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 .
Status of Claims
Claims 1, 4-5, 7-10 and 14-27 are pending following the Reply filed 05/18/2026. Claim 6 has been cancelled. Claims 1, 5, 7, 8, 24 and 25 have been amended without introducing new matter. Claims 1, 4-5, 7-10 and 14-27 have been examined on the merits.
Withdrawn
Any objection or rejection of claim 6 is moot because the claim has been cancelled.
The Claim Warning under 37 CFR 1.75, that if claim 15, 21 and 26 were found to be allowable, claim 17, 22 and 27 would be objected to as being substantial duplicates thereof, is withdrawn in light of Applicant’s arguments. See Claim Interpretation and Response to Arguments below for further discussion.
The rejections under 35 U.S.C. 112(b) are withdrawn in light of the amendments.
Claim Interpretation
The specification states, “As used herein, the term ‘subject’ denotes a mammal” (see pg. 5, line 10). Therefore, it is interpreted that the term “subject”, where recited in the claims, refers 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 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”. It was set forth by the examiner in the previous office action that the scope of the claims are identical (see Claim Objections (Warning)), because both claims require the subject to be infected with S. Heidelberg. However, upon reconsideration, it can be reasonably concluded that inhibiting translocation of the pathogen across the intestinal epithelium does not require the subject to have an active infection when administering the B. fragilis. Therefore, the subject of claim 15 is interpreted to be infected with S. Heidelberg, while the subject of claim 17 may or may not be infected with S. Heidelberg. See Response to Arguments below for further discussion.
Maintained rejections and new rejections necessitated by amendment
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.
Claim 7 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 7 recites the method according to claim 1, “wherein the subject is a fish or a mammal”. This further limitation improperly broadens the scope of the claim, because, as discussed under Claim Interpretation, the “subject” of claim 1 is limited to being a mammal.
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, 4-5, 7, 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. (previously cited), 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.
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 as well (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 7, 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) 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, 4-5, 7, 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. (previously cited), hereafter, “Gradel”.
Regarding claim 8, 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 teaches that probiotic bacteria decrease adhesion of both pathogens and their toxins to the intestinal epithelium and stimulate intestinal epithelial cell responses (e.g., restitution of damaged epithelial barrier, production of antibacterial substances and cell-protective proteins, and blockades of cytokine-induced intestinal epithelial cell apoptosis), while probiotic-derived antibacterial substances exert their effects alone or synergistically to inhibit the growth of pathogens (see pg. 4, para. [0035] to pg. 5, para. [0036]).
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). In the population-based cohort study with complete follow up, Gradel discloses that an increased risk of IBD was demonstrated in individuals notified in laboratory registries with an episode of Salmonella gastroenteritis (see pg. 495, col. 1, CONCLUSIONS). Gradel concludes that these results have implications for the understanding of pathogenesis of IBD and for clinicians who should be aware of higher risk of IBD in Salmonella gastroenteritis patients, both in the short and long-term (see pg. 500, col. 1, para. 3).
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 diseases of the GI tract and also produces anti-bacterial substances, while 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 had a reasonable expectation that administering a supernatant from a B. fragilis culture to a subject suffering from IBD, further aggravated by the presence of an S. Heidelberg infection, would confer a therapeutic effect. 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 Interpretation, the subject of claim 17 may or may not be infected with S. Heidelberg. Here, the phrase “inhibiting translocation”, recited in the preamble, is directed to an inherent property of administering the B. fragilis which 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)(Emphasis added). 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. (previously cited), 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 15 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 Declaration
The Declaration under 37 CFR 1.132 filed 05/18/2026 is insufficient to overcome the obviousness rejections of the claims under 35 U.S.C. 103 set forth in the last Office action.
The filed declaration could not be fully considered by the examiner because the experimental evidence presented therein is supported by drawings wherein the text is illegible. In the interest of furthering prosecution, the examiner will respond to the co-inventor’s conclusions regarding these experiments and their arguments regarding predictability and unexpected results. However, the experimental data provided in the form of drawings are insufficient to fully consider any of these conclusions as factual evidence without a legible copy of the drawings.
