CTNF 18/551,553 CTNF 98213 Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. DETAILED ACTION Claim Status Applicant’s amendment filed September 20, 2023 was received and entered. Claims 5 and 7-8 have been amended. 12-151-10 AIA 12-51-10 Claim 6 has been canceled. Claims 10-16 have been added. Claims 1-5 and 7-16 are pending and under consideration. Priority 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. This application is a 371 of PCT/EP2022/057750 filed March 24, 2022, which claims priority to foreign application EP 21164883.7 filed March 25, 2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Information Disclosure Statements The information disclosure statements (IDSs) submitted June 3, 2024, September 11, 2024, and January 21, 2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner. Claim Objections Claims 2-5, 7-8, 10-12, and 16 are objected to for the following informalities: Claims 2-5 and 10-12 recite “ A pharmaceutical combination according to claim…”, however, the claim should read “ The pharmaceutical combination according to claim…”. Claims 5, 10-12, and 16 recite the term “Yersinia”, which should be italicized, “ Yersinia ”. Claim 7 is missing a comma after “delay of progression”. Claim 8 recites “ A method according to claim 7”, however, should read “ The method according to claim 7”. Appropriate correction is required. 07-30-03-h AIA Claim Interpretation The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. Claim 1 is being interpreted as not requiring one or more pharmaceutically acceptable diluents, excipients or carriers, as this is an optional limitation. Claim 9 is being interpreted as not requiring the package insert to comprise instructions for treating a subject for cancer, as this is an optional limitation. Claim Rejections - 35 USC § 112(b) The following is a quotation of 35 U.S.C. 112(b): (b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention. Claims 1-5 and 7-16 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. Claims 1 and 9 recite a recombinant Gram-negative bacterial strain. Claim 5, 10-12, and 16 further limit the Gram-negative bacteria as being a strain of Yersinia . One of ordinary skill in the art would recognize that Gram-negative bacteria include both pathogenic and nonpathogenic species. However, it is unclear if the recombinant Gram-negative bacteria recited in the claims are avirulent or attenuated. The instant specification discloses that in one embodiment the Gram-negative strain is deficient in producing at least one T3SS effector protein which is virulent toward eukaryotic cells [pg. 65]. However, it is unclear whether the Gram-negative bacteria of the instant invention are deficient in at least one effector protein. The claims further recite the bacterial strain is from the Yersinia genus which contains three pathogenic species, i.e., Y. pestis, Y . pseudotuberculosis , and Y. enterocolitica , which cause fatal infections to humans and would not be candidates for a pharmaceutical composition without further attenuation of one or more virulence factors. Claims 1 and 9 recite the term “optionally ”, which renders the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(h). Claims 2-5, 7-8, and 10-16 are included in the rejection because they depend from or otherwise require all the limitations of a rejected claim but do not clarify the issue. Claims 3 and 14 recite the term “other CARD domain containing proteins”, however, there is no antecedent basis for this limitation in the claims. 07-34-10 Claims 3 and 14 recite the term “such as ”, which renders the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). For purposes of examination, the limitations after the term “such as” will be interpreted as part of the claimed invention. Claims 3-4 and 14-15 recited “RIG-I-like” and “DisA-like” proteins, however, it is unclear what proteins are or are not RIG-I-like or DisA-like. The specification does not provide any definition to clarify the issue. Accordingly one would not know whether they were infringing on the claims if they cannot identify what is or is not a RIG-I-like or DisA-like protein. Appropriate correction is required. Claim Rejections - 35 USC § 112(a) 07-30-01 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. Written Description Claims 1-2, 5, 7-10, 13, and 16 are rejected under 35 U.S.C. 112(a) , as failing to comply with the written description requirement. The claim contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor had possession of the claimed invention. Claims 1 and 9 recite a recombinant Gram-negative bacterial strain that encodes a heterologous protein. Claims 2 and 13 recite the heterologous protein is involved in in induction or regulation