that “in its enterotoxigenic form, B. fragilis is a known cause of diarrheal illness, is associated with inflammatory bowel disease, and has been recently characterized in patients with colon cancer” (see, e.g., Fathi, abstract).
Regarding claims 176 and 198 pertaining to the bacterial mixture not comprising B. fragilis, Fathi teaches that B. fragilis has been shown to cause a wide range of pathologies in humans, such as abscess formation, bacteremia, diarrheal disease, inflammatory bowel disease, and is associated with colon cancer (see, e.g., Fathi, abstract). Additionally, Fathi teaches that toxins produced by B. fragilis have been shown to include NF-kB signaling (see, e.g., Fathi, Introduction, pg. 57); therefore, one of ordinary skill in the art would recognize that B. fragilis is pro-inflammatory. Therefore, based on the pathogenicity and pro-inflammatory nature of B. fragilis, one of ordinary skill in the art would exclude B. fragilis from a bacterial composition, wherein the bacterial composition is produced to treat bacterial infections.
It would have been first obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce Berry’s bacterial mixture for suppression of Klebsiella pneumoniae infection, as taught by Bengoechea. One would have been motivated to do so because Bengoechea teaches that “K. pneumoniae is gaining attention due to the rise in the number of infections and the increasing number of strains resistant to antibiotics” (see, e.g., Bengoechea, Introduction, pgs. 123-124). Additionally, Bengoechea teaches that “Klebsiella species cause a wide range of diseases including pneumonia, urinary tract infections (UTIs), bloodstream infections and sepsis. These infections are particularly a problem among neonates, elderly and immunocompromised individuals” (see, e.g., Bengoechea, abstract). Moreover, Bengoechea teaches infections caused K. pneumoniae, wherein K. pneumoniae induces Th1 responses (see, e.g., Bengoechea, Introduction, pg. 123 & Contribution of Host Signaling in Defence Against K. pneumoniae Infections, pg. 127).Therefore, one would have been motivated to produce an anti-inflammatory composition since the bacterial composition taught by Berry is capable of reducing Th1 cells (see, e.g., Berry, [0497]-[0499]), and inhibits the growth of a pathogen 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 (see, e.g., Berry, [0199], [0348]-[0349]). Therefore, one of ordinary skill in the art would readily understand that administration of Berry’s bacterial composition, wherein the composition reduces Th1 responses, in order to treat K. pneumoniae, which induces Th1 responses, would exhibit immunomodulatory and anti-inflammatory activity and be effective in treating K. pneumoniae infections. Additionally, Berry teaches “the probiotic composition reduces inflammation in the gastrointestinal tract of the subject. In one embodiment of the foregoing aspect, the probiotic composition comprises an anti-inflammatory bacterial population. In one embodiment of the foregoing aspect, the anti-inflammatory bacterial population decreases secretion of pro-inflammatory cytokines and/or increases secretion of anti-inflammatory cytokines by human peripheral blood mononuclear cells (PBMCs). In one embodiment of the foregoing aspect, the anti-inflammatory bacterial population decreases secretion of a pro-inflammatory cytokine selected from the group consisting of IFNγ, IL-12p70, IL-1α, IL-6, IL-8, MCP1, MIP1α, MIP1β, TNFα, and combinations thereof. In one embodiment of the foregoing aspect, the anti-inflammatory bacterial population increases secretion of an anti-inflammatory cytokine selected from the group consisting of IL-10, IL-13, IL-4, IL-5, TGFβ and combinations thereof. In one embodiment of the foregoing aspect, the anti-inflammatory bacterial population produces short chain fatty acids” (see, e.g., Berry, [0011]). Therefore, Berry’s bacterial composition exhibits anti-inflammatory activity. Furthermore, the bacterial composition taught by Berry can be used for “the prevention, control, and treatment of transplant disorders and conditions, in particular diseases associated with graft versus host disease (GVHD)” (see, e.g., Berry, [0004]). Therefore, based on the teachings of Berry and Bengoechea it would have been obvious to administer Berry’s bacterial mixture in order to inhibit survival of K. pneumoniae. One would have expected success because Berry and Bengoechea both teach treatment of bacterial infections.
