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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/12/2025 has been entered.
Amendments
Amendments to the specification are as follows: claims 1, 8 and 15 are amended; claims 2-3 are cancelled; and claims 17-27 are added.
Status of Claims
Following the Reply filed 11/12/2025, claims 1, 4-10 and 14-27 are pending and have been examined on the merits.
Claim Objections (Warning)
Applicant is advised that should claim 15 be found allowable, claim 17 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
In the instant case, the only difference between the claims are in the preambles. Claim 15 recites “A method of treating an infection caused by Salmonella Heidelberg (S. Heidelberg) in a subject in need thereof”, whereas claim 17 recites “A method of inhibiting translocation of Salmonella Heidelberg (S. Heidelberg) across the intestinal epithelium of a subject in need thereof”. In view of Applicant’s disclosure, “inhibiting translocation” is the underlying effect of administering the cell-free supernatant to treat the infection (see, e.g., the instant specification at pg. 13, lines 29-31; pg. 14, lines 1-2). Here, the scope of the claims are identical, because in both cases the “subject in need thereof” is one who is infected with the same microorganism, and the same effects are achieved by the same method steps. Examiner notes that MPEP 608.01(m) states that “court decisions have confirmed applicant’s right to restate (i.e., by plural claiming) the invention in a reasonable number of ways. Indeed, a mere difference in scope between claims has been held to be enough.” However, in the instant case, there is no difference in scope.
Applicant is further advised that should claim 21 (which depends from claim 15) be found allowable, claim 22 (which depends from claim 17) will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. Here, the dependent claims recite the same further limitations and cover the same subject matter.
Applicant is further advised that should claim 26 (which depends from claim 15) be found allowable, claim 27 (which depends from claim 17) will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. Here, the dependent claims recite the same further limitations and cover the same subject matter.
Claim Objections
Claim 6 is objected to because of the following informalities: the claim recites “The method according claim 1”. Please amend the claim to read “The method according to claim 1”. Appropriate correction is required.
Claim Interpretation
Page 5, line 10 of the specification states, “As used herein, the term ‘subject’ denotes a mammal” (see pg. 5, line 10). Hence, it is interpreted that “a subject in need thereof”, recited in independent claims 1, 8, 15 and 17, is limited to a mammal.
Claim 4 recites the further limitation “wherein the Bacteroides fragilis strain is administered as a probiotic”. The specification states, “As used herein the term ‘probiotic’ denotes live microorganisms” (see pg. 4, lines 9-10; Emphasis added). Hence, in order for claim 4 to provide a further limitation to claim 1 and be in compliance with 35 U.S.C. 112(d), the Bacteroides fragilis strain of claim 1 must include non-living microorganisms. The examiner notes that the specification also states “the Bacteroides fragilis strain can be ingested live or not in adequate quantities to exert beneficial effects…particularly to treat disease or infections induced by Enterobacteria like Salmonella Heidelberg” (see pg. 3, lines 20-24, Emphasis added). Accordingly, the Bacteroides fragilis strain of claim 1 is interpreted as including non-living microorganisms (e.g., killed/inactivated bacterial cells), as well as live microorganisms.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 4-10, 14, 20 and 23-25 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation, “administering to the subject a therapeutically effective amount of a composition consisting of a Bacteroides fragilis strain” (Emphasis added) which renders the claim indefinite. On one hand, the plain meaning of this limitation is that the composition is administered in a form that excludes any element or ingredient other than the bacterial strain itself. See MPEP 2111.03(II) which discusses the transitional phrase, “consisting of”. However, a person of ordinary skill would recognize that the step of administering would require the composition to comprise further elements when administered, leading to broader interpretations of the claim. For example, the specification teaches that compositions for oral administration can be in the form of a suspension, tablet, pill, capsule, granulate or powder (see pg. 6, lines 17-19). The specification also discusses embodiments for rectal administration where the composition is in the form of suppository, enema or foam (see pg. 7, lines 9-11) and food compositions in the form of a suspension, pill, capsule, granulate, powder or yogurt (see pg. 7, line 14-16). All of these forms require additional elements (e.g., excipients, binders, fillers, reconstitution in a liquid, etc.). Even if the bacteria were lyophilized (see pg. 6, lines 24-25) to form a powder and made to be substantially free of any other ingredient (e.g., water), the prior art teaches that such compositions require reconstitution (e.g., adding of water) before using (see Muller et al., cited on Form 892, at pg. 1369, col. 1, para. 1 to pg. 1370, col. 1, para. 2). Thus, a person of ordinary skill would not be reasonably apprised as to the scope of the claim.