of an interferon (IFN) response. The claims encompass a large genus of undefined proteins with no recited structure or function. The state of the art is such that generating recombinant bacteria to produce heterologous proteins is a is extremely complex process and requires a deep understanding of microbial genetics and bacterial delivery systems. In regard to Gram-negative bacteria in particular, Burdette et al. (2018; cited IDS 9/11/2024) teaches they are favored as bacterial hosts for protein production, as they can express a broad range of heterologous proteins. However, intracellular overexpression of recombinant proteins in bacteria often leads to the formation of insoluble aggregates, or inclusion bodies [pg. 2, col. 1]. Burdette further teaches that selecting a strain of Gram-negative bacteria is dependent on the type of secretion system and compatibility with the desired protein product, as folding kinetics, folding complexity, and protein size can play a role in secretion efficiency. Therefore, secretion efficiency is highly dependent on the heterologous protein, yet no concrete design rules exist [pg. 3-4]. Regarding heterologous proteins involved in IFN regulation and/or induction, Negishi et al. (2018) teaches the regulation of an IFN response is a complex process that is still not fully understood. Negishi teaches there are three types of IFNs which are regulated by IFN regulatory factor (IRF) transcription factors which has nine family members, which each comprise a multitude of different proteins that are involved in the regulation of IFN [pg. 2-3]. A recent publication (Wang et al. , 2024) illustrates the complexity of the major proteins directly involved in regulation of an IFN response [Fig. 3]. PNG media_image1.png 746 708 media_image1.png Greyscale The specification discloses "a heterologous protein or a fragment thereof” includes naturally occurring and engineered proteins or a fragments thereof which do not belong to the proteome of the Gram-negative bacterial strain. Particularly preferably, the heterologous protein or a fragment thereof is selected from the group consisting of proteins involved in induction or regulation of an interferon (IFN) response, proteins involved in apoptosis or apoptosis regulation, cell cycle regulators, ankyrin repeat proteins, reporter proteins, small GTPases, GPCR related proteins, nanobody fusion constructs, bacterial T3SS effectors, bacterial T4SS effectors and viral proteins [pg. 34-35]. Multiple proteins are listed in the specification, however, only examples of two heterologous proteins (RIG-I and cGAS) that were delivered by the Gram-negative Y. enterocolitica strain are provided [pg. 38]. The instant application has not provided a sufficient description showing possession of the necessary functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus of heterologous proteins encompassing various structures, delivery mechanisms, and functions. Given the infinite number of possible heterologous proteins, the skilled artisan would not have been in possession of the vast repertoire of heterologous proteins encompassed by the claimed invention; one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genus of heterologous proteins, including those that are involved with the induction or regulation of an IFN response, with the claimed specificity and functional attributes, broadly encompassed by the claimed invention. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus. The Court has interpreted 35 U.S.C. § 112, first paragraph, to require the patent specification to “describe the claimed invention so that one skilled in the art can recognize what is claimed. Enzo Biochem, Inc. v. Gen-Probe, Inc. , 63 USPQ2d 1609 and 1618 (Fed. Cir. 2002). In evaluating whether a patentee has fulfilled this requirement, our standard is that the patent’s “disclosure must allow one skilled in the art ‘to visualize or recognize the identity of’ the subject matter purportedly described.” Id . (quoting Regents of Univ. of Cal. v. Eli Lilly & Co. , 48 USPQ2d 1398 (Fed Cir. 1997)). Vas-Cath Inc. v. Mahurkar , 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description’ inquiry, whatever is now claimed." (See Vas-Cath , p. 1117). The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath , p. 1116). Also, it is noted that the Court has held that the disclosure of screening assays and general classes of compounds was not adequate to describe compounds having the desired activity: without disclosure of which peptides, polynucleotides, or small organic molecules have the desired characteristic, the claims failed to meet the description requirement of § 112. See University of Rochester v. G.D. Searle & Co., Inc. , 69 