DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . The amendment filed on 08/03/2026 has been entered. Claims 1-181 are cancelled. Claims 182-201 are pending in this application. Claims 188 and 195-201 are withdrawn. Claims 182-187 and 189-194 are currently under examination.
Priority
This application is a 371 of PCT/US2022/021660 filed on 03/24/2022 and claims benefit of US PRO 63/273,051 filed on 10/28/2021 and US PRO 63/165,639 filed on 03/24/2021.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 63/165,639, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Claims 189-194 recite “isovalerate, or valerate”, “administering… broad-spectrum antibiotics… increases the risk of graft-versus-host disease (GVHD) to the subject”, “a decreased abundance of one or more commensal bacteria… compared to a control or reference sample from… a subject to whom the one or more broad-spectrum antibiotics are not administered”, “the severity of GVHD, wherein the one or more carbohydrate substrates… comprise arabinose, fructose, fucose… dextran, and/or α-mannan”, “does not exhibit symptoms of GVHD… diagnosed with GVHD; and/or the subject has GVHD due to the one or more broad-spectrum antibiotics”, and/or “diagnosed with GVHD… until the subject no longer exhibits symptoms of GVHD or is determined to be cured of GVHD”, which are not disclosed or supported by the prior-filed Application No. 63/165,639. Thus, the priority date of claims 189-194 is 10/28/2021.
Election/Restrictions
Applicant's election without traverse of Group I invention (claims 182-194) and species (azithromycin for targeting growth or expansion of Akkermansia; marrow-suppressive agents, as the cancer therapy; a subject who is diagnosed with neutropenia after administration of the cancer therapy but who does not become febrile or develop neutropenic fever, as the control or reference subject; and xylose as the carbohydrate substrate) in the reply filed on 08/03/2026 is acknowledged. Claims 188 and 195-201 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Thus, claims 182-187 and 189-194 are currently under examination.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 12/12/2023 and 02/25/2025 with appropriate assertion under 37 CFR 1.98 have been considered.
Claim Objections
Claims 182, 183, 190, and 193 are objected to because of the following informalities: In claim 182, change the incorrect recitation “administering to a subject” (line 3) to “administering to the subject” because the preceding clause has recited “a subject”. In claims 183 and 193, change the incorrect recitation “when the composition” (line 2) to “before the composition” to be consistent with the timing of administration in the preceding claim; also in claim 93, change the incorrect conjunction “and/or” (line 4) to “or” because the recited subjects cannot exit at the same time. In claim 190, change the incorrect recitation “on or more” (line 2) to “one or more”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 182-187 and 189-194 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for reducing the severity or likelihood of cancer therapy-induced neutropenic fever in a subject receiving a cancer therapy and having an increase of one or more genera of mucus-degrading bacteria in the gut microbiome, does not reasonably provide enablement for treating, preventing, or reducing the severity of cancer therapy-induced neutropenic fever in a subject receiving a cancer therapy. The term “treating” refers to “intervention in an attempt to alter the natural course of the subject being treated, and may be performed either for prophylaxis or during the course of pathology of a disease or condition” in the specification (p. 25, [0082]). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or to use the invention commensurate in scope with these claims. Claims 183-187, 189, 191, and 194 depend from claim 182.
Applicants claim a method of treating (encompassing preventing) cancer therapy-induced neutropenic fever in a subject receiving a cancer therapy recited in claim 182. However, no limiting definition of “preventing" or “prevention” is given in the instant Specification. In the absence of a limiting definition by the Applicants, "prevention" as described according to the Institute for International Medical Education (pages 15 and 16), is a preventive measure, such as preserving physical fitness in primary prevention and effective intervention to correct departures from good health in secondary prevention. More specifically, tertiary prevention, which is most relevant as used in the context of the instant invention, "consists of the measures available to reduce or eliminate long-term impairments and disabilities, [and to] minimize suffering caused by existing departures from good health". Thus, the claimed method of treating (encompassing preventing) cancer therapy-induced neutropenic fever in a subject receiving a cancer therapy as interpreted by a skilled practitioner of the medical or pharmaceutical arts would be to reduce for long-term the occurrence of or to eliminate cancer therapy-induced neutropenic fever in a subject receiving a cancer therapy by the method.