In the interest of compact prosecution, the composition of claim 1 is interpreted as comprising a Bacteroides fragilis strain.
Claim 5 recites the limitation, "the disease caused by Enterobacteriae”. There is insufficient antecedent basis for this limitation in the claim.
In the interest of compact prosecution, “the disease caused by Enterobacteriae” of claim 5 is reasonably interpreted to be a disease in the subject caused by S. Heidelberg.
Claim 8 recites “A method of treating an Inflammatory Bowel Disease and/or an Irritable Bowel Syndrome… wherein the Inflammatory Bowel Disease and/or an Irritable Bowel Syndrome is caused by Salmonella Heidelberg (S. Heidelberg).” Here, the claim does not specify whether the subject is infected by S. Heidelberg, only that the IBD and/or IBS was “caused by” S. Heidelberg. In view of the specification, IBD includes complex chronic inflammatory disorders in a genetically predisposed host (see pg. 4, lines 24) which may be induced by the colonization of Enterobacteriae in the gastrointestinal tract (see pg. 4, lines 11-15). The prior art of Gradel et al. (cited on Form 892) teaches that IBD may be triggered by a Salmonella infection, wherein the patient may be at an increased risk of IBD for years after the infection (see pg. 499, para. 1). In view of Sefik et al. (US 20180193391 A1; previously cited) methods involving the administration of Bacteroides fragilis to treat inflammatory bowel disease are known in the art and do not appear to require the subject to have an infection (see, e.g., claim 28). Hence, it may be broadly interpreted that the instantly claimed method includes treating IBD/IBS in individuals who are not actively infected by Salmonella Heidelberg. However, in view of Applicant’s disclosure, the therapeutic effect of administering the cell-free supernatant of B. fragilis is the inhibition of S. Heidelberg translocation (see pg. 13, lines 29-31), which would require an active infection in the host. Hence, it is unclear whether the method includes or excludes subjects who are not presently infected with S. Heidelberg when treated.
In the interest of compact prosecution, the subject of claim 8 is broadly interpreted as having an inflammatory bowel disease and/or irritable bowel syndrome caused by S. Heidelberg, but the subject is not required to be actively infected with S. Heidelberg.
The term “severe” in claims 23-24 is a relative term which renders the claims indefinite. The term “severe” is not defined by the claims, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. In the instant case, it is not clear what extra-intestinal infections would be excluded as not being “severe”. In view of the prior art of Le Gall-David et al. (cited on Form 892), Salmonella Heidelberg causes invasive “extra-intestinal infections associated with severe disease symptoms” (see pg. 65, col. 1, para. 1). Hence, it may be interpreted that any extra-intestinal infection caused by S. Heidelberg is “severe”. On the other hand, it may also be interpreted that a subject with more “mild” or “moderate” symptoms relative to someone else may be somehow excluded by the limitation. However, it has not been clearly set forth on record what level of severity is excluded or how this is determined.
Claims 4, 6-7, 9-10, 14, 20 and 25 are rejected for depending from an indefinite claim and for failing to rectify the indefiniteness of the claim(s) from which they depend.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 6 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 6 recites the method according to claim 1, “wherein the subject is an animal”. This further limitation improperly broadens the scope of the claim, because, as discussed under Claim Interpretation, the subject of claim 1 is a mammal. Hence, claim 5 fails to further limit the subject matter of claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(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.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1, 4-6, 10, 20 and 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Newburg (US 2012/0294840 A1; previously cited), and further in view of Le Gall-David et al. (cited on Form 892), hereafter, “Gall-David”.
Regarding claim 1, Newburg teaches a method of stimulating the growth of bacteria in the gastrointestinal tract of a subject comprising administering to the gastrointestinal tract a composition (see claim 15) comprising probiotic bacteria Bacteroides fragilis (see claim 22), wherein the growth of pathogenic bacteria in the gastrointestinal tract is inhibited (see claim 19), and wherein the pathogenic bacteria is Salmonella enterica (see claim 24). Examiner notes that the Bacteroides fragilis strain used by Newburg is ATCC 25285 (see pg. 7, col. 2, Table 1) which is the same type strain used by the present inventors in their Examples (see instant specification at pg. 10, lines 5-7). Hence, Newburg teaches a method of treating an infection caused by Salmonella enterica in a subject in need thereof comprising administering to the subject a composition comprising a Bacteroides fragilis strain.