USPQ2d 1886,1895 (Fed. Cir. 2004). Meeting the written description threshold requires showing that the applicant was in “possession” of the claimed invention at the time of filing. Vas-Cath , 935 F.2d at 1563-1564. Support need not describe the claimed subject matter in exactly the same terms as used in the claims. Eiselstein v. Frank , 52 F.3d 1035, 1038 (Fed. Cir. 1995). This support cannot be based on obviousness reasoning — i.e., what the written description and knowledge in the art would lead one to speculate as to modifications the inventor might have envisioned, but failed to disclose. Lockwood v. American Airlines, Inc. , 107 F.3d 1565, 1572 (Fed. Cir. 1997). Ariad points out, the written description requirement also ensures that when a patent claims a genus by function, the specification recites sufficient materials to accomplish that function - a problem that is particularly acute in biological arts." Ariad , 598 F.3d at 1352-3. Note the following Court Decisions regarding the written description of antibodies in the context of the current claims. Given the claimed broadly class of heterologous proteins, in the absence of sufficient disclosure of relevant identifying characteristics, the patentee must establish “a reasonable structure-function correlation” either within the specification or by reference to the knowledge of one skilled in the art with functional claims. Centocor Ortho Biotech Inc. v. Abbott Laboratories , 97 USPQ2d 1870 (Fed. Cir. 2011). There is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed antibodies to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC , No. 2017-1480 (Fed. Cir. 2017). Thus, one of skill in the art would conclude that the specification fails to provide adequate written description to demonstrate that Applicant was in possession of the claimed genus. See Eli Lilly , 119 F. 3d 1559, 43, USPQ2d 1398. Therefore, there is insufficient written description for the genus of heterologous proteins in method of treatment of a subject with cancer encompassed by the claimed invention to provide sufficient structure for the heterologous proteins claimed at the time the invention was made and as disclosed in the specification as filed under the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph. Claims 5, 7-8, 10, and 16 are included in the rejection because they depend from or otherwise require all the limitations of a rejected claim and fail to clarify the issue. Enablement Claims 7-8 and 13-16 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for delay of progression and/or treating cancer in a subject; does not reasonably provide enablement for preventing cancer as broadly claimed. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation.” In re Wright , 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc. , 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson , 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc. , 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc. , 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC , 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright , 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc. , 49 USPQ2d 1370. The factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Wands , 8 USPQ2d 1400 (Fed. Cir. 1988). Among these factors are: (1) the nature or 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. When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck , 20 USPQ2d 1438, 1444. (1) The nature of the invention and (5) The breadth of the claims: Claim 7 is drawn to a method for the prevention, delay of progression or treatment of cancer by administering the pharmaceutical combination recited in claim 1, comprising a recombinant Gram-negative bacterial strain which comprises a polynucleotide molecule comprising a nucleotide sequence encoding a heterologous protein and a delivery signal from a bacterial effector protein that is operably linked to a promoter and an immune checkpoint modulator (ICM). The claims are broad and inclusive of all types of all types of cancer in humans generally. The breadth of the claim exacerbates the complex nature of the subject matter to which the present claims are directed. The claims are extremely broad due to the vast number of possible cancer types represented by the terms “prevention of cancer in a subject”. Cancer is not a single disease, or cluster of closely related disorders. There are hundreds of cancers, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, and can occur in most parts of the body. The following are examples of some of the major classes of cancer, each having numerous types: CNS cancers. Leukemias. Carcinomas of the liver. Lung and pleural cancers. Thyroid cancers. Melanomas. Colorectal