It would have been secondly obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce Berry’s bacterial mixture, wherein the bacterial mixture does not comprise Bacteroides fragilis, as taught by Henn. One would have been motivated to do so because Fathi teaches that B. fragilis is an opportunistic pathogen that causes abscess formation, bacteremia, diarrheal disease, inflammatory bowel disease, and is associated with colon cancer (see, e.g., Fathi, abstract). Additionally, Fathi teaches that toxins produced by B. fragilis have been shown to activate NF-kB signaling (see, e.g., Fathi, Introduction, pg. 57); therefore, one of ordinary skill in the art would readily understand that B. fragilis is pro-inflammatory. The bacterial composition taught by Berry is anti-inflammatory and inhibits the growth of bacterial infections, such as K. pneumoniae infections (see, e.g., Berry, [0011]) Therefore, based on the teachings of Berry, Henn, and Fathi, it would have been obvious to produce a bacterial mixture, wherein the bacterial mixture does not comprise B. fragilis because B. fragilis is a pro-inflammatory pathogen that causes a wide variety of diseases; therefore, one of ordinary skill in the art would understand that inclusion of B. fragilis in Berry’s bacterial composition would not be beneficial in treating K. pneumoniae infections. One would have expected success because Berry, Henn, and Fathi all teach compositions comprising bacterial mixtures for treatment of diseases.
Claim 193 is rejected under 35 U.S.C. 103 as being unpatentable over Berry, Bengoechea, Henn, and Fathi as applied to claims 176, 182-184, 190-192, and 198-199 above, and further in view of Budic (Escherichia coli Bacteriocins: Antimicrobial Efficacy and Prevalence among Isolates from Patients with Bacteraemia; 2011 – previously cited).
The teachings of Berry, Bengoechea, Henn, and Fathi herein referred to as modified-Berry-Bengoechea-Henn-Fathi, are discussed above as it pertains to a bacterial mixture for treating K. pneumoniae infections.
However, modified-Berry-Bengoechea-Henn-Fathi does not teach: wherein the bacterial strain belonging to the species Escherichia coli comprises one or more bacteriocin-encoding genes (claim 193).
Budic’s general disclosure relates to E. coli and bacteriocin-produced thereby (see, e.g., Budic, abstract). Moreover, Budic discloses that “Colicins have been shown to be effective against E. coli strains associated with diarrhea including serotype O157:H7, as well as postweaning diarrhea (PWD) and edema disease in swine” (see, e.g., Budic, Results and Discussion, pg. 2). Furthermore, Budic discloses that the prevalence of bacteriocins are significantly decreased in immunocompromised individuals (see, e.g., Budic, pg. 4)
Regarding claim 193 pertaining to E. coli bacteriocins, Budic teaches that bacteriocins are antimicrobial peptides generally active against bacteria closely related to the producer and that Escherichia coli produces two types of bacteriocins, colicins and microcins (see, e.g., Budic, abstract). Moreover, Budic teaches that colicins are plasmid encoded, wherein microcin encoded genes are found in the chromosome (see, e.g., Budic, Introduction, pg. 1). Additionally, Budic discloses that E. coli bacteriocins have been shown to be effective against pathogenic E. coli strains, such as O157:H7 and F18-positive enterotoxigenic E. coli, as well as Listeria monocytogenes, which is the causative agent of human listeriosis, and Salmonella strains (see, e.g., Budic, Results and Discussion, pg. 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce modified-Berry-Bengoechea-Henn-Fathi’s bacterial mixture comprising E. coli, wherein the E. coli comprises bacteriocin-encoding genes, as taught by Budic. One would have been motivated to do so because Budic teaches that bacteriocins are antimicrobial peptides that are active against bacteria, such as pathogenic E. coli strains, Listeria monocytogenes, and Salmonella strains (see, e.g., Budic, abstract & Discussion, pg. 2). Furthermore, modified-Berry-Bengoechea-Henn-Fathi teaches an anti-inflammatory bacterial composition that can be used to prevent, control, and treat disorders and conditions, in particular diseases associated with graft versus host disease (see, e.g., Berry, [0004]). Therefore, based on the teachings of modified-Berry-Bengoechea-Henn-Fathi and Budic, it would have been obvious to produce a bacterial mixture comprising E. coli, wherein the E. coli comprises bacteriocin-encoding genes, because, since the prior art of Budic teaches the antimicrobial effect of bacteriocins against pathogenic microorganisms, one would reasonably conclude that the antimicrobial effect would be beneficial in treating K. pneumoniae infections since K. pneumoniae is a pathogenic bacterium, as taught by modified-Berry-Bengoechea-Henn-Fathi. One would have expected success because modified-Berry-Bengoechea-Henn-Fathi and Budic both teach E. coli and treatment of infections.
Claim 195 is rejected under 35 U.S.C. 103 as being unpatentable over Berry (US 2016/0193258; Date of Publication: July 7, 2016 – previously cited) in view of Bengoechea (Klebsiella pneumoniae infection biology: living to counteract host defences; 2018 – previously cited), Henn (US 2014/0147425; Date of Publication: May 29, 2014 – previously cited), Fathi (Isolation, Detection, and Characterization of Enterotoxigenic Bacteroides fragilis in Clinical Samples; 2016 – previously cited), and Schneider (U.S. Patent No. 9,999,641; Date of Publication: June 19, 2018 – previously cited).