In summary, the declaration attempts to set forth results from experiments conducted according to the same in vitro procedures described in the instant specification. According to the declaration, the results of these experiments showed:
(1) the translocation of the Salmonella enterica serovar Derby is not affected by the presence of B. fragilis or its supernatant;
(2) however, the co-infection of Salmonella Derby with B. fragilis did show beneficial effects on the integrity of the cellular barrier with a significant increase of “TEER” (“transepithelial electrical resistance” analysis as described in the instant specification on pg. 7, lines 28-29) and a significant decrease in cytotoxicity;
(3) the translocation of Salmonella enterica serovar Senftenberg SS209 strain was significantly inhibited in the presence of B. fragilis;
(4) the translocation of Salmonella enterica serovar Senftenberg SS209 strain was not inhibited in the presence of B. fragilis supernatant;
(5) however, the co-infection of Salmonella Senfenberg SS209 with B. fragilis had an effect on the integrity of the cell barrier with a significant increase of TEER and a significant decrease in cytotoxicity.
The declaration states that these results differ from those obtained with S. Heidelberg as described in the present application, wherein translocation was inhibited by the presence of B. fragilis or a supernatant thereof. The declaration concludes, “Thus, all Salmonella serovars do not react to the presence of B. fragilis or its supernatant in the same way, and one of skill in the art cannot predict the results that will be obtained with one serovar based on results previously obtained with a different serovar.”
This evidence is not sufficient to overcome the rejections under 35 U.S.C. 103 for the following reasons.
Per MPEP 716.02, any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
(1) The allegedly unexpected results of the experiments are not commensurate in scope with the claims. The experiments attempt to show that inhibiting the translocation of Salmonella Heidelberg across the intestinal epithelium of a subject by the administration of the cell-free supernatant was an unexpected result. However, only claim 17 and its dependents recite a method of inhibiting translocation of S. Heidelberg across the intestinal epithelium by administering the supernatant. The remainder of the claims do not.
(2) Furthermore, the results of the experiments appear to show that co-infection with B. fragilis had beneficial effects in the presence of both tested serovars, which is particularly relevant to the rejection of claim 1 and its dependents, which are drawn to administering the B. fragilis strain, not the supernatant. Per MPEP 716.02(c), "Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967). In the instant case, the declaration fails to demonstrate that a person of skill would not have had a reasonable expectation of achieving these advantages when performing the method according to the claims.
(3) The prior art rejections were made on the basis that a person of ordinary skill would have had a reasonable expectation of achieving a beneficial effect, not whether administering B. fragilis or its supernatant would specifically “inhibit translocation” of S. Heidelberg in the same manner demonstrated in Applicant’s in vitro experiments. The fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
In the instant case, the declaration fails to demonstrate that a person of ordinary skill would not have had a reasonable expectation of achieving some beneficial effect in vivo (e.g., stimulating the growth of beneficial bacteria, inhibiting pathogenic bacteria, preventing the invasion of pathogenic bacteria, the proliferation of γδ T cells, promoting recovery of tissues, as discussed in the rejections) when administering the B. fragilis strain, or its supernatant, to a subject infected by S. Heidelberg and/or having an inflammatory bowel disease.
(4) The results of the co-inventor’s experiments only compare the S. Heidelberg serovar to two other Salmonella serovars. While the prior art of Gradel (previously cited) teaches that S. Heidelberg is the third most common serovar causing invasive extra-intestinal infections associated with severe disease symptoms (see pg. 65, para. 1), the prior art of Gal-Mor, et al. (Same species, different diseases: how and why typhoidal and non-typhoidal Salmonella enterica serovars differ. Front. Microbiol. 5:391, 2014), Salmonella enterica consists of more than 2600 different serovars (see Abstract). Per MPEP 716.02(e), an applicant does not have to test all the compounds taught by each reference, "[h]owever, where an applicant tests less than all cited compounds, the test must be sufficient to permit a conclusion respecting the relative effectiveness of applicant’s claimed compounds and the compounds of the closest prior art." Id. (quoting In re Payne, 606 F.2d 303, 316, 203 USPQ 245, 256 (CCPA 1979)) (emphasis in original). In the instant case, the results provided in the declaration do not reasonably permit a conclusion that it would have been unpredictable to have achieved the beneficial effects disclosed by the prior art when administering B. fragilis (or its supernatant) to prevent or treat diseases associated with S. Heidelberg.