cancers. Renal carcinomas. Prostate cancers Breast cancers. Ovarian and uterine cancers. Testicular cancers. Esophageal cancers. Cervical cancers. Cardiothoracic cancers. Bladder cancers. (2) The state of the prior art and (4) The predictability or unpredictability of the art: The state of the art teaches there is no known anticancer agent that can prevent any type of cancer. The art of cancer prevention involves a very high level of unpredictability. While the state of the art is relatively high with regard to the treatment of specific cancers with specific agents, it has long been underdeveloped with regard to the prevention of cancers broadly. The lack of significant guidance from the present specification or prior art with regard to the actual prevention of cancer in a subject, with the claimed active ingredient makes practicing the claimed invention unpredictable. With regard to cancer prevention, Umar et al. (2012) teaches cancer prevention remains a promising strategy for reducing the mortality and incidence rates of cancer, however, prevention is more about reducing risk factors than it is about eliminating cancer [Abstract]. In addition, both Umar and Bode et al. (2009), teach cancer prevention is not about eliminating cancer altogether, but reducing risk factors and exposure with the goal of inhibiting progression of cancer to more invasive stages [Umar; pg. 835, col. 2, par. 2; pg. 836, col. 1, par. 2; pg. 839, col. 2, par. 2-3] [Bode; pg. 511, col. 3, par. 2]. Moreover, Sarfati et al . (2022) teaches that primary prevention of cancer through eradication or mitigation of modifiable risk factors is the best hope of reducing the future cancer burden [pg. 541, col. 1]. For example, Umar teaches stopping tobacco use is one lifestyle change that can reduce both the risk of selected cancers and other diseases but does not completely (i.e., 100%) prevent cancer [pg. 836, col. 1, par. 2]. Importantly, even vaccination has yet to achieve 100% prevention, as seen with the hepatitis B virus (HBV) vaccine. The vaccine is aimed at reducing HBV infections and subsequent hepatocellular cancer (HCC), and has an estimated 69% reduction rate in prevention HBV-HCC [Umar; pg. 842, col. 1, par. 3), not 100% prevention. Although cancer vaccines can serve as preventive measures in high-risk populations and provide treatment options for individuals already diagnosed with cancer [Kaczmarek et al ., 2023; pg. 2, par. 2], they also face a myriad of obstacles depending on the target, type of vaccine, delivery method, and type of cancer (Kaczmarek et al., pg. 21, section 7). Given the lack of predictability in preventing cancer, one of skill in the art would have to engage in undue experimentation to first identify individuals to which the instant method would apply, and also to identify which heterologous proteins would treat each specific type of cancer. 6) the amount of direction or guidance provided by the inventor; 7) the existence of working examples; The instant specification sets forth in vivo examples demonstrating the effect of the instantly claimed pharmaceutical combination on tumor growth in mouse models of breast cancer, melanoma, and colon cancer. However, none of the models demonstrate prevention of tumor growth, or prevention of cancer broadly. One of skill in the art would be required to engage in extensive, difficult experimentation to identify the heterologous protein that would possess the required functionality in combination with an ICM that for each specific type of cancer. This required experimentation is undue. In conclusion, the claimed invention does not provide enablement for prevention of any cancer. Thus for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention. Claims 8 and 13-16 are included in the rejection because they depend from or otherwise require all the limitations of a rejected claim. Claim Rejections - 35 USC § 103 07-06 AIA 15-10-15 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. 07-20-aia AIA 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. 07-23-aia AIA 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. 07-20-02-aia AIA 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. 