The teachings of Berry are discussed above as it pertains to a bacterial mixture for inhibiting the growth of a bacterium.
Regarding claim 195 pertaining to the purified bacterial composition, Berry teaches a purified bacterial composition containing combinations of commensal bacteria of human gut microbiota with the capacity to meaningfully provide functions of a healthy microbiota when administered to a mammalian subject, wherein the composition inhibits the growth of a pathogen 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 (see, e.g., Berry, [0199], [0348]-[0349]). The bacterial compositions can comprise 15 or more bacterial species, wherein those bacterial strain can belong to the species of Bacteroides ovatus, Bacteroides vulgatus, Bifidobacterium longum, Blautia coccoides, Clostridium citroniae, Clostridium clostridioforme, Clostridium innocuum, Dorea longicatena, Erysipelatoclostridium ramosum, Blautia obeum, Alistripes putredinis, Collinsella aerofaciens, Phasocolarctobacterium faecium, Fusobacterium mortiferum, and Escherichia coli (see, e.g., Berry, [0206]-[0207] & Table 1).
Regarding claim 195 pertaining to the sequence identities, Berry teaches that the sequences associated with the 15 species as the following: Bacteroides ovatus (SEQ ID NO: 287), Bacteroides vulgatus (SEQ ID NO: 331), Bifidobacterium longum (SEQ ID NO: 356), Blautia coccoides (SEQ ID NO: 573), Clostridium citroniae (SEQ ID NO: 569), Clostridium clostridioforme (SEQ ID NO: 571), Clostridium innocuum (SEQ ID NO: 595), Dorea longicatena (SEQ ID NO: 774), Erysipelatoclostridium ramosum (SEQ ID NO: 617), Blautia obeum (SEQ ID NO: 1664), Alistripes putredinis (SEQ ID NO: 132), Collinsella aerofaciens (SEQ ID NO: 659), Phasocolarctobacterium faecium (SEQ ID NO: 1462), Fusobacterium mortiferum (SEQ ID NO: 897), and Escherichia coli (SEQ ID NO: 825) (see, e.g., Berry, Table 1). Berry’s SEQ ID NOs: 287, 331, 356, 573, 569, 774, 617, 1664, 132, 659, 1462, 897, and 825 have 97.4%, 97.9%, 97%, 100%, 99.2%, 98.9%, 99.4%, 99.5%, 99.4%, 93.2%, 100%, 96.9%, 99.2%, 98.9%, and 99.7% identity to this present application’s SEQ ID NO: 4, 7, 9, 11, 12, 13, 15, 18, 19, 25, 26, 27, 31, 34, and 36, respectively.
However, Berry does not teach: a pathogenic bacterium belonging to the species Klebsiella pneumoniae (claim 195); or wherein the purified bacterial mixture: (i) does not comprise a bacterial strain comprising a 16s rDNA sequence with at least 97% sequence identity to the nucleotide sequence of SEQ ID NO: 33, (ii) does not comprise a bacterial strain comprising a 16s rDNA sequence with at least 97% sequence identity to the nucleotide sequence of SEQ ID NO: 35, and/or (iii) does not comprise a bacterial strain comprising a 16s rDNA sequence with at least 97% sequence identity to the nucleotide sequence of SEQ ID NO: 16 (claim 195); or a bacterial strain comprising a 16s rDNA sequence with at least 97% sequence identity to the nucleotide sequence of SEQ ID NO: 25 (claim 195).
Bengoechea’s general disclosure relates to understanding Klebsiella pneumoniae host-pathogen interactions, and K. pneumoniae immune invasion strategies, to develop new therapeutics for treating K. pneumoniae infection (see, e.g., Bengoechea, abstract). Moreover, Bengoechea discloses “Klebsiella species cause a wide range of diseases including pneumonia, urinary tract infections (UTIs), bloodstream infections and sepsis. These infections are particularly a problem among neonates, elderly and immunocompromised individuals” (see, e.g., Bengoechea, abstract). Furthermore, Bengoechea discloses that that the “Defining features of these infections are the ability to metastatically spread and their significant morbidity and mortality” (see, e.g., Bengoechea, Introduction).
Regarding claim 195 pertaining to K. pneumoniae, Bengoechea teaches infections caused K. pneumoniae, wherein K. pneumoniae induces Th1 responses (see, e.g., Bengoechea, Introduction, pg. 123 & Contribution of Host Signaling in Defence Against K. pneumoniae Infections, pg. 127). Additionally, Bengoechea teaches that K. pneumoniae infections are primarily a problem among neonates, elderly, and immunocompromised individuals within the healthcare setting (see, e.g., Bengoechea, Introduction, pg. 123).