Regarding the limitation, “a composition consisting of a Bacteroides fragilis strain”, Newburg teaches that modification of the composition and metabolic activity of the intestinal bacterial community is performed through the administration of (1) prebiotic oligosaccharides alone, (2) beneficial microorganisms (i.e., probiotics), or (3) a combination of prebiotics and probiotics (see pg. 3, para. [0030]). Hence, Newburg teaches embodiments wherein probiotic bacteria, such as Bacteroides fragilis, are administered alone, without prebiotics.
Newburg also teaches that probiotic bacteria exert direct antibacterial effects on pathogens through production of antibacterial substances, including bacteriocins and acid. Newburg teaches that these probiotic-derived antibacterial substances exert their effects alone or synergistically to inhibit the growth of pathogens, and probiotics administered to the gastrointestinal tract decrease adhesion of both pathogens and their toxins to the intestinal epithelium. Newburg teaches that several strains of beneficial bacteria are able to compete with pathogenic bacteria, including Salmonella enterica, for intestinal epithelial cell binding, and can displace pathogenic bacteria even if the pathogens have attached to intestinal epithelial cells prior to probiotic administration. See pg. 4, para. [0035].
Newburg also teaches that probiotic bacteria stimulate intestinal epithelial cell responses, including restitution of damaged epithelial barrier, production of antibacterial substances and cell-protective proteins, and blockades of cytokine-induced intestinal epithelial cell apoptosis (see pg. 5, para. [0036]).
Newburg does not teach the method wherein the infection is caused by Salmonella Heidelberg.
Gall-David’s disclosure investigates the interaction between epithelial cells and a Salmonella Heidelberg strain with a hypermutator phenotype (see pg. 66, col. 1, para. 3). Gall-David teaches Salmonella Heidelberg is a serovar of Salmonella enterica subsp. enterica (see pg. 67, col. 1, para. 3). Gall-David teaches that Salmonella is one of the most important pathogens causing severe foodborne disease (see pg. 73, col. 1, para. 5), and Salmonella Heidelberg is the third most common serovar causing invasive extra-intestinal infections associated with severe disease symptoms (see pg. 65, col. 1, para. 1). Gall-David teaches that intestinal epithelial cells are the primary host targets during the initial phase of enteroinvasive Salmonella infections, and Salmonella are able to replicate inside the intestinal cells and induce cell death (see pg. 65, col. 2, para. 2). Gall-David teaches a B182 hypermutator strain of Salmonella Heidelberg was demonstrated to induce epithelial cells morphology changes with a higher susceptibility to cell death (see pg. 72, col. 2, para. 1). Gall-David speculates that the B182 hypermutator strain has accumulated mutations to adapt to its environment and to facilitate a more rapid niche expansion by using apoptosis as a virulence factor (see pg. 73, col. 1, para. 2).
It would have been obvious at the time of filing for a person of ordinary skill in the art to have arrived at the claimed invention by combining the teachings of Newburg and Gall-David for at least the following reasons: (1) Newburg teaches a method that is effective for inhibiting Salmonella enterica in the gastrointestinal tract of a subject by administering Bacteroides fragilis; (2) both Newburg and Gall-David teach Salmonella enterica strains to adhere to intestinal epithelial cells during infection, which Gall-David teaches can lead to severe extra-intestinal infections; (3) Newburg teaches that probiotic bacteria, such as Bacteroides fragilis, can effectively reduce the adhesion of Salmonella enterica to intestinal epithelial cells, repair damaged epithelial cells, and block apoptosis; and (4) Gall-David teaches hypermutator strains of the Salmonella enterica serovar Heidelberg are highly virulent and contribute to severe food-borne disease.
Accordingly, one would have recognized from Newburg that the B. fragilis strain of the disclosure could be administered to the gastrointestinal tract of a subject infected with Salmonella Heidelberg with a reasonable expectation of success. One would have recognized that this serovar is a member of Salmonella enterica which is taught by Newburg. Thus, one would have been motivated to apply the methods taught by Newburg, because S. Heidelberg is disclosed by Gall-David to be a particularly virulent serovar of Salmonella, which are responsible for severe foodborne disease. Hence, the combination would have been readily apparent and deemed to be a mere (A) combining of prior art elements according to known methods to yield predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103).