07-21-aia AIA Claim s 1-5 and 7-16 are rejected under 35 U.S.C. 103 as being unpatentable over Ittig et al. (WO 2018/115140; cited IDS 6/3/2024) (“Ittig”), in view of Stevenson et al. (WO 2019/141998) (“Stevenson”) as evidenced by National Cancer Institute (www.cancer.gov/publications/dictionaries/cancer-drug/def/ezabenlimab; Accessed 18 March 2026) . The instant claims are drawn to a pharmaceutical combination comprising (a) a recombinant Gram-negative bacterial strain from the genus Yersinia comprising a nucleotide sequence encoding a heterologous protein or a fragment thereof fused in frame to the 3'end of a nucleotide sequence encoding a delivery signal from a bacterial effector protein that is operably linked to a promoter, and (b) an immune checkpoint modulator (ICM), wherein the ICM is ezabenlimab and wherein the heterologous protein is involved in induction or regulation of an interferon (IFN) response. The IFN is a type I IFN induced or regulated by the heterologous proteins recited in instant claims 3-4. Also claimed is a method for the prevention, delay of progression or treatment of cancer in a subject, the method comprising administering the pharmaceutical combination, and additionally comprises detection of a biomarker, a kit of parts comprising the items recited in instant claim 9. Ittig discloses a recombinant virulence attenuated Gram-negative bacterial strain which comprises a nucleotide molecule comprising a nucleotide sequence encoding a heterologous protein fused in frame to the 3' end of a nucleotide sequence encoding a delivery signal from a bacterial effector protein, wherein the nucleotide sequence encoding the delivery signal from a bacterial effector protein is operably linked to a promoter [claim 1]; and a pharmaceutical composition comprising the recombinant virulence attenuated Gram-negative bacterial strain and a pharmaceutically acceptable carrier [pg. 6, lines 31-33] ( instant claim 1 ), wherein the recombinant virulence attenuated Gram-negative bacterial strain is a Yersinia strain [claim 8] ( instant claims 5, 10-12, 16 ). Ittig further discloses the heterologous protein is a protein involved in induction or regulation of an interferon (IFN) response [claim 1] ( instant claims 2, 13 ), wherein the protein is involved in a type I IFN response, wherein the protein is selected from a protein from the RIG-I-like receptor (RLR) family, other CARD domain containing proteins involved in antiviral signaling and type I IFN induction, and cyclic dinucleotide generating enzymes such as cyclic-di-AMP, cyclic-di-GMP and cyclic-di-GAMP cyclases selected from the group consisting of WspR, DncV, DisA and DisA-like, CdaA, CdaS and cGAS, leading to stimulation of STING [claim 2] ( instant claims 3, 14 ), wherein the protein involved in induction or regulation of a type I IFN response is selected from the group consisting of RIG 1, MDA5, MAVS/IPS-1, WspR, DncV, DisA, and DisA-like, CdaA, and cGAS or a fragment thereof [claim 3] ( instant claims 4, 15 ). Ittig discloses the recombinant virulence attenuated Gram-negative bacterial strain can be used in a method of treating cancer, comprising administering said bacterial strain to a subject [claim 29] ( instant claim 7 ). For example, Ittig teaches administering the recombinant Gram-negative bacterial strain and contacting a cell of a malignant solid tumor wherein a delivery signal from a bacterial effector protein and the heterologous protein is expressed and translocated into the cell of a malignant solid tumor. The heterologous protein is then cleaved from the delivery signal from the bacterial effector protein inside of the tumor cell [pg. 84, lines 16-31] A number of assays can be used to determine whether the delivery of the fusion protein is successful such as detection via immunofluorescence using antibodies recognizing a fused tag [pg. 85, lines 26-31] ( instant claim 8 ). In addition, Ittig teaches a kit for treating cancer comprising the recombinant virulence attenuated Gram-negative bacterial strain or the pharmaceutical composition, and instructions for using the kit. The kits include a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) including one of the separate elements to be used in a method for treating cancer [pg. 90, lines 3-10] ( instant claim 9 ). Ittig generated multiple recombinant virulence attenuated Yersinia enterocolitica strains engineered to express the T3SS effector YopE for translocation of heterologous proteins [pg. 108, lines 25-34]. Table IV lists the Y. enterocolitica strains transformed with different proteins [pg.112]. Further, Ittig engineered the two N-terminal CARD domains of RIG-I of human or murine origin fused to a N-terminal bacterial secretion signal for delivery by the T3SS and assessed functionality of delivered proteins on a reporter cell line for type I IFN induction [pg. 121]. Ittig also cloned WspR that produces cyclic di-GMP to be expressed and delivered by Y. enterocolitica via the T3SS in order to activate the cGAS/STING pathway involved in the signaling pathway leading to transcription of type I IFN and other coregulated genes [pg 123-124]. The strains were used in several in vitro and in vivo assays demonstrating induction of type I IFN