Henn’s general disclosure relates to bacterial mixture compositions, wherein the bacteria synergistically interact to inhibit a pathogenic bacterium, in order to prevent, treat, and reduce symptoms associated with a dysbiosis in a mammalian subject (see, e.g., Henn, abstract & [0008]).
Regarding claim 195 pertaining to SEQ ID NO: 33 corresponding to Bacteroides fragilis, Henn teaches that the bacterial composition does not comprise Bacteroides fragilis corresponding to Henn’s SEQ ID NO: 279, wherein SEQ ID NO: 279 has 99.9% sequence similarity to instant SEQ ID NO: 33 (see, e.g., Henn, [0033], [0075]).
Fathi’s general disclosure relates to the isolation and characterization of Bacteroides fragilis in clinical samples (see, e.g., Fathi, abstract). Moreover, Fathi discloses that B. fragilis is an opportunistic pathogen that can cause abscess formation and bacteremia in humans (see, e.g., Fathi, abstract). Additionally, Fathi discloses that “in its enterotoxigenic form, B. fragilis is a known cause of diarrheal illness, is associated with inflammatory bowel disease, and has been recently characterized in patients with colon cancer” (see, e.g., Fathi, abstract).
Regarding claim 195 pertaining to the bacterial mixture not comprising B. fragilis, Fathi teaches that B. fragilis has been shown to cause a wide range of pathologies in humans, such as abscess formation, bacteremia, diarrheal disease, inflammatory bowel disease, and is associated with colon cancer (see, e.g., Fathi, abstract). Therefore, based on the pathogenicity of B. fragilis, one of ordinary skill in the art would exclude B. fragilis from a bacterial composition, wherein the bacterial composition is produced to treat bacterial infections.
Schneider’s general disclosure relates to compositions and methods for the treatment or prevention of pathogenic infections (see, e.g., Schneider, abstract & [81]). Moreover, Schneider teaches that the bacterial composition “induces the proliferation and/or accumulation of regulatory T cells (Tregs)” (see, e.g., Schneider, [78]), and that the bacterial composition is effective in eliminating pathogenic bacteria, such as C. difficile, from the body (see, e.g., Schneider, [36]).
Regarding claim 195 pertaining to instant SEQ ID NO: 25 corresponding to Blautia obeum, Schneider teaches a composition comprising Blautia obeum associated with Schneider’s SEQ ID NO: 84, which has 99.3% identity to the present application’s SEQ ID NO: 25 (see, e.g., Schneider, Table F1, Table F2). Additionally, Schneider teaches this strain of Blautia obeum produces short chain fatty acids, such that the short chain fatty acids produced provide a synergistic effect with the other bacteria in the composition to suppress growth of pathogens and/or stimulate growth of non-pathogens in the intestinal track (see, e.g., Schneider at col. 20, lines 15-56).
It would have been first obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce Berry’s bacterial mixture for suppression of Klebsiella pneumoniae infection, as taught by Bengoechea. One would have been motivated to do so because Bengoechea teaches that “K. pneumoniae is gaining attention due to the rise in the number of infections and the increasing number of strains resistant to antibiotics” (see, e.g., Bengoechea, Introduction, pgs. 123-124). Additionally, Bengoechea teaches that “Klebsiella species cause a wide range of diseases including pneumonia, urinary tract infections (UTIs), bloodstream infections and sepsis. These infections are particularly a problem among neonates, elderly and immunocompromised individuals” (see, e.g., Bengoechea, abstract). Therefore, one would have been motivated to produce an anti-inflammatory composition since the bacterial composition taught by Berry is capable of reducing Th1 cells (see, e.g., Berry, [0497]-[0499]), and inhibits the growth of a pathogen 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 (see, e.g., Berry, [0199], [0348]-[0349]). Additionally, Berry teaches “the probiotic composition reduces inflammation in the gastrointestinal tract of the subject. In one embodiment of the foregoing aspect, the probiotic composition comprises an anti-inflammatory bacterial population. In one embodiment of the foregoing aspect, the anti-inflammatory bacterial population decreases secretion of pro-inflammatory cytokines and/or increases secretion of anti-inflammatory cytokines by human peripheral blood mononuclear cells (PBMCs). In one embodiment of the foregoing aspect, the anti-inflammatory bacterial population decreases secretion of a pro-inflammatory cytokine selected from the group consisting of IFNγ, IL-12p70, IL-1α, IL-6, IL-8, MCP1, MIP1α, MIP1β, TNFα, and combinations thereof. In one embodiment of the foregoing aspect, the anti-inflammatory bacterial population increases secretion of an anti-inflammatory cytokine selected from the group consisting of IL-10, IL-13, IL-4, IL-5, TGFβ and combinations thereof. In one embodiment of the foregoing aspect, the anti-inflammatory bacterial population produces short chain fatty acids” (see, e.g., Berry, [0011]). Furthermore, the bacterial composition taught by Berry can be used for “the prevention, control, and treatment of transplant disorders and conditions, in particular diseases associated with graft versus host disease (GVHD)” (see, e.g., Berry, [0004]). Therefore, based on the teachings of Berry and Bengoechea it would have been obvious to administer Berry’s bacterial mixture in order to inhibit survival of K. pneumoniae One would have expected success because Berry and Bengoechea both teach treatment of bacterial infections.