Regarding claim 4, Newburg teaches the Bacteroides fragilis to be a probiotic bacteria, as discussed above. Newburg teaches the term “probiotics” to mean “live microorganisms” (see pg. 1, col. 2, para. [0005]). Examiner notes that the instant specification defines the term “probiotic” to denote live microorganisms (see pg. 4, lines 9-10).
Regarding claim 5, Newburg teaches the subject has been diagnosed with traveler’s diarrhea (see pg. 2, para. [0014]).
Regarding claim 6, Newburg teaches the subject is a mammal (see pg. 2, para. [0014]).
Regarding claim 10, Newburg teaches that the bacterial strain isolate used for Bacteroides fragilis is ATCC 25285 (see pg. 7, para. [0054] and Table 1). This strain is acknowledged by the inventors of the present application to be a non-toxigenic strain (see instant specification at pg. 10, lines 2-3).
Regarding claim 20, Gall-David teaches hypermutator strains of S. Heidelberg, as discussed above.
Regarding claim 23, Gall-David teaches Salmonella Heidelberg causes invasive extra-intestinal infections associated with severe disease symptoms (see pg. 65, col. 1, para. 1). Hence, it would have been obvious to have applied the method wherein the infection is a severe extra-intestinal infection for the same reasons discussed regarding claim 1.
Claim(s) 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Newburg and Gall-David as applied to claims 1, 4-6, 10, 20 and 23 above, and further in view of Santos et al. (cited on Form 892), hereafter, “Santos”.
Newburg teaches the method wherein the subject is an animal grown for food consumption, which includes pigs and chickens (see pg. 2, para. [0014]). Gall-David teaches that Salmonella, one of the most important pathogens causing severe foodborne disease, can be transferred to humans via animals along the food chain impacting health and productivity (see pg. 73, col. 1, para. 5).
Newburg and Gall-David do not teach the method wherein the subject is a fish.
Santos teaches that Salmonella spp. were recently detected in the carcasses of native fish in Brazilian slaughterhouses, presenting the risk of foodborne-related salmonellosis, and the disclosure details the isolation and classification of S. enterica isolates, including serotype Heidelberg, obtained from water and fish samples (see Abstract). Santos teaches that aquaculture is the fastest growing sector in animal production over the last few decades, and Salmonella spp. are some of the most important human and animal pathogens, representing the main etiologic agents of foodborne-related diarrhea in humans (see pg. 304, col. 1 to col. 2)
Santos discloses that the main serotypes of S. enterica that were found in Brazilian fish are typically associated with poultry and swine, and these serotypes included S. Heidelberg (see pg. 310, col. 1, para. 5 to col. 2, para. 1). Santos also suggests that probiotics administered through feed offers a potential strategy to reduce Salmonella shedding in feces (see pg. 311, col. 1, para. 3), and probiotics might be used strategically prior to harvest to reduce Salmonella infection in fish herds, thereby decreasing the potential for carcass contamination (see Abstract).
It would have been obvious at the time of filing for a person of ordinary skill in the art to have arrived at the claimed invention by combining the teachings of Newburg, Gall-David and Santos, because all three references relate to the problem of Salmonella enterica as a foodborne pathogen. One of ordinary skill would have recognized from Newburg that probiotics, such as Bacteroides fragilis, can be used to treat Salmonella enterica infections in poultry and swine, which Santos teaches are infected with the same serotypes Santos discloses to infect fish. Among these serotypes, S. Heidelberg is taught by both Santos and Gall-David to be the cause of foodborne diseases which can be transferred to humans via animals along the food chain impacting health and productivity. One would have also recognized that both Newburg and Santos teach the administration of probiotics to animals grown for food production and would have recognized that there would have been a reasonable expectation of success in applying Newburg’s methods to fish. One would have been particularly motivated to combine these teachings in order to solve the problem of foodborne infections in the world’s fastest growing sector of animal-based food production. Hence, the combination would have been readily apparent and deemed to be a mere (A) combining of prior art elements according to known methods to yield predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103).
Claim(s) 8-9 and 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Newburg and Gall-David, as applied to claims 1, 4-6, 10, 20 and 23 above, and further in view of Zeng (US 20210069260 A1; effectively filed 01/23/2018; previously cited), and Gradel et al. (cited on Form 892), hereafter, “Gradel”.