response and tumor regression [pg. 130-132]. Ittig does not teach the pharmaceutical composition further comprises an immune checkpoint modulator (ICM), or that the ICM is ezabenlimab. Stevenson teaches a combination of a composition comprising a bacterial strain ( Enterococcus gallinarum ) and an inhibitor ( BI 754091 ), for treating or preventing cancer [pg. 1, lines 4-9] ( instant claims 1, 9 ). Stevenson teaches immune checkpoint inhibitors (ICIs), including therapeutic antibodies against PD-1/PD-L1, have been shown to be effective in the treatment of cancer, with long lasting and significant clinical effects. However, a significant percentage of patients are non-responsive or only partially responsive to ICI treatment [pg. 2, lines 7-16]. Specifically, Stevenson teaches the therapeutic combination is for treating or preventing cancer in a subject in which the ICI (i.e., BI 754091) or the bacterial composition alone cannot provide effective treatment or prevention of cancer in the subject, comprising reducing tumor size, reducing tumor growth and/or preventing metastasis to an extent which will result in complete or partial remission of the cancer [pg. 7, lines 11-16]. Therefore, treatment of cancer using the therapeutic combination results in synergistic clinical effects as compared to treatment with the ICI alone or the bacterial composition alone [pg. 21, lines 2-4]. The inhibitor BI 754091 taught by Stevenson is an anti-PD-1 monoclonal antibody also known as ezabenlimab (National Cancer Institute) ( instant claims 1, 9 ). The teachings of Ittig differ from the present invention in that although pharmaceutical compositions comprising the identical recombinant Gram-negative bacterial strain as recited in the instant claims for use in the treatment of cancer is taught, the treatment is not explicitly taught as being combined with an ICM such as ezabenlimab. Given that Stevenson teaches a treatment for cancer comprising a therapeutic bacterial strain in combination with a PD-1/PD-L1 inhibitor demonstrates greater antitumor activity as compared to either treatment as a monotherapy, it would have been obvious to one of ordinary skill in the art to expand the treatment comprising the recombinant Gram-negative bacterial strain taught by Ittig with the addition of an anti-PD-1 antibody such as ezabenlimab which is taught by Stevenson as a preferred ICM. One would have a reasonable expectation in success in combining the protocols of Ittig and Stevenson as combination treatments comprising the administration of immune checkpoint inhibitors are known to have a synergistic effect, as evidenced by Stevenson, thus improving the overall therapeutic potential as compared to monotherapy with either agent. Accordingly, the combination of prior art references provided a prima facie case of obviousness . 08-29 Nonstatutory Double Patenting Pursuant to 37 CFR 1.78(f), when two or more applications filed by the same applicant or assignee contain patentably indistinct claims, elimination of such claims from all but one application may be required in the absence of good and sufficient reason for their retention during pendency in more than one application. Applicant is required to either cancel the patentably indistinct claims from all but one application or maintain a clear line of demarcation between the applications. See MPEP § 822. 08-33 AIA The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg , 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman , 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi , 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum , 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel , 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington , 418 F.2d 528, 163 USPQ 644 (CCPA 1969). A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b). The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13. The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA/25, or PTO/AIA/26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer. 08-36 AIA Claim s 1-5 and 7-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim s 1-3, 8, 14, 23, and 29 of US Patent No. 12,358,955, in view of Ittig et al. (WO 2018/115140; cited IDS 6/3/2024) (“Ittig”), and further in view of Stevenson et al. (WO 2019/141998) (“Stevenson”), as evidenced by National Cancer Institute (www.cancer.gov/publications/dictionaries/cancer-drug/def/ezabenlimab; Accessed 18 March 2026) . Although the claims at issue are not identical, they are not patentably distinct from each other because they teach the identical recombinant Gram-negative bacterial strain which comprises a nucleotide sequence encoding a heterologous protein fused in frame to the 3' end of a delivery