It would have been secondly obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce Berry’s bacterial mixture, wherein the bacterial mixture does not comprise Bacteroides fragilis corresponding to 99.9% sequence identity to instant SEQ ID NO: 33, as taught by Henn. One would have been motivated to do so because Fathi teaches that B. fragilis is an opportunistic pathogen that causes abscess formation, bacteremia, diarrheal disease, inflammatory bowel disease, and is associated with colon cancer (see, e.g., Fathi, abstract). Additionally, Fathi teaches that toxins produced by B. fragilis have been shown to activate NF-kB signaling (see, e.g., Fathi, Introduction, pg. 57); therefore, one of ordinary skill in the art would readily understand that B. fragilis is pro-inflammatory. The bacterial composition taught by Berry is anti-inflammatory and inhibits the growth of bacterial infections, such as K. pneumoniae infections (see, e.g., Berry, [0011]) Therefore, based on the teachings of Berry, Henn, and Fathi, it would have been obvious to produce a bacterial mixture, wherein the bacterial mixture does not comprise B. fragilis because B. fragilis is a pro-inflammatory pathogen that causes a wide variety of diseases; therefore, one of ordinary skill in the art would understand that inclusion of B. fragilis in Berry’s bacterial composition would not be beneficial in treating K. pneumoniae infections. One would have expected success because Berry, Henn, and Fathi all teach compositions comprising bacterial mixtures for treatment of diseases.
It would have been thirdly obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce Berry’s bacterial mixture comprising Blautia obeum corresponding to Schneider’s SEQ ID NO: 84. One would have been motivated to do so because Schneider teaches that this strain of Blautia obeum produces short chain fatty acids, such that the short chain fatty acids produced provide a synergistic effect with the other bacteria in the composition to suppress growth of pathogens and/or stimulate growth of non-pathogens in the intestinal track (see, e.g., Schneider at col. 20, lines 15-56). Moreover, the bacterial composition taught by Berry can be used for “the prevention, control, and treatment of transplant disorders and conditions, in particular diseases associated with graft versus host disease (GVHD)” (see, e.g., Berry, [0004]). Therefore, based on the teaching of Berry and Schneider, it would have been obvious to produce a bacterial mixture composition comprising Blautia obeum because the short chain fatty acids produced by Blautia obeum can provide a synergistic effect with the other bacterial species within the mixture in order to inhibit infections. Therefore, one of ordinary skill in the art would readily understand that inclusion of Blautia obeum in the Berry’s bacterial composition would be beneficial in treating K. pneumoniae infections because of the synergistic effects B. obeum exhibits in order to inhibit pathogenic infection, as taught by Schneider. One would have expected success because Berry and Schneider both teach purified bacterial mixture compositions for treatment of diseases.
Claim 197 is rejected under 35 U.S.C. 103 as being unpatentable over Berry, Bengoechea, Henn, Fathi, and Schneider as applied to claim 195 above, and further in view of Honda (U.S. Patent No. 11,633,433; Effective Filing Date: July 19, 2017 – previously cited).
The teachings of Berry, Bengoechea, Henn, Fathi, and Schneider, herein referred to as modified-Berry-Bengoechea-Henn-Fathi-Schneider, are discussed above as it pertains to a bacterial mixture composition for inhibiting growth of K. pneumoniae.
Regarding claim 197 pertaining to the sequence identities, modified-Berry-Bengoechea-Henn-Fathi-Schneider teaches Bacteroides ovatus (SEQ ID NO: 287), Bacteroides vulgatus (SEQ ID NO: 331), Bifidobacterium longum (SEQ ID NO: 356), Blautia coccoides (SEQ ID NO: 573), Clostridium citroniae (SEQ ID NO: 569), Clostridium clostridioforme (SEQ ID NO: 571), Clostridium innocuum (SEQ ID NO: 595), Dorea longicatena (SEQ ID NO: 774), Erysipelatoclostridium ramosum (SEQ ID NO: 617), Blautia obeum (SEQ ID NO: 1664), Alistripes putredinis (SEQ ID NO: 132), Collinsella aerofaciens (SEQ ID NO: 659), Phasocolarctobacterium faecium (SEQ ID NO: 1462), Fusobacterium mortiferum (SEQ ID NO: 897), and Escherichia coli (SEQ ID NO: 825) (see, e.g., Berry, Table 1). SEQ ID NOs: 287, 331, 356, 573, 569, 774, 617, 1664, 132, 659, 1462, 897, and 825 (see, e.g., Berry, Table 1) have 97.4%, 97.9%, 97%, 100%, 99.2%, 98.9%, 99.4%, 99.5%, 99.4%, 93.2%, 100%, 96.9%, 99.2%, 98.9%, and 99.7% identity to the instant application’s SEQ ID NO: 4, 7, 9, 11, 12, 13, 15, 18, 19, 25, 26, 27, 31, 34, and 36, respectively.
