DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s election of the invention of Group I in the reply filed on 03/05/2026 is acknowledged. Because Applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.03(a)).
Claims 27-29 are withdrawn from further consideration by the Examiner under 37 C.F.R. § 1.142(b) as being drawn to nonelected inventions. (and species)
Claims 1-7, 11-13, 19-22 and 36-37 are presently under consideration.
3. 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.
4. Claims 1-7, 11-13, 19-22 and 36-37 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
(i) Claims 1 and 3 are indefinite in the recitations of “using” an immune agonist antibody and “use” of an immune checkpoint inhibitor, because it is unknown how the antibody and the inhibitor are used.
(ii) Claims 1, 6, 11 and 19 are indefinite in the recitation of the step of “modifying the gut microbiota,” because the types or directions of modifications within the scope of the claims are unknown.
(iii) Claims 6 and 20 are indefinite in the recitation of “suitable” foods and/or supplements, because it is unknown how the suitability is defined or determined.
(iv) Claims 2-7, 12, 20-22 and 36-37 are indefinite, because they encompass the indefinite limitations of the claim(s) on which they depend.
In view of the above, a person of ordinary skill in the art cannot unequivocally interpret the metes and bounds of the claims so as to understand how to avoid infringement. Applicant is reminded that any amendment must point to a basis in the specification so as not to add New Matter. See MPEP 714.02 and 2163.06.
5. The following is a quotation 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.
6. Claims 1-7, 11-13, 19-22 and 36-37 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for a method of reducing side effects associated with administration of anti-CD-40 or anti-CD137 immunotherapy, with or without anti-PD1 or anti-PD-L1 antibody, in cancer patients comprising administering an antibiotic,
does not reasonably provide enablement for a method of reducing side effects associated with administration of
generically recited immune agonist antibody, including anti-CD28, anti-GITR, anti-OX40, anti-CD27, and anti-ICOS antibodies,
with or without generically recited immune checkpoint inhibitor, including anti-CTLA4, anti-TIGIT, an-Lag3, and anti-Tim3 antibodies,
comprising a generically recited step of modifying the gut microbiota, including administration to the subject of probiotic bacteria, a faecal transplant, a prebiotic, a probiotic with a prebiotic, suitable foods or supplements, or bacteriophage.
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 use the invention commensurate in scope with these claims without undue experimentation.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized in In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, limited working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to make and use the claimed invention.
The claimed method encompasses reducing side effects of anti-CD-40, anti-CD137, anti-CD28, anti-GITR, anti-OX40, anti-CD27, anti-ICOS, and any other immune agonist antibody. The listed antibodies exert their therapeutic effects, and generate side effects, by affecting distinct signaling pathways in different cell types and compartments of the immune system. For example, as noted in the present specification, anti-CD40 induced liver toxicity is driven by macrophages, whereas anti-CD137 induced liver toxicity is driven by CD8+ T cells ([0209] and [0220] of US 20230002502).
The claims further encompass antibodies PD1, CTLA4, PDL1, TIGIT, Lag3, Tim3, and any other immune checkpoint inhibitor. As one of skill in the art would be aware, immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in various tissues. In addition to a handful of better-studies checkpoints, there is a growing number of putative, suspected or postulated negative regulators of immune response such as A2AR, IDO, B7-H3, VISTA, PKC-η, and others (reviewed e.g. by Khair et al. 2019). Like immune agonist antibodies, checkpoint inhibitors function via distinct mechanisms in different compartments of the immune system, and so differ in both their therapeutic and adverse event profiles (Id).
The claims also encompass a step of “modifying” gut microbiota, which includes mutually exclusive methods of non-selectively suppressing gut microbiota by antibiotics or by an unspecified bacteriophage, and non-selectively enhancing gut microbiota with prebiotics or unknown “suitable” foods or supplements, or adding unspecified probiotic bacteria or a fecal transplant. It would be clear to a skilled artisan that opposite interventions are not expected the same clinical effect.
The specification describes working examples of mouse model experiments wherein administration of antibiotics reduced liver toxicity caused by an anti-CD40 antibody alone or in combination with an anti-PD-1 antibody. The specification does not appear to provide guidance, direction, or working examples of practicing the method with any other immune agonist antibodies or immune checkpoint inhibitors within the scope of the claims, or with any method of modifying gut microbiota other than antibiotics.