signal from a bacterial effector protein, and a promoter operably linked to the delivery signal, and wherein the heterologous protein is a protein involved in induction or regulation of an interferon (IFN) response as recited in the instant claims for use in a method of treating cancer in a subject. The issued claims differ from the instant claims in that they do not teach the recombinant Gram-negative bacterial strain as part of a pharmaceutical combination with an immune checkpoint modulator (ICM), wherein the ICM is ezabenlimab; a method for detection, or a kit comprising the pharmaceutical combination. The teachings of Ittig and Stevenson have been set forth above. Specifically, Ittig teaches immunofluorescence detection methods using antibodies recognizing a fused tag can be used to determine whether protein delivery is successful [pg. 85, lines 26-31]. In addition, Ittig teaches a kit for treating cancer comprising the recombinant virulence attenuated Gram-negative bacterial strain or the pharmaceutical composition, and instructions for using the kit, which is comprised of one or more containers to be used in a method for treating cancer [pg. 90, lines 3-10]. Ittig does not teach the pharmaceutical composition further comprises an immune checkpoint modulator (ICM), or that the ICM is ezabenlimab. Stevenson teaches a combination of a composition comprising a Gram-positive bacterial strain ( Enterococcus gallinarum ) and a PD-1 inhibitor (BI 754091), for treating or preventing cancer [pg. 1, lines 4-9]. Treatment of cancer using the therapeutic combination results in synergistic clinical effects as compared to treatment with the ICI alone or the bacterial composition alone [pg. 21, lines 2-4]. The inhibitor BI 754091 taught by Stevenson is an anti-PD-1 monoclonal antibody also known as ezabenlimab (National Cancer Institute). Given that Stevenson teaches a treatment for cancer comprising a therapeutic bacterial strain in combination with a PD-1/PD-L1 inhibitor demonstrates greater antitumor activity as compared to either treatment as a monotherapy, it would have been obvious to one of ordinary skill in the art to modify the issued claims to include an immune checkpoint inhibitor using an anti-PD-1 antibody such as ezabenlimab. One would have a reasonable expectation in success in combining the protocols as combination treatments comprising the administration of immune checkpoint inhibitors are known to have a synergistic effect, as evidenced by Stevenson, thus improving the overall therapeutic potential as compared to monotherapy with either agent. As such, the instant claims are an obvious modification of the issued claims in view of Ittig and Stevenson. Similarly, claims 1-5 and 7-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over one or more claims of the following US Patents, in view of Ittig and Stevenson as set forth above. US Patent No. 11,518,789 - claims 1, 11 US Patent No. 11,702,663 - claim 1 Additionally, claims 1-5 and 7-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over one or more claims of the following copending applications, in view of Ittig and Stevenson as set forth above. Application No. 18/551,502 - claims 1-8, 12, and 14-15 Application No. 19/232,635 claims 1-3, 8, and 29 These are provisional nonstatutory double patenting rejections. The issued patents and copending applications have overlapping subject matter that renders obvious one or more claims of the instant invention. In the interest of compact prosecution, Applicant is invited to indicate whether or not the differences between the instant claims and the issued and/or copending claims are obvious, as they are drawn to recombinant Gram-negative bacterial strain which comprises a nucleotide sequence encoding a heterologous protein fused in frame to the 3' end of a delivery signal from a bacterial effector protein, and a promoter operably linked to the delivery signal for the treatment of cancer. Conclusion No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAUREEN DRISCOLL whose telephone number is (571) 270-0730. The examiner can normally be reached Monday through Friday. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached on (571) 270-3503. The fax phone number for the organization where this application or proceeding is assigned is (571) 273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at (866) 217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call (800) 786-9199 (IN USA OR CANADA) or (571) 272-1000. /MAUREEN VARINA DRISCOLL/ Examiner, Art Unit 1642 /SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642 Application/Control Number: 18/551,553 Page 2 Art Unit: 1642 Application/Control Number: 18/551,553 Page 3 Art Unit: 1642