The Applicant's attention is drawn to In re Wands, 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set forth eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) The nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: The rejected invention is drawn to A method of treating, preventing, or reducing the severity of cancer therapy-induced neutropenic fever in a subject receiving a cancer therapy, the method comprising prophylactically administering to a subject a therapeutically effective amount of a composition comprising one or more of the following: a) one or more agents targeting growth or expansion of one or more genera of mucus-degrading bacteria in the gut microbiome of the subject; b) one or more mucus-degrading enzyme inhibitors to inhibit mucus degradation by one or more genera of mucus-degrading bacteria in the gut microbiome of the subject; and/ or c) one or more mediators of organic acid metabolite levels produced following metabolism of mucin-derived carbohydrates by one or more genera of mucus-degrading bacteria in the gut microbiome of the subject; wherein the one or more genera of mucus-degrading bacteria comprise Akkermansia or Bacteroides (claim 182), further comprising administering to the subject a therapeutically effective amount of a composition comprising one or more broad-spectrum antibiotics to treat, prevent, or reduce the severity of cancer therapy-induced neutropenic fever in the subject (claim 190); or further comprises administering to the subject a therapeutically effective amount of a composition comprising one or more carbohydrate substrates metabolized by the one or more genera of mucus-degrading bacteria in the gut microbiome to treat, prevent, and/or reduce the severity of GVHD (claim 192); or the subject has GVHD due to the one or more broad-spectrum antibiotics received by the subject to treat, prevent, and/or reduce the severity of the cancer therapy-induced neutropenic fever in the subject (claim 193).
Relative skill of those in the art: The relative skill of those in the art is from biomedical field (see the cited reference below).
Breadth of claims: The claim is extremely broad in that it encompasses the prevention of cancer therapy-induced neutropenic fever in a subject receiving a cancer therapy or reducing of the severity of cancer therapy-induced neutropenic fever in any subject receiving a cancer therapy using the instantly claimed method.
State of the prior art/Predictability or unpredictability of the art: There is no teaching or suggestion in the state of the prior art that application of certain pharmaceutical method can prevent or can reduce the severity of cancer therapy-induced neutropenic fever in any subject receiving any cancer therapy. Klastersky et al. (International Journal of Antimicrobial Agents 30S (2007) S51-S59) disclosed that a total of 2142 patients with febrile neutropenia resulting from cancer chemotherapy were registered. There were 499 (23%) patients with bacteraemia. Prophylactic antibiotics but not granulopoiesis stimulating factors were associated with a lower incidence of Gram-negative bacteraemia; however, neither prophylactic approach influenced the subsequent rate of complications in the patients who developed bacteraemia. Table 3. Demographic data of all patients included in the study (n= 2142).
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Table 4. Incidence of causative pathogens and outcome according to microbiology.
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(page S51, Abstract; page S53, Table 3; page S54, Table 4). Zhang et al. (Thorac Cancer 2021; 12:3293–3303) disclosed that the abundance of Akkermansia mucous was associated with the effects of immunotherapy in (epithelial tumor) patients undergoing fecal genomics analysis before treatment. Patients over 60 years old had a higher relative abundance of Bacteroides stercoris, Eubacterium eligens, and Bacteroides plebeius than those under 60. Moreover, patients over 60 years old had significantly greater Bacteroides sp. 31 40A and Bacteroides vulgatus compared to those under 60 years old. Chemotherapy efficacy was evaluated after two cycles. Patients with non-small cell lung cancer (NSCLC) whose efficacy was assessed, and CR were classified as responders (group A1), whereas those whose efficacy was assessed as PD were classified as nonresponders (group A2). Responders had higher abundances of Bacteroides coprocola, Bacteroides intestinalis, Bacteroides fluxus, and uncultured Bacteroides sp. compared to nonresponders (page 3294, left col., para. 3; page 3296, right col., para. 1; page 3298, left col., para. 3, right col., para. 1). One of skilled artisan would understand (a) febrile neutropenia may not be contributed by baxteremia and bacteremia may not be caused by one or more genera of Bacteroides, and (b) one or more genera of Akkermansia or Bacteroides are beneficial for treatment or survival of cancer patients, such as epithelial tumor or non-small cell lung cancer patients, described above. Thus, inhibition of growth or activities of one or more genera of Akkermansia or Bacteroides does not always enable the prevention or severity reduction of cancer therapy-induced neutropenic fever in a subject receiving a cancer therapy. The claimed method would only enable for reducing the severity or likelihood of cancer therapy-induced neutropenic fever in the preamble for a subject receiving a cancer therapy and having an increase of one or more genera of mucus-degrading bacteria in the gut microbiome.