The knowledge in the art clearly indicates that effects of gut microbiota on cancer immunotherapy outcomes are species- and strain-specific. As Khair (2019) reviews at pp. 14-15, a patient's gastrointestinal microbiota can both positively and negatively influence cancer susceptibility: “The effects of the microbiome in cancer susceptibility, progression and response to treatment are far reaching insofar as the microbiome is known to guide the immune system's response, host metabolism of medication and endogenously produced chemicals, and can also influence the balance of cell growth and death.” In melanoma patients undergoing anti-PD-1 therapy, “favorable” gut microbiota (characterized by higher gut microbe diversity and levels of Ruminococcaceae/Faecalibacterium) mediated higher levels of antigen presentation and T-eff function, which promoted better systemic and anti-tumor immune responses compared with patients with “unfavorable” microbiomes. Bacteroides has been linked to a poorer anti-tumor response in patients treated with ipilimumab and patient microbiomes enriched with Faecalibacterium and Firmicutes have also been correlated with more efficacious clinical response to ipilimumab.
Based on this, a person of ordinary skill in the art will conclude that the clinical outcomes achieved in combining a specific immunotherapy regimen with a specific modification of gut microbiota cannot be extrapolated to a different immunotherapy modality and/or a different modification of gut microbiota. Accordingly, the outcomes of the multitude of immunotherapy-microbiome combinations within the scope of the claims are unpredictable, and so experimentation required to discover effective combinations would be unnecessarily, and improperly, extensive and undue.
7. 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.
8. Claims 1-7, 11, 19-20, 22 and 36-37 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Gonzalez et al. (US 20150368349).
Gonzalez teaches a method of treating cancer comprising administering to the subject an anti-GITR antibody in combination with one or more antibiotics (e.g. [0900]), and/or checkpoint inhibitors such as anti-PD1 or anti-CTLA4 antibodies (e.g. [0167], [0860]).
Since the method taught by Gonzalez is within the scope of the instantly claimed method as recited in independent claims 1, 11 and 19, all outcomes of practicing the method taught by Gonzalez are inherently the same as the outcomes of practicing the instantly clamed method, including the reduction of side effects associated with anti-GITR immunotherapy.
Accordingly, Gonzalez teaches all of the limitations of claims 1-7, 11, 19-20, 22 and 36-37, and as such anticipates these claims.
9. Claims 1-7, 11-12, 19-22 and 36-37 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Miller et al. (US 20210260092).
Miller teaches a method of treating pancreatic cancer comprising administering to the subject a cancer therapy and a composition that inhibits the growth of Malassezia fungi in the gastrointestinal microbiota of the subject (e.g. claims 1, 15 and 23), wherein the cancer therapy is immunotherapy with immune agonist antibodies such as anti-41BB [anti-CD137] or anti-OX40 antibodies, and/or checkpoint inhibitors such as anti-PD1 or anti-CTLA4 antibodies (e.g. [0177]).
The method further comprises determining the level of at least one strain of fungi from the genus Malassezia in the gastrointestinal microbiota of the subject (e.g. claim 82).
The method further comprises administering to the subject a probiotic and/or prebiotic composition that comprises, or stimulates the growth of, one or more strains of fungi from the genera Saccharomyces and Candida in the gastrointestinal microbiota of the subject (e.g. claims 12-14).
Since the method taught by Miller is within the scope of the instantly claimed method as recited in independent claims 1, 11 and 19, all outcomes of practicing the method taught by Miller are inherently the same as the outcomes of practicing the instantly clamed method, including the reduction of side effects associated with anti-CD137 or anti-OX40 immunotherapy.
Accordingly, Miller teaches all of the limitations of claims 1-7, 11-12, 19-22 and 36-37, and as such anticipates these claims.
10. Conclusion: no claim is allowed.
11. The following prior art is cited of record but not presently relied upon:
US 20210299188 teaches that gut microbiota can modulate the response to cancer immunotherapy and susceptibility to toxic side effects, and modification of the microbiota with an increase of diversity is suggested to improve efficacy and reduce the toxicity [0111].
US 20210138028 teaches that depleting gut commensal bacteria renders hepatic NKT cells a stronger anti-tumor function [0252].
US 11351252 claims a method of enhancing efficacy of checkpoint inhibitor cancer immunotherapy comprising administering an antibacterial agent that inhibits the growth of host bacterial cells comprised by the gut microbiota.
US 20190282632 teaches methods and products for modulating microbiota composition for improving the efficacy of a cancer treatment with an immune checkpoint blocker (entire document).
US 20090136494 that combination of a GITR binding molecule and a cytotoxic antibiotic decreases tumor burden in an animal model of colon carcinoma (entire document).
US 20210361721 teaches methods for identifying donors of fecal matter that can improve a subject's response to a checkpoint inhibitor in the treatment of cancer (entire document).
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to ILIA I OUSPENSKI whose telephone number is (571)272-2920. The examiner can normally be reached 9 AM - 5:30 PM.
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/ILIA I OUSPENSKI/ Primary Examiner, Art Unit 1644
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