Regarding claim 197 pertaining to the sequence identities modified-Berry-Bengoechea-Henn-Fathi-Schneider teaches a composition comprising Blautia obeum (see, e.g., Schneider, SEQ ID NO: 84), which has 99.3% identity to the present application’s SEQ ID NO: 25 (see, e.g., Schneider at Table F1, Table F2). Additionally, modified-Berry-Bengoechea-Henn-Fathi-Schneider teaches a composition comprising Bacteroides ovatus (see, e.g., Schneider, SEQ ID NO: 101), which has 99.0% identity to the instant application’s SEQ ID NO: 4 (see, e.g., Schneider at col. 43, lines 23-40).
However, modified-Berry-Bengoechea-Henn-Fathi-Schneider does not teach: bacterial strains of B. vulgatus, B. longum, and C. aerofaciens having 99% identity to SEQ ID NO. 7, 9, and 27 (claim 197).
Honda’s general disclosure relates to an antibacterial composition against oral bacteria and the like capable of inducing Th1 cell proliferation or activation in an intestinal tract, wherein the composition comprises isolated intestinal bacteria (see, e.g., Honda, abstract). Additionally, Honda discloses that “the present invention relates to use of the intestinal bacterium for producing a pharmaceutical composition for treating, alleviating, or preventing a disease attributable to Th1 cells” (see, e.g., Honda, [2]). Moreover, Honda discloses a bacterial composition that suppresses the colonization of Th1 cell-inducible bacteria, such as K. pneumoniae (see, e.g., Honda, [11], [14]).
Regarding claim 197 pertaining to the sequence identities, Honda teaches an antimicrobial composition against a bacterium capable of inducing Th1 proliferation or activation in an intestinal tract, wherein the composition comprises B. vulgatus (associated with Honda’s SEQ ID NO: 24), B. longum (associated with Honda’s SEQ ID NO: 69), and C. aerofaciens (associated with Honda’s SEQ ID NO: 110) which have 99.6%, 100%, and 100% identity to the present application’s SEQ ID NO: 7, 9, and 27, respectively (see, e.g., Honda at col. 3, lines 24-32; col. 27-28, Table 2, Table 4, Table 5). Moreover, Honda teaches that bacterial compositions comprising B. vulgatus, B. longum, and C. aerofaciens exhibits antibacterial activity against bacteria capable of inducible Th1 cell proliferation or activation in an intestinal tract (see, e.g., Honda, pg. 26, col. 3, lines 50-55), wherein a bacterium capable of inducing Th1 cells is K. pneumoniae (see, e.g., Honda, [11], [14]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce modified-Berry-Bengoechea-Henn-Fathi-Schneider’s bacterial mixture, wherein the bacterial mixture comprises B. vulgatus, B. longum, and C. aerofaciens, corresponding to SEQ ID NOs: 21, 69, and 110, as taught by Honda. One would have been motivated to do so because Honda teaches that B. vulgatus, B. longum, and C. aerofaciens have antibacterial activity against bacteria capable of inducing Th1 cell proliferation or activation in the intestinal tract (see, e.g., Honda, col. 4, lines 5-8). Moreover, Honda teaches that K. pneumoniae is a bacterium capable of inducing Th1 cell proliferation (see, e.g., Honda, [11], [14[), and that the bacterial composition comprising B. vulgatus, B. longum, and C. aerofaciens, as taught by Honda, is capable of inhibiting K. pneumoniae proliferation (see, e.g., Honda, Figure 12). Furthermore, modified-Berry-Bengoechea-Henn-Fathi-Schneider teaches that “Klebsiella species cause a wide range of diseases including pneumonia, urinary tract infections (UTIs), bloodstream infections and sepsis. These infections are particularly a problem among neonates, elderly and immunocompromised individuals” (see, e.g., Bengoechea, abstract). Therefore, based on the teachings of modified-Berry-Bengoechea-Henn-Fathi-Schneider and Honda, it would have been obvious to produce a bacterial mixture comprising B. vulgatus, B. longum, and C. aerofaciens because these bacteria have antibacterial activity against bacteria that induce Th1 responses in the intestines, such as K. pneumoniae. One would have expected success because modified-Berry-Bengoechea-Henn-Fathi-Schneider and Honda both teach bacterial mixture compositions for treating diseases.