Newburg teaches a method of treating an infection caused by Salmonella enterica in a subject in need thereof comprising administering to the subject a composition comprising a Bacteroides fragilis strain, as discussed above. Newburg also teaches the method wherein the subject has been diagnosed with an inflammatory bowel disease (see pg. 2, para. [0014]). Newburg teaches that common members of the human microbiota, including Bacteroides fragilis, reduce infections and inflammatory diseases of the gastrointestinal tract (see pg. 6, para. [0047]).
Newburg does not teach the method wherein the subject is administered a therapeutically effective amount of a cell-free supernatant obtained from a culture of a Bacteroides fragilis strain.
Zeng teaches a method of inducing a proliferation and/or accumulation of γδ T cells, comprising administering a Bacteroides fragilis culture supernatant to a subject in need thereof (see claims 1 and 3). Zeng teaches that intestinal bacteria provide a strong immune reaction against invading pathogenic microorganisms, and a dysregulation of the cross-talk between the symbiotic bacteria and immune system may cause an immune overreaction to environmental antigens, thereby leading to an inflammatory bowel disease (see pg. 1, para. [0003]). Zeng teaches a composition comprising Bacteroides fragilis, or a physiological active substance obtained from the Bacteroides fragilis, to induce a proliferation and an effector function of γδ T cells (see pg. 1, para. [0008]). Zeng teaches γδ T cells prevent the invasion of bacterial pathogens and play an important role in the maintenance of tissue homeostasis and recovery of tissues during the inflammatory response and post-inflammation (see pg. 1, para. [0006]). Zeng teaches the composition containing Bacteroides fragilis as an active ingredient is excellent in inducting the proliferation and accumulation of γδ T cells or promoting their effector functions, and the composition may be used for prevention or treatment of autoimmune diseases or allergic diseases (see pg. 2, para. [0032]).
Newburg and Zeng do not teach wherein the Inflammatory Bowel Disease and/or an Irritable Bowel Syndrome is caused by Salmonella Heidelberg.
Gradel teaches that inflammatory bowel disease (IBD) may be triggered by a Salmonella infection, wherein the patient may be at an increased risk of IBD for years after the infection (see pg. 499, para. 1). Gradel teaches that the etiology of inflammatory bowel disease (IBD) probably involves numerous genetic and environmental factors, and an abundance of clinical epidemiologic and animal model studies have assessed the impact of various commensal and potentially pathogenic enteric bacteria that may trigger or exacerbate IBD (see pg. 495, col. 1, para. 1 to col. 2, para. 2). In Gradel’s study, it was found that patients with a documented Salmonella infection in the past 15 years had an increased risk of Crohn’s disease and ulcerative colitis (see pg. 495, col. 1, RESULTS).
It would have been obvious at the time of filing for a person of ordinary skill in the art to have combined the teachings of Newburg and Zeng, because both references relate to treating inflammatory bowel disease by administering Bacteroides fragilis. One would have recognized from Newburg that Bacteroides fragilis is effective in treating inflammatory bowel disease, and Zeng teaches that the culture supernatant obtained from B. fragilis can be used to treat IBD. One would have also recognized from Zeng that pathogenic infections may lead to inflammatory disease, while Gradel teaches that Salmonella infections increase the risk of IBD, such as ulcerative colitis and Crohn’s disease. Accordingly, one would have expected that administering a supernatant from a B. fragilis culture to a subject having IBD caused by S. Heidelberg to have the same benefit as taught by Zeng. As Gall-David teaches S. Heidelberg to be a particularly virulent strain that damages intestinal epithelial cells, one would have been particularly motivated to apply the method taught by Zeng to individuals having an inflammatory bowel disease caused by S. Heidelberg. Hence, the combination would have been readily apparent and deemed to be a mere (A) combining of prior art elements according to known methods to yield predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103).
Regarding claim 9, Gradel teaches Salmonella infections can trigger inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis, as discussed above.
Regarding claim 14, Zeng teaches that the bacterial solution containing B. fragilis was inactivated prior to obtaining the culture supernatant and administering to mice (see pg. 4, para. [0064]-[0066]). Hence, Zeng teaches the supernatant is inactivated prior to administration.
Claim(s) 15-19, 21-22 and 24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Newburg, Zeng and Gall-David.