Per MPEP 2144.08 (“Obviousness of Species When Prior Art Teaches Genus”), obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988). Further, absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. See MPEP 2145 (Example 1).
Therefore, there is no requirement for one to have expected that all Salmonella serovars would “react to the presence of B. fragilis or its supernatant in the same way”, as set forth in the declaration, in order to maintain the rejections at issue. This evidence is not sufficient to permit a conclusion that amounts to an unreasonable level of unpredictability.
Therefore, the declaration is insufficient to overcome the rejections made under 35 U.S.C. 103.
Response to Arguments
Regarding the Claim Warning that should claim 15 be found allowable, claim 17 will be objected to under 37 CFR 1.7 as being a substantial duplicate thereof, Applicant argues that claim 15 recites a method of treating an infection caused by Salmonella Heidelberg (i.e., an existing infection) whereas claim 17 recites a method of inhibiting translocation of Salmonella Heidelberg across the intestinal epithelium whether or not an infection is pre-existing. Thus, the subject matter of claims 15 and 17 is not duplicative.
Applicant’s arguments have been fully considered and are persuasive.
The examiner agrees that the broadest reasonable interpretation of a method of inhibiting S. Heidelberg from crossing the intestinal epithelium includes both preventing and treating subjects that may or may not be infected with S. Heidelberg. Therefore, the scopes of claims 15 and 17 are not the same. Therefore, the Claim Warning has been withdrawn.
Regarding the rejections under 35 U.S.C. 103 in view of Newburg and Gall-David, Applicant argues that the Examiner specifically states that "Newburg does not teach the method wherein the infection is caused by Salmonella Heidelberg". Applicant concurs. Newburg is silent with respect to this specific serotype. Newburg does not show or suggest methods of treating infections caused by Salmonella Heidelberg but only various other Salmonella enterica.
Applicant’s arguments have been fully considered but they are not persuasive.
Applicant is reminded that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, Newburg teaches Salmonella enterica, which Gall-David teaches to include S. Heidelberg, one of the most common Salmonella serovars known to cause invasive extra-intestinal infections associated with severe disease symptoms, as discussed in the rejection.
Moreover, Newburg explicitly teaches Salmonella enterica, which does not imply “only various other Salmonella enterica.” The fact that Newburg does not mention this particular serovar does not reasonably imply that Newburg only teaches “other” serovars. Applicant’s argument fails to point to any evidence from Newburg that expressly, or even implicitly, excludes this particular serovar from Newburg’s methods.
Applicant further argues that the examiner assumes that all Salmonella serovars would predictably react to the presence of Bacteroides fragilis in the same way. Applicant summarizes the results of the accompanying declaration, concluding that “one of skill in the art could not, at the time the present application was filed, have predicted that Salmonella Heidelberg as described by Gall-Davis would respond identically compared to the Salmonella enterica tested by Newburg. The only way to know the outcome of the presence of a B. fragilis or its supernatant on Salmonella Heidelberg was to do experiments designed to demonstrate that outcome.”
Applicant’s arguments have been fully considered but they are not persuasive.
First, Applicant is remined that obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988). The examiner has addressed the results presented in the accompanying declaration as they relate to Applicant’s arguments regarding predictability (see Response to Declaration above). In particular, there is no requirement under 35 U.S.C. 103 that an ordinary artisan would have had to have expected the S. enterica serovar taught by Gall-Davis to “respond identically” to what is disclosed by Newburg.
Furthermore, Applicant’s arguments are directed to rejections that were made against claim 1 and its dependents, which are directed to administering a composition comprising a Bacteroides fragilis strain itself, not its supernatant. Therefore, it is noted that the features upon which applicant relies (i.e., “supernatant”) are not recited in the rejected claim(s). 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, the results of the experiments set forth in the declaration show that co-infection with B. fragilis had beneficial effects in the presence of both tested serovars, as discussed under Response to Declaration.