Examiner’s Response to Arguments
Applicant’s amendments and arguments filed on 12/10/2025 have been fully considered but they are not persuasive and deemed insufficient to overcome the prior arts of record.
In response to Applicant’s argument that Berry provides no reason to select any given species from Table 1 of Berry and arrive at the combination of the 15 bacterial strains recited in the claims (remarks, pages 16 and 18-19), this argument is not persuasive for multiple reasons:
First, the claims contain the transitional phrase “comprising”, which is “inclusive or open-ended as does not exclude additional, unrecited elements or steps” (see, e.g., MPEP 2111.03(I)). Therefore, due to the use of “comprising” as the transitional phrase, this can include all of the bacteria taught by Berry. Moreover, Berry teaches that the bacteria are anti-inflammatory (see, e.g., Berry, [0011]) and Berry teaches that the bacterial mixture composition inhibits the growth of a pathogen 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 (see, e.g., Berry, [0144], [0199], [0348]-[0349]); therefore, one would expect the use of all the bacteria to treat diseases associated with pathogenic bacteria, such as K. pneumoniae.
Secondly, the claims are examined under the Broadest Reasonable Interpretation (BRI) guidelines. The BRI of claim 176 is a method of suppressing Klebsiella pneumoniae by administering a composition comprising Bacteroides ovatus, Bacteroides vulgatus, Bifidobacterium longum, Blautia coccoides, Clostridium citroniae, Clostridium clostridioforme, Clostridium innocuum, Dorea longicatena, Erysipelatoclostridium ramosum, Blautia obeum, Alistipes putredinis, Collinsella aerofaciens, Phascolarctobacterium faecium, Fusobacterium mortiferum, and Escherichia coli. Therefore, based on the BRI of the claimed invention, this can include unrecited elements, such as other bacterial strains.
Thirdly, although Berry teaches bacterial mixture compositions comprising more than the 15 claimed bacterial species, Berry still teaches that the bacterial strains within the mixture can belong to the species of Bacteroides ovatus, Bacteroides vulgatus, Bifidobacterium longum, Blautia coccoides, Clostridium citroniae, Clostridium clostridioforme, Clostridium innocuum, Dorea longicatena, Erysipelatoclostridium ramosum, Blautia obeum, Alistripes putredinis, Collinsella aerofaciens, Phasocolarctobacterium faecium, Fusobacterium mortiferum, and Escherichia coli (see, e.g., Berry, [0206]-[0207] & Table 1). Therefore, based on this, the claimed invention is obvious in view of Berry.
Fourthly, the ordinary artisan would have been motivated to use 15 or more bacterial species listed in Berry’s Tables 1, 1A, and 1B in a method of administering the composition to a subject in need thereof in order to inhibit the replication and/or survival of K. pneumoniae because Berry teaches that the composition can be administered to help treat liver, heart, and inflammatory disorders (see, e.g., Berry, [0119, [0206]-[0207], [0348]-[0349], [0361, [0507]-[0508], [0840], Table 1, Table 1A, Table 1B). Moreover, Berry teaches that the bacterial mixture composition inhibits the growth of a pathogen 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 (see, e.g., Berry, [0144], [0199], [0348]-[0349]). Therefore, one of ordinary skill in the art would have a reasonable expectation of success that Berry’s mixture comprising Bacteroides ovatus, Bacteroides vulgatus, Bifidobacterium longum, Blautia coccoides, Clostridium citroniae, Clostridium clostridioforme, Clostridium innocuum, Dorea longicatena, Erysipelatoclostridium ramosum, Blautia obeum, Alistipes putredinis, Collinsella aerofaciens, Phascolarctobacterium faecium, Fusobacterium mortiferum, and Escherichia coli can be used to suppress pathogens within the intestines, which can include K. pneumoniae. Moreover, Berry teaches that the bacterial composition can be used for treatment of dysbiosis (or pathobiont imbalance in the gut microbiota), wherein the pathogenic organism is capable of altering a proportion of the immune subpopulations, e.g., T cell subpopulations, in the subject (see, e.g., Berry, [0496]). In particular, the bacterial composition is capable of reducing Th1 cells (see, e.g., Berry, [0497]-[0499])., and Bengoechea teaches infections caused K. pneumoniae, wherein K. pneumoniae induces Th1 responses (see, e.g., Bengoechea, Introduction, pg. 123 & Contribution of Host Signaling in Defence Against K. pneumoniae Infections, pg. 127). This is motivation for one of ordinary skill in the art to apply Berry’s bacterial mixture to treat K. pneumoniae infections.
