DETAILED ACTION
Claims 1-16 are currently pending.
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 .
Election/Restrictions
Applicant’s election without traverse of Invention Group I, claims 1-12, and Group I species (a) (claims 10-12), in the reply filed on 11/12/2025 is acknowledged.
Claims 7-9 and 13-16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected invention Group II and nonelected Group I species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/12/2025.
Priority
Acknowledgement is made of the instant application which claims the benefit of provisional application No. 63/287,233, filed 12/8/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on May 22, 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
It is additionally noted that the listing of references in the specification (pages 84-90) is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
Claim 5 is objected to because of the following informalities: the abbreviations “BHB” and “MNS” should first be spelled out upon the first usage in a claim.
Appropriate correction is required.
Claim Rejections – Improper Markush
Claim 5 is rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
It is noted the grouping of alternatives recited in claim 5 is set forth as “wherein the IL-1 pathway inhibitor is an …..” and is considered alternatives as set forth as “wherein the material is A, B, or C”, as indicated at MPEP 2117(I).
The Markush grouping of IL-1 pathway inhibitor is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: the alternatives are not all members of a recognized chemical class, e.g., monoclonal antibody or small molecule inhibitor. Claim 5 as currently written recites, for example, monoclonal antibodies (e.g., canakinumab, gevokizumab), inzomelid (small molecule), glyburide (e.g., sulfonourea), partheonlide (e.g., NF-kB inhibitor), transilast (e.g., PGD2 inhibitor), oridonin (e.g., herbal extract), CYT013 (e.g., virus-like particle vaccine). Thus, the recited alternatives do not share a single structural similarity and a common use that flows from the substantial structural feature. See MPEP § 2117.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claim(s) 1-6 and 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over Mao et al., (Frontiers in Immunology, November 2018, Vol. 9, Article 2566, pages 1-9; see PTO-892) (“Mao”), in view of Standaert-Vitse (American Journal of Gastroenterology, Abstract, vol. 104(7): p 1745-1753, July 2009, published online 26 May 2009; see PTO-892) (“AJG”), Ho et al., (Immunology, 162, 11-16 (2020); see PTO-892) (“Ho”) and Camilli et al., (PLOS Pathogens (2020), 16(10): e1008975, pages 1-10; see PTO-892) (“Camilli”), as evidenced by Joly et al., (The Journal of Immunology, 2009, 183: 3578-3581; see PTO-892) (“Joly”).
Regarding claim 1, Mao is directed to studying the role of NLRP3 and IL-1β in the pathogenesis of inflammatory bowel disease (IBD). Mao particularly notes that over-active (hyperactive) NLRP3 inflammasome activity (that results from definable point mutations) results in gut inflammation driven by IL-1β, and the gut inflammation is treatable by using agents that block the effects of IL-1β (i.e. IL-1 pathway inhibitor) (Abstract).
Mao further teaches that the genetically determined increases (definable point mutations) in NLRP3 inflammasome activity, and thus excessive production of IL-1β that causes IBD, comes from the studies of patients with a loss-of-function mutation in CARD8. The studies included three members of a kindred (proband, his mother and his aunt), each with Crohn’s and having a mutation in the T60 isoform of CARD8 that resulted in defective inhibition of NLRP3 inflammasome. Mao discloses that proof that the increased NLRP3 inflammasome-mediated production of IL-1β is the cause of Crohn’s disease in these kindred comes from the fact that the proband had severe Crohn’s that did not respond to anti-TNFα treatment, but did response to agents that inhibited the production of IL-1β, i.e., anakinra and canakinumab (as recited in claim 5) (page 7, right col, second paragraph).
Mao teaches the review of the relationship of IL-1β to human IBD establishes that IBD is exacerbated when IL-1β production is increased due to various genetic factors, and responds to IL-1β inhibition by the IL-1β blockers anakinra and canakinumab. Mao suggests that IBD patients suffering from Crohn’s disease would benefit from administration of IL-1β blockers (Summary, page 8). Thus, Mao teaches treating a patient suffering from an intestinal inflammatory disorder by administering to the patient an effective amount of an IL-1 pathway inhibitor.
Mao does not further comment on whether or not the gut tissue of the IBD patients comprises a population of candidalysin-secreting C. albicans. However, AJG discusses Candida albicans colonization in familial Crohn’s disease (inflammatory bowel disease) and specifically discloses investigating the differences in the presence of C. albicans in the digestive tracts of Crohn’s patients, their healthy relatives and non-related controls. AJG teaches determining the presence of C. albicans by collecting mouth swabs and stool specimens from 129 Crohn’s patients (CD), 113 healthy relatives (HR) and 14 control families.
AJG teaches that C. albicans was isolated more frequently from the Crohn’s patients (44%) and their healthy relatives (38%), as compared to the controls (22%), concluding that Crohn’s patients are more frequently and more heavily colonized by C. albicans that the controls (Abstract).
Thus, it is reasonable to consider that Mao’s disclosed IBD patients are colonized with C. albicans.