Amount of guidance/Existence of working examples: It is worth noting that there are no working examples in the instant application to show that the claimed method is effective for preventing or reducing the severity of cancer therapy-induced neutropenic fever in any subject receiving any cancer therapy as recited in the claim. Examples of the Specification (p. 128-146) merely present: Example 1 (A. Mucus-degrading intestinal bacteria are associated with development of fever following onset of neutropenia in HCT patients; B. Systemic cytotoxic therapy increases the relative abundance of mucus-degrading intestinal bacteria in mice; C. Dietary restriction increases the relative abundance of mucus-degrading intestinal bacteria in mice; D. Bacterial metabolites link dietary restriction to mucolytic bacteria; E. Strategies targeting mucolytic bacteria in mice receiving RT preserve colonic mucus, reduce hypothermia, and reduce colonic inflammation; F. Levels of vitamin B12 are an important determinant of propionate levels; G. Identification of Additional Compounds to Inhibit Akkermansia Growth); and Example 2 (A. Meropenem treatment during allo-HSCT is associated with increased intestinal GVHD in both allo-HSCT patients and mice; B. Meropenem treatment during allo-HSCT results in loss of Clostridia and expansion of Bacteroides in both patients and mice; C. Bacteroides thetaiotaomicron contributes to meropenem-exacerbated colonic GVHD in mice; D. Meropenem treatment induces thinning of the colonic mucus layer and impairment of epithelial barrier integrity in mice with GVHD; E. Meropenem treatment during GVHD upregulates in vivo expression of mucus-degrading enzymes by BT).
Quantity of experimentation: In order to practice the full scope of the invention, one skilled in the art would need to undertake a novel and extensive research program to show that a preventive or severity-reducing measure can be achieved after applying the claimed method. Furthermore, one of ordinary skill in the art would need to test a representative number of animals before one of ordinary skill in the art would be able to conclude that any method can be used to prevent or to reduce the severity of cancer therapy-induced neutropenic fever in any subject receiving any cancer therapy. Because this research would have to be exhaustive, and because it would involve such a wide and unpredictable scope of use in prevention or severity reduction of cancer therapy-induced neutropenic fever in any subject receiving any cancer therapy, it would constitute an undue and unpredictable experimental burden.
Lack of a working example is a critical factor to be considered, especially in a case involving an unpredictable and undeveloped art. See MPEP § 2164. Genetech, 108 F.3d at 1366, states that "a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion" and "[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable".
Therefore, in view of the Wands factors as discussed above, including the amount of guidance provided and the predictability of the art and the lack of working examples to practice the full scope of the claimed invention herein, a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
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 184 and 185 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.
Claims 184 and 185 recite “a control or reference sample”, “an average person in the general population receiving the cancer therapy”, and/or “the control or reference sample is a sample from: a healthy subject; a subject who is diagnosed with neutropenia but who does not become febrile or develop neutropenic fever; a subject who is diagnosed with neutropenia after administration of the cancer therapy but who does not become febrile or develop neutropenic fever; a subject who is diagnosed with neutropenia who becomes febrile or develops neutropenic fever; and/ or a subject who is diagnosed with neutropenia after administration of the cancer therapy who becomes febrile or develops neutropenic fever”, in which the “control” or “reference” is defined in the Specification as “the term "reference," "standard," "control," or grammatically comparable comparative terms, describe a value relative to which a comparison is performed. Typically, as would be understood by those skilled in the art, a reference, standard, or control is determined or characterized under comparable conditions or circumstances to those under assessment” (p. 24, [0079]), but provides no definitive scope for the “value relative to which a comparison is performed” or how the “reference, standard, or control” is determined or characterized. The “an average person in the general population receiving the cancer therapy” is not defined and thus its scope is unclear. Also, there is no evidence that the “a healthy subject; a subject who is diagnosed with neutropenia but who does not become febrile or develop neutropenic fever; a subject who is diagnosed with neutropenia after administration of the cancer therapy but who does not become febrile or develop neutropenic fever; a subject who is diagnosed with neutropenia who becomes febrile or develops neutropenic fever; and/ or a subject who is diagnosed with neutropenia after administration of the cancer therapy who becomes febrile or develops neutropenic fever” is a legitimate control or reference. On the contrary, the abundancy, functional activity, or levels of one or more organic acid metabolites of the one or more genera of mucus-degrading bacteria comprising Akkermansia or Bacteroides is/are age-, treatment-, and/or cancer-type-dependent, as evidenced by the references under 112(a) rejection above. Furthermore, it is confusing that the “control or reference” in claim 184 is further limited by four distinct control or reference samples in claim 185.