Fifthly, the claimed invention is a combination of prior art elements (i.e., known bacterial strains and combinations thereof), combined according to known methods as taught by Berry, to yield predictable results, namely bacterial compositions suitable for treating heart, liver, autoimmune, and inflammatory diseases and disorders, exactly as taught and disclosed in view of the prior art. Each prior art element would merely perform its art-recognized function in combination, and wherein variations within the scope of the prior art (e.g., different combinations) would be expected to be functionally equivalent absent objective evidence to the contrary (see, e.g., MPEP 2143(I)(A), (F), (G) & 2144.07 & 2144.06(I)-(II)).
Regarding Applicant’s argument pertaining to the declaration submitted by the Applicant (remarks, pages 10-11), this argument is not persuasive for multiple reasons:
First, as reiterated above, the claims contain the transitional phrase “comprising”, which is “inclusive or open-ended as does not exclude additional, unrecited elements or steps” (see, e.g., MPEP 2111.03(I)). Therefore, due to the use of “comprising” as the transitional phrase, this can include all of the bacteria taught by Berry, which include the 15 claimed bacterial species.
Secondly, Applicant is arguing limitations pertaining to Fusobacterium which are not claimed. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Furthermore, in regards to Applicant’s argument that Fusobacterium species can actually enhance K. pneumoniae growth, this would lead to an enablement issue with the present invention since the present invention includes Fusobacterium mortiferum and there is no evidence from the Applicant that this Fusobacterium species does not lead to enhanced K. pneumoniae growth. Moreover, arguments by Applicant cannot take the place of evidence (see, e.g., MPEP 716.01(c)(II).
Thirdly, Applicant’s declaration is considered opinion evidence (see, e.g., MPEP 716.01(c)(III). The declaration sets forth opinions and/or statements that are not supported by factual evidence. For example, the declaration states that it is implausible that any given combination of bacteria listed in Berry, let alone a combination of all listed bacteria, would be effective in inhibiting K. pneumoniae replication or survival (see, e.g., declaration, pgs. 5-6); however, there is no factual support or evidence of this. The declaration states that combining the NIAID Priority Pathogens in Berry’s table would result in multiple infectious diseases (see, e.g., declaration, pg. 6); however, there is no factual support or evidence of this. The declaration states that even if the NIAID Priority Pathogens, opportunistic pathogens, and Fusobacterium species were removed from Berry’s list, there remaining bacteria could enhance K. pneumoniae growth or would not inhibit K. pneumoniae growth (see, e.g., declaration, pg. 6), however, there is no factual support or evidence of this. The declaration states that there could be interference between the over 1,000 species of bacteria listed by Berry (see, e.g., declaration, pg. 7); however, there is no factual support or evidence of this. The declaration states that the data of Berry “related to preferred carbon sources of the Epv bacteria; changes in serum IFN-γ levels, serum LPS levels, and microbiome composition following xylose administration; and microbiome perturbations following vancomycin administration” are not relevant to K. pneumoniae (see, e.g., declaration, pg. 9); however, there is no factual support or evidence of this. Therefore, these are merely conclusionary statements that are unsupported by objective factual evidence and are not found to be of substantial evidentiary value.
Regarding Applicant’s argument pertaining to there being no reasonable expectation that the bacterial species taught by Berry would inhibit K. pneumoniae infection (remarks, pages 12-14), this argument is not persuasive for multiple reasons:
First, as reiterated above, the claims contain the transitional phrase “comprising”, which is “inclusive or open-ended as does not exclude additional, unrecited elements or steps” (see, e.g., MPEP 2111.03(I)). Therefore, due to the use of “comprising” as the transitional phrase, this can include all of the bacteria taught by Berry.
Secondly, Berry teaches that the pathogenic organism is a pathobiont that is in the intestine of the subject or part of the gut microbiota of the subject (see, e.g., Berry, [0199], [0329]), and Bengoechea teaches that K. pneumoniae is a pathobiont, or opportunistic pathogen (see, e.g., Bengoechea, Introduction). Moreover, Bengoechea teaches that K. pneumoniae infections are primarily a problem among neonates, elderly, and immunocompromised individuals within the healthcare setting (see, e.g., Bengoechea, Introduction, pg. 123).Therefore, based on the teachings of Berry and Bengoechea, one of ordinary skill in the art would have been motivated to apply Berry’s bacterial composition for treatment of K. pneumoniae infections.
Conclusion
Claims 176, 182-184, 190-193, 195, and 197-199 are rejected.
No claims are allowed.
Correspondence Information
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/NATALIE IANNUZO/Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653