Regarding the rejection of claim 7 under 35 U.S.C. 103 in view of Newburg, Gall-David and Santos, Applicant argues that Santos does not cure the defects of Newburg and Gall-David, contributing only a teaching that S. enterica isolates, including serotype Heidelberg, were obtained from water and fish samples and that the use of probiotics might be helpful in aquaculture to prevent S. enterica infections.
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 rejections under 35 U.S.C. 103 in view of Newburg, Gall-David, Zeng and Gradel, Applicant argues that Zeng only teaches a composition containing Bacteroides fragilis as an active ingredient is excellent in inducting the proliferation and accumulation of γδT cells or promoting their effector functions, and the composition may be used for prevention or treatment of autoimmune diseases or allergic diseases. Zeng makes no mention of Salmonella infections. Gradel teaches only that inflammatory bowel disease (IBD) may be triggered by a Salmonella infection but does not show or suggest the use of a probiotic to treat the disease, and in particular does not refer to Salmonella Heidelberg.
Applicant’s arguments have been fully considered but they are not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, Zeng is relied upon for the relevant teachings of treating both inflammatory bowel disease and preventing the invasion of bacterial pathogens by the administration of a B. fragilis supernatant, while Gradel’s disclosure demonstrates that pathogenic bacteria, particularly Salmonella, are involved in the pathogenesis of inflammatory bowel disease, as discussed in the rejection. Applicant is reminded that the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Regarding the rejection under 35 U.S.C. 103 in view of Newburg, Gall-David and Ferrari, Applicant argues that Ferrari only teaches that Salmonella spp. are among the most important foodborne pathogens and the third leading cause of human death among diarrheal diseases worldwide and that production animals are often asymptomatic carriers. However, this reference does not teach the properties of Salmonella Heidelberg with respect to B. fragilis and/or B. fragilis supernatant.
Applicant’s arguments have been fully considered but they are not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, Ferrari teaches that asymptomatic carriers of this pathogen used in food production are the main transmission route to humans, as discussed in the rejection. 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 combine the prior art teachings of the aforementioned references in order to treat asymptomatic carriers of S. Heidelberg to prevent foodborne transmissions. Applicant is reminded that the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Regarding the rejections under 35 U.S.C. 103 in view of Newburg, Gall-David, Zeng and Ferrari, Applicant argues that none of these references show or suggest that B. fragilis and/or B. fragilis supernatant could be used to successfully treat an infection caused by Salmonella Heidelberg (S. Heidelberg), and the data in the accompanying declaration shows that all Salmonella serovars do not respond in the same way to B. fragilis and/or B. fragilis supernatant. “The response cannot be predicted; the experiments must be done.” Applicant further argues that Ferrari fails to provide data specific to Salmonella Heidelberg.
Applicant’s arguments have been fully considered but they are not persuasive.
First, Applicant is reminded that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references, and the test for obviousness is what the combined teachings of those references would have suggested to those of ordinary skill in the art, as discussed regarding Ferrari above.
Second, Applicant’s statement that the “response cannot be predicted” without experimentation assumes that obviousness requires absolute predictability. Applicant is reminded that absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. See MPEP 2145 (Example 1). In the instant case, the evidence regarding predictability presented in the accompanying declaration has been addressed above.
Furthermore, Applicant seems to suggest that if an ordinary artisan were motivated to administer the B. fragilis to a subject infected with S. Heidelberg, they must first test every other known serovar. The examiner contends that this is not a reasonable argument. Once a motivation and a reasonable expectation of success have been properly established, it is presumed that the ordinary artisan would proceed to apply the combination, as presented in the rejection, to administer the B. fragilis (supernatant), specifically, to a subject infected with S. Heidelberg. As discussed in the rejection, Gall-David specifically points to the prevalence of S. Heidelberg and the need to address this particular strain, which is a member of the same species that Newburg teaches can be treated with B. fragilis whose supernatant is known to have beneficial effects against pathogenic bacterial infections in view of Zeng. Therefore, a person of skill would not need to test other serovars in order to have a motivation to apply the prior art combination with a reasonable expectation of success.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/DENNIS IGNATIUS ARMATO JR/Examiner, Art Unit 1651
/MELENIE L GORDON/Supervisory Patent Examiner, Art Unit 1651
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