As to the disclosed C. albicans and secretion of candidalysin, it is noted that AJG does not further comment on secretion of candidalysin. However, Ho teaches that elevated incidences of candidiasis is linked to inflammatory bowel disease (IBD) and weakened immunity that occurs as a result of the disease may favor the shift of harmless commensal C. albicans yeast to infectious, opportunistic fungi (filamentous growth), a role for C. albicans in perpetuating ongoing disease and promoting acute or chronic pathology may warrant consideration in the context of its secreted toxin, candidalysin, which is a cytotoxic peptide secreted from pathogenic hyphal C. albicans (Introduction, right col, page 11).
Thus, absent evidence to the contrary, it is reasonable to consider that Mao’s IBD patients who are suffering from candidiasis, are colonized with candidalysin-secreting C. albicans.
Camilli further teaches inflammatory bowel disease (IBD), e.g., ulcerative colitis, Crohn’s disease, comprises chronic inflammation of the GI tract, and IBD patients have increased populations of C. albicans. Camilli further supports there is increased IL-1β expression when the IBD GI tract is populated with C. albicans (page 6, Candida, inflammasomes, and inflammatory bowel disease), and progression of IBD in genetically susceptible individuals results from a vicious cycle of inflammation and mucosal invasion of C. albicans, thus further exacerbating tissue damage.
Additionally, Camilli teaches that dysregulation of the inflammasome, i.e., hyperactivation, leads to host damage and excessive inflammation. Thus, targeting the inflammasome pathways may provide effective therapeutics that neutralize the proinflammatory mediators that exacerbate the pathogenesis of C. albicans infection, particularly the administration of IL-1β inhibitors such as anakinra, known to reduce NLRP3-driven inflammation. Camilli further teaches using the NLRP3 inhibitor MCC950 or glyburide, which also inhibited the activation of the inflammasome and reduced IL-1β production following Candida exposure or stimulation with candidalysin. Camilli notes that their findings demonstrate the potential therapeutic use of inflammasome inhibitors or anti- IL-1β treatment to control hyperactivation of the inflammasome in C. albican diseases.
Therefore, given that Mao teaches administering IL-1 pathway inhibitors anakinra and canakinumab to suppress hyperactivation of the inflammasome in IBD patients, thus reducing IL-1b production, and given that Camilli further teaches administering IL-1β inhibitors such as anakinra, MCC950 or glyburide, known to suppress hyperactivation of the inflammasome and reduce production of pro-inflammatory IL-1β in C. albicans diseases and in response to exposure to candidalysin, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to treat a patient suffering from a fungal-associated inflammatory disorder (IBD) by administering to the patient an effective amount of an IL-1 pathway inhibitor (IL-1β inhibitor, e.g., anakinra, MCC950 or glyburide), wherein the gut tissue of the patient comprises a population of candidalysin-secreting C. albicans, thus meeting the limitation of claims 1, 4-5 and 11-12.
The person of ordinary skill in the art would have been motivated to modify the method of Mao to include IBD patients that have increased populations of candidalysin-secreting C. albicans., as taught by Camilli, for the predictable result of reducing hyperactivation of the inflammasome and inhibiting the exacerbation of gut inflammation by reducing IL-1β levels.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Mao and Camilli because each of these teachings are directed at therapeutic uses of IL-1β inhibitors that reduce the hyperactivation of the inflammasome inpatients suffering from IBD.
Regarding claims 2-3, as set forth above, AJG teaches it is well-known to determine the presence of C. albicans by collecting mouth swabs and stool specimens (i.e., a fecal sample) from 129 Crohn’s patients in order to select patients for treatment.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to collect such samples and determine the quantity of C. albicans since doing so would permit selection of patients in need of administering an effective amount of the therapeutic agent for treating the intestinal inflammatory disorder.
Regarding claims 6 and 10, Joly evidences that C. albicans that lack EFG1 expression (efg1 Δ/Δ) are deficient in producing hyphae and are thus non-filamentous (page 3581, right col). Thus, the reference non-filamentous C. albicans strain recited in claim 6 is considered to express no EGF1. Therefore, absent evidence to the contrary, the prior art pathogenic filamentous C. albicans are considered to express elevated levels of EGF1, as compared to the reference non-filamentous C. albicans, thus meeting the limitation of claims 6 and 10.
Regarding claim 11, Camilli further supports there is increased IL-1β expression when the IBD GI tract is populated with C. albicans (page 6, Candida, inflammasomes, and inflammatory bowel disease), thus meeting the limitation of claim 11.
Regarding claim 12, Camilli acknowledges that neutrophils are essential for innate immunity and resistance to fungal pathogens, and IL-1β participates in driving neutrophil recruitment at the site of infection. Thus, the prior art proinflammatory response (IL-1B production) is considered to necessarily result in neutrophil infiltration, thus meeting the limitation of claim 12.
Conclusion
No claim is allowed. No claim is free of prior art.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to E. YVONNE PYLA whose telephone number is (571)270-7366. The examiner can normally be reached M-F 9am - 6pm.
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E. YVONNE PYLA
Primary Examiner
Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633