Regarding claim 15, in view of the prior art previously discussed:
Newburg teaches a method of stimulating the growth of bacteria in the gastrointestinal tract of a subject comprising administering to the gastrointestinal tract a composition (see claim 15) comprising probiotic bacteria Bacteroides fragilis (see claim 22), wherein the growth of pathogenic bacteria in the gastrointestinal tract is inhibited (see claim 19), and wherein the pathogenic bacteria is Salmonella enterica (see claim 24). Newburg also teaches that probiotic bacteria stimulate intestinal epithelial cell responses, including restitution of the damaged epithelial barrier, production of antibacterial substances and cell-protective proteins, and blockades of cytokine-induced intestinal epithelial cell apoptosis (see pg. 5, para. [0036]).
Gall-David teaches Salmonella Heidelberg is a serovar of Salmonella enterica subsp. enterica (see pg. 67, col. 1, para. 3). Gall-David teaches that Salmonella is one of the most important pathogens causing severe foodborne disease (see pg. 73, col. 1, para. 5), and Salmonella Heidelberg is the third most common serovar causing invasive extra-intestinal infections associated with severe disease symptoms (see pg. 65, col. 1, para. 1). Gall-David teaches that intestinal epithelial cells are the primary host targets during the initial phase of enteroinvasive Salmonella infections, and Salmonella are able to replicate inside the intestinal cells and induce cell death (see pg. 65, col. 2, para. 2). Gall-David teaches a B182 hypermutator strain of Salmonella Heidelberg was demonstrated to induce epithelial cells morphology changes with a higher susceptibility to cell death (see pg. 72, col. 2, para. 1). Gall-David speculates that the B182 hypermutator strain has accumulated mutations to adapt to its environment and to facilitate a more rapid niche expansion by using apoptosis as a virulence factor (see pg. 73, col. 1, para. 2).
Zeng teaches a method of inducing a proliferation and/or accumulation of γδ T cells, comprising administering a Bacteroides fragilis culture supernatant to a subject in need thereof (see claims 1 and 3). Zeng teaches that intestinal bacteria provide a strong immune reaction against invading pathogenic microorganisms, and a dysregulation of the cross-talk between the symbiotic bacteria and immune system may cause an immune overreaction to environmental antigens, thereby leading to an inflammatory bowel disease (see pg. 1, para. [0003]). Zeng teaches a composition comprising Bacteroides fragilis, or a physiological active substance obtained from the Bacteroides fragilis, to induce a proliferation and an effector function of γδ T cells (see pg. 1, para. [0008]). Zeng teaches γδ T cells prevent the invasion of bacterial pathogens and play an important role in the maintenance of tissue homeostasis and recovery of tissues during the inflammatory response and post-inflammation (see pg. 1, para. [0006]). Zeng teaches the composition containing Bacteroides fragilis as an active ingredient is excellent in inducting the proliferation and accumulation of γδ T cells or promoting their effector functions (see pg. 2, para. [0032]).
It would have been obvious for a person of ordinary skill in the art to have arrived at the claimed invention by combining the teachings of Newburg, Zeng and Gall-David for at least the following reasons: (1) Newburg teaches a method that is effective for inhibiting Salmonella enterica in the gastrointestinal tract of a subject by administering Bacteroides fragilis; (2) both Newburg and Gall-David teach Salmonella enterica strains to adhere to intestinal epithelial cells during infection, which Gall-David teaches can lead to severe extra-intestinal infections; (3) Newburg teaches that probiotic bacteria, such as Bacteroides fragilis, can effectively reduce the adhesion of Salmonella enterica to intestinal epithelial cells, repair damaged epithelial cells, and block apoptosis; (4) Gall-David teaches hypermutator strains of the Salmonella enterica serovar Heidelberg are highly virulent and contribute to severe food-borne disease; and (5) Zeng teaches the administration of a Bacteroides fragilis supernatant increases the proliferation of γδ T cells which prevent the invasion of bacterial pathogens and play an important role in the maintenance of tissue homeostasis and recovery of tissues during the inflammatory response to pathogens.
Hence, while both Newburg and Zeng teach the benefits of administering Bacteroides fragilis to subjects suffering from inflammatory bowel conditions caused by pathogenic bacteria, Zeng further teaches that administering the supernatant obtained from a Bacteroides fragilis may also alleviate many of the same effects associated with these infections. One would have also recognized from Newburg that probiotic bacteria are known to produce antibacterial substances and epithelial cell repairing proteins, while Gall-David teaches intestinal epithelial cells to be targeted, damaged and killed during infections caused by S. Heidelberg which leads to severe extra-intestinal infections. Accordingly, one would have recognized the combination to be advantageous to treat infections caused by S. Heidelberg. Hence, the combination would have been readily apparent and deemed to be a mere (A) combining of prior art elements according to known methods to yield predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103).
Regarding claim 16, Zeng teaches that the bacterial solution containing B. fragilis was inactivated prior to obtaining the culture supernatant and administering to mice (see pg. 4, para. [0064]-[0066]). Hence, Zeng teaches the supernatant is inactivated prior to administration.
Regarding claim 17, as discussed under Claim Warning, “inhibiting translocation” is the same underlying effect of administering the cell-free supernatant to treat the infection in the method of claim 15. Hence, the phrase “inhibiting translocation”, recited in the preamble, is directed to an inherent property that does not affect the structure or steps of the claimed invention. As the prior art combination teaches the same process of administering the same composition to the same patient population to treat an infection caused by S. Heidelberg, the effects and properties of said method and composition are presumed to be inherent and the claimed method is obvious for the same reasons discussed regarding claim 15. "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).
Regarding claim 18, the further limitation, “wherein the supernatant does not affect the growth of the S. Heidelberg”, is directed to an inherent property that does not affect the structure or steps of the claimed invention. As the prior art combination teaches the same process of administering the same composition to the same patient population to treat an infection caused by S. Heidelberg, the effects and properties of said method and composition are presumed to be inherent and the claimed method is obvious for the same reasons discussed regarding claims 15 and 17.
Regarding claim 19, the further limitation, “wherein the supernatant does not impact intestinal epithelial barrier integrity”, is directed to an inherent property that does not affect the structure or steps of the claimed invention. As the prior art combination teaches the same process of administering the same composition to the same patient population to treat an infection caused by S. Heidelberg, the effects and properties of said method and composition are presumed to be inherent and the claimed method is obvious for the same reasons discussed regarding claims 15 and 17.
Regarding claim 21, Gall-David teaches hypermutator strains of S. Heidelberg, as discussed regarding claim 1.
Regarding claim 22, Gall-David teaches hypermutator strains of S. Heidelberg, as discussed regarding claim 1.
Regarding claim 24, Gall-David teaches Salmonella Heidelberg causes invasive extra-intestinal infections associated with severe disease symptoms (see pg. 65, col. 1, para. 1). Hence, it would have been obvious to have applied the method wherein the infection is a severe extra-intestinal infection.
Claim(s) 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Newburg and Gall-David as applied to claims 1, 4-6, 10, 20 and 23 above, and further in view of Ferrari et al. (cited on Form 892), hereafter, “Ferrari”.
Regarding claim 25, Ferrari teaches that Salmonella spp. are among the most important foodborne pathogens and the third leading cause of human death among diarrheal diseases worldwide (see Abstract). Ferrari teaches that animals are the primary source of this pathogen, and animal-based foods are the main transmission route to humans (see Abstract). Ferrari teaches that the four most worrying Salmonella serovars regarding public health include S. Heidelberg (see pg. 9, para. 2) which is able to infect a broad range of hosts (see pg. 9, para. 3). Ferrari teaches that production animals are often asymptomatic carriers, and after entering the slaughterhouse, Salmonella can be transferred to other substrates during industrial processing (see pg. 3, para. 1). Ferrari teaches that pigs (which are mammals) are one of the most common sources of Salmonella infections in humans and are frequently asymptomatic carriers and disseminators of this pathogen through the production chain (see pg. 7, para. 2).
Therefore, it would have been obvious to have applied the method of claim 1 to a subject that is infected with S. Heidelberg but has no symptoms of a disease, because Ferrari teaches that asymptomatic carriers of this pathogen used in food production are the main transmission route to humans. A person of ordinary skill would have recognized from Ferrari that while the subject in need may not have symptoms of a disease, the subject still retains the ability to transmit this dangerous pathogen to humans. Hence, one would have been motivated to use the method to treat asymptomatic carriers of S. Heidelberg to prevent foodborne transmissions. Thus, in addition to the reasons discussed regarding claim 1, claim 25 would have been obvious further in view of Ferrari.