Applicant is advised to change the recitation “compared to a control or reference sample” in claim 184 to “after receiving the cancer therapy”, which is supported by the Examples 1 and 2 of the Specification; to delete the recitation “and wherein the subject is at a higher risk than an average person in the general population receiving the cancer therapy of developing cancer therapy-induced neutropenic fever and/or the cancer therapy-induced neutropenic fever poses a greater risk to the health or life of the subject than such a condition would pose to an average person in the general population receiving the cancer therapy” in claim 184; and to make changes accordingly in claim 185 because the elected “a subject who is diagnosed with neutropenia after administration of the cancer therapy but who does not become febrile or develop neutropenic fever” is also not clear. To advance the prosecution, the elected “a subject who is diagnosed with neutropenia after administration of the cancer therapy but who does not become febrile or develop neutropenic fever” is interpreted as “a sample collected from the subject before developing neutropenic fever after the cancer therapy”.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(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.
Claims 182-187 and 189-194 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Van Den Brink et al. (US 2017/0258854, Sep. 14, 2017, hereinafter referred to as Van Den Brink ‘854, also listed in IDS filed on 12/12/2023).
With regard to structural limitations “a method comprising administering to a subject receiving a cancer therapy (or marrow-suppressive agents (elected); or the subject does not exhibit symptoms of cancer therapy-induced neutropenic fever, or the subject has been diagnosed with neutropenia; or the subject has an increased abundance of mucus-degrading bacteria or increased functional activity and/or expression levels of one or more mucus-degrading enzymes in the gut microbiome compared with a sample from the subject before treatment of a broad-spectrum antibiotic) a therapeutically effective amount of a composition comprising one or more of the following: one or more agents (or antibiotics) targeting growth or expansion of one or more genera of mucus-degrading bacteria in the gut microbiome of the subject; and/or one or more mediators (or prebiotics) of organic acid metabolite levels produced following metabolism of mucin-derived carbohydrates by one or more genera of mucus-degrading bacteria in the gut microbiome of the subject; wherein the one or more genera of mucus-degrading bacteria comprise Akkermansia” (claims 182-187 and 189), and “further comprising administering to the subject a therapeutically effective amount of a composition comprising one or more broad-spectrum antibiotics that increased abundance of the one or more genera of mucus-degrading bacteria and/or decreased abundance of one or more commensal bacteria in the gut microbiome of the subject (or further comprises administering to the subject a therapeutically effective amount of a composition comprising one or more carbohydrate substrates or xylose (elected) after the subject has been diagnosed with GVHD; or the subject does not exhibit symptoms of GVHD)” (claims 190-194):
Van Den Brink ‘854 disclosed a method for reducing the risk, incidence or severity of graft versus host disease (GVHD) in a subject undergoing a bone marrow transplant (BMT) or hematopoietic stem cell transplant (HSCT), the method comprising administering to the subject a therapeutically effective amount of an antibiotic selected from oral vancomycin or ampicillin when the subject has been treated for neutropenic fever with an intravenous antibiotic selected from the group consisting of metronidazole, piperacillin-tazobactam (pip-tazo), imipenem. Administration of the oral antibiotic reduces abundance of Akkermansia muciniphila and the risk of GVHD is reduced or eliminated. The method also comprises determining the abundance of Akkermansia muciniphila in a sample of fecal material from the subject. The abundance of Akkermansia muciniphila is determined prior to transplant, following antibiotic treatment for transplant-related neutropenic fever or both. For patients with hematologic malignancies such as leukemias, lymphomas and other related cancers, allogeneic blood marrow transplantation (allo BMT) or hematopoietic stem cell transplant (HSCT) is a critically important therapy that can produce cures when chemotherapy alone cannot. FIGS. 17A-17K shows the results of broad-spectrum Imipenem treatment after allo-HSCT results in inflammatory and barrier changes in the colon. (G) Quantification of gene sequences by homology was performed on stool samples collected on day 21. Amuc_0953, a sulfatase, and