DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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.
Applicant's response, filed on 03/17/2026, has been fully considered. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Status of claims
Canceled:
1-20
Amended:
21, 31-40
New:
none
Pending:
21-40
Withdrawn:
none
Examined:
21-40
Independent:
21, 31, 36
Allowable:
none
Priority
As detailed on the 08/23/2022 filing receipt, this application claims domestic priority to as early as 06/13/2017 the filing date of provisional application 62/518,787.
Information Disclosure Statement
The Information Disclosure Statement filed on 04/06/2026 is compliance with the provisions of 37 CFR 1.97 and have been considered in full. A signed copy of the list of references cited from each IDS is included with this Office Action.
Drawings
The drawings filed 03/18/2022 are accepted.
Withdrawn Rejections/Objections
The rejection of claims 21, 23-24, 31, 33-34, 36 and 38-39 under 35 U.S.C. §103 over Sheu in view of Buerki and Joyce, in the Office action mailed 11/17/2025 is withdrawn in view of the amendments filed 03/17/2026. However, a new rejection is applied in view of claim amendments.
The rejection of claims 22, 25-27, 29-30, 32, 35, 37, and 40 under 35 U.S.C. §103 over Sheu in view of Buerki and Joyce and in further view of Wu, in the Office action mailed 11/17/2025 is withdrawn in view of the amendments filed 03/17/2026. However, a new rejection is applied in view of claim amendments.
The rejection of claim 28 under 35 U.S.C. §103 over Sheu in view of Buerki and Joyce and in further view of Merico, in the Office action mailed 11/17/2025 is withdrawn in view of the amendments filed 03/17/2026.
The rejection of claims 21-27 and 29-40 on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 and 13-32 of Application No. 16871755, Patent No.: US 11,424,008 B2 (reference application) is withdrawn in view of the terminal disclaimer filed 03/17/2026 and approved 03/23/2026.
The rejection of claims 21, 26, and 29-30 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8-9, 12, and 15-16 of U.S. Application Serial No.:16/006,572, U.S. Patent No. 10,650,911 (reference application) is withdrawn in view of the terminal disclaimer filed 03/17/2026 and approved 03/23/2026.
The rejection of claims 21, 23-25, 27-28, 33-35, and 38-40 over claims 1, 3-5, 12-16 and 10-16 of U.S. Application Serial No.: 16/006,593, U.S. Patent No. 11,322,226 (reference application) is withdrawn in view of the terminal disclaimer filed 03/17/2026 and approved 03/23/2026.
The rejection of claims 1, 3-6, 8-10, 15, 17-19, and 21-22, of U.S. Application Serial No.: 16/006,462, U.S. Patent No. 11,367,509 (reference application) is withdrawn in view of the terminal disclaimer filed 03/17/2026 and approved 03/23/2026.
The rejection of claims 21, 23-28, 31, 33-36, and 38-40 over claims 1-12, 14, 18, and 21-23 of U.S. Application Serial No.: 16/006,481, U.S. Patent No. 11,984,200 (reference application) is withdrawn in view of the terminal disclaimer filed 03/17/2026 and approved 03/23/2026.
The rejection of claims 21-27 and 29-40 over claims 1-6, 8-10, 16-17, 21-22, 24-25, 28-38, and 40-42 of U.S. Application Serial No.: 16/006,555, U.S. Patent No. 10,311,967 (reference application) is withdrawn in view of the terminal disclaimer filed 03/17/2026 and approved 03/23/2026.
The rejection of claims 23-27, 30-31, 33-36, and 38-40 over claims 21-35 and 41-42 of U.S. Application Serial No.: 16/391,221, U.S. Patent No. 10,395,761 (reference application) is withdrawn in view of the terminal disclaimer filed 03/17/2026 and approved 03/23/2026.
The rejection of claims 21-24, 26-34, and 36-39 over claims 21-24, 26-33, and 35-39 of U.S. Application Serial No.: 18/628,544 (reference application) is withdrawn in view of the terminal disclaimer filed 03/17/2026 and approved 03/23/2026.
Regarding 35 USC 101
Claims 21-40 are patent-eligible under 35 U.S.C. 101 because independent claims 21, 31 and 36 recites identifying, using the first gene group expression levels for the subject, at least one anti-cancer therapy to administer to the subject; and administering to the subject the at least one anti-cancer therapy identified using the first gene group expression levels for the subject. The claims are implementing a judicial exception with, or using a judicial exception to affect a particular treatment or prophylaxis for a disease or medical condition, as discussed in MPEP § 2106.04(d)(2). Therefore, the judicial exception is integrated into a practical application under Step 2A, 2nd prong of the 101 analysis.
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.
Claims 21 and 23-24 are rejected under 35 U.S.C. 103 as being unpatentable over Sheu ("Cytokine regulation networks in the cancer microenvironment." Front Biosci 13.13 (2008): 6255-6268., published 2008; cited on the 11/17/2025 “Notice of References Cited” form 892), in view of Buerki (US 11,035,005 B2; Date of Patent: Jun. 15, 2021; Prior Publication Data US 2014/0066323 A1: Mar. 6, 2014; cited on the 11/17/2025 “Notice of References Cited” form 892) and Joyce ("Therapeutic targeting of the tumor microenvironment." Cancer cell 7.6 (2005): 513-520., published 2017; cited on the 11/17/2025 “Notice of References Cited” form 892) and Garg ("Immunological metagene signatures derived from immunogenic cancer cell death associate with improved survival of patients with lung, breast or ovarian malignancies: A large-scale meta-analysis." Oncoimmunology 5.2 (2016): e1069938.; cited on the attached “Notice of References Cited” form 892).
Regarding independent claim 21, Sheu teaches the claim limitation of determining, using the first RNA expression data, first gene group expression levels for the subject corresponding to respective gene groups in a set of gene groups, the set of gene groups comprising gene groups associated with cancer malignancy and different gene groups associated with cancer microenvironment with “IL-8 (CXCL-8), a CXC chemokine, is produced by a variety of human carcinoma cells. In the pancreatic tumor microenvironment, IL-8 mRNA can be enhanced by TNF-α, LIF, IL-1β, IL-6, IL-8, or IFN-β, suggesting a pivotal role in the progression of cancers.” (Page 6260, col. 1, para. 3); “Moreover, cutaneous melanomas expressing both IL-15 and IL-15R mRNA have been correlated with increased malignancy (132).” (Page 6262, col. 2, para. 1) and “…