Claim(s) 26-27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Newburg, Gall-David and Zeng, as applied to claims 15-19, 21-22 and 24 above, and further in view of Ferrari.
Regarding claim 26, Ferrari teaches that Salmonella spp. are among the most important foodborne pathogens and the third leading cause of human death among diarrheal diseases worldwide (see Abstract). Ferrari teaches that animals are the primary source of this pathogen, and animal-based foods are the main transmission route to humans (see Abstract). Ferrari teaches that the four most worrying Salmonella serovars regarding public health include S. Heidelberg (see pg. 9, para. 2) which is able to infect a broad range of hosts (see pg. 9, para. 3). Ferrari teaches that production animals are often asymptomatic carriers, and after entering the slaughterhouse, Salmonella can be transferred to other substrates during industrial processing (see pg. 3, para. 1). Ferrari teaches that pigs (which are mammals) are one of the most common sources of Salmonella infections in humans and are frequently asymptomatic carriers and disseminators of this pathogen through the production chain (see pg. 7, para. 2).
Therefore, it would have been obvious to have applied the method of claim 1 to a subject that is infected with S. Heidelberg but has no symptoms of a disease, because Ferrari teaches that asymptomatic carriers of this pathogen used in food production are the main transmission route to humans. A person of ordinary skill would have recognized from Ferrari that while the subject in need may not have symptoms of a disease, the subject still retains the ability to transmit this dangerous pathogen to humans. Hence, one would have been motivated to use the method to treat asymptomatic carriers of S. Heidelberg to prevent foodborne transmissions. Thus, in addition to the reasons discussed regarding claim 15, claim 26 would have been obvious further in view of Ferrari.
Regarding claim 27, the claim is obvious for the same reasons discussed regarding claims 15, 17 and 26.
Response to Arguments
Regarding the rejections under 35 U.S.C. 102/103 in view of Newburg, Applicant argues that the claims have been amended to specify that what is treated is an infection caused by Salmonella Heidelberg, and Newburg is silent with respect to this serotype.
Applicant’s arguments have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Newburg and Gall-David.
Applicant further argues that Newburg teaches probiotic-derived substances exert effects to inhibit the growth of pathogens, whereas the present inventors found that a Bacteroides fragilis strain or a cell-free supernatant obtained from a Bacteroides fragilis strain did not inhibit the growth of Salmonella Heidelberg but did inhibit translocation across the intestinal epithelial barrier.
Applicant’s arguments have been fully considered but are not persuasive, because Newburg teaches probiotics to have various effects on pathogenic bacteria, and “[s]pecific probiotics or probiotic combinations are selected based on their ability to inhibit or displace a specific pathogen” (see pg. 4, para. [0035]; Emphasis added). Newburg also suggests that probiotics may provide an increased barrier to translocation (see pg. 4, para. [0034]) or decrease adhesion of both pathogens and their toxins to the intestinal epithelium (see pg. 4, para. [0035]). Hence, a person of ordinary skill would have recognized from Newburg’s disclosure that probiotics inhibit the activity of pathogens by various mechanisms, and there would have been sufficient motivation to have selected a probiotic taught by Newburg to treat a Salmonella enterica infection, regardless of the specific mechanism(s) responsible for its therapeutic effects.
Regarding the rejection of claim 7 under 35 U.S.C. 103 in view of Newburg and Terhune, Applicant argues that Terhune is also silent with respect to the Salmonella Heidelberg serotype and growth conditions.
Applicant’s arguments with respect to claim(s) 7 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Regarding the rejection of claims 8-9 and 14 under 35 U.S.C. 103 in view of Sefik and Zeng, Applicant argues that both references are silent with respect to the Salmonella Heidelberg serotype and growth conditions.
Applicant’s arguments with respect to claim(s) 8-9 and 14 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Regarding the rejection of claims 15-16 under 35 U.S.C. 103 in view of Sefik, Zeng and Honda, Applicant argues that Sefik and Zang are silent with respect to the Salmonella Heidelberg serotype and growth conditions, and Honda does not cure this defect.
Applicant’s arguments with respect to claim(s) 15-16 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Conclusion
No claims are allowed.
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/DENNIS IGNATIUS ARMATO JR/Examiner, Art Unit 1651
/MELENIE L GORDON/Supervisory Patent Examiner, Art Unit 1651