Amuc_2164 a glycosyl hydrolase, are two predicted secreted mucolytic genes found in the genome of Akkermansia muciniphila ATCC BAA-835, isolated from human feces. Inhibition of over-represented bacteria, for example, Akkermansia by administering an antibiotic that will ablate those organisms and prevent the "crowding out" of the beneficial Clostridial species. Provision of nutritional supplements comprising sugars, for example, xylose, raffinose, cellobiose and melizitose may be suitable for administration to a subject as a prebiotic strategy for reducing GVHD (page 48/68, [0023, 0024]; pages 50/68 to 51/68, [0043, 0057]; pages 52/68 to 53/68, [0071, 0085]). Paired stool samples are collected from patients prior to as well as following initiation of specific antibiotics during the course of allo-HSCT. Representative cases of patients treated for neutropenic fever, as well as of patients who did not require therapeutic antibiotics (but did receive prophylactic antibiotics) are included. Imipenem depleted Clostridiales in both patients and mice, when given in the first weeks after allo-HSCT and similar to the frequent clinical scenario of post-transplant fever/neutropenia. Lethally irradiated 129S1 recipients were transplanted with C57BL/6 T-cell depleted bone marrow (TCD-BM) cells. In mice with GVHD, imipenem treatment led to an expansion of Akkermansia muciniphila, a common commensal bacteria found in the intestinal tract of humans, mice and other animals. Notably, this bacterium is unusual in its ability to utilize mucin as a source of carbon and nitrogen. Breakdown of the colonic mucus layer has been observed. (pages 61/68 to 62/68, [0138, 0141, 0142]).
Thus, these teachings of Van Den Brink ‘854 anticipate Applicant’s claims 182-187 and 189-194.
Claim Rejections - 35 USC § 103
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 182-187 and 189-194 are rejected under 35 U.S.C. 103 as being unpatentable over Van Den Brink et al. (US 2017/0258854, Sep. 14, 2017, hereinafter referred to as Van Den Brink ‘854, also listed in IDS filed on 12/12/2023) in view of Parker et al. (Scientific Reports 7:9168, 2017, hereinafter referred to as Parker ‘2017). Claims 182-187 and 189-194 are rejected here because they have been rejected by the primary reference under 102 above. The above disclosure of Van Den Brink ‘854 is thus incorporated in its entirety here.
Van Den Brink ‘854 did not explicitly disclose the elected “azithromycin” for targeting growth or expansion of Akkermansia, required by claim 187.
Parker ‘2017 disclosed that azithromycin induced a reduction in the relative abundance of Verrucomicrobia (specifically Akkermansia muciniphila) in 6–11 month-old infants who received a 3-day course of azithromycin. After treatment (day 14), azithromycin recipients had a significantly lower OTU count than placebo recipients (68.1 ± 15.4 vs 73.6 ± 13.7; linear regression, p = 0.027 for the effect of study arm after adjusting for age). Similar trends were observed when day-0 and day-14 samples within the azithromycin arm were compared in a longitudinal analysis (mean of 72.1 ± 14.1 OTUs on day 0 versus 68.1 ± 15.4 on day 14; Wilcoxon’s test, p = 0.063). Azithromycin treatment significantly reduced the prevalence of potentially pathogenic intestinal bacteria as well as the levels of several faecal biomarkers of intestinal inflammation and permeability (page 1, Abstract; page 3, para. 2; page 2, para. 1).
Thus, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute the vancomycin or ampicillin to reduce abundance of Akkermansia muciniphila in the gut and the risk of GVHD including febrile neutropenia as taught by Van Den Brink ‘854 with azithromycin to reduce abundance of Akkermansia muciniphila in the gut in view of Parker ‘2017 because azithromycin treatment further reduces the prevalence of potentially pathogenic intestinal bacteria as well as the levels of several faecal biomarkers of intestinal inflammation and permeability, described above. Thus, one of skill in the art would have a reasonable expectation that by substituting the vancomycin or ampicillin to reduce abundance of Akkermansia muciniphila in the gut and the risk of GVHD including febrile neutropenia as taught by Van Den Brink ‘854 with azithromycin to reduce abundance of Akkermansia muciniphila in the gut in view of Parker ‘2017, one would achieve Applicant’s claims 182-187 and 189-194. "Exemplary rationales that may support a conclusion of obviousness include: (B) Simple substitution of one known element for another to obtain predictable results". See MPEP § 2143 [R-01.2024] [I].
Conclusion
No claims are allowed.
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/YIH-HORNG SHIAO/Primary Examiner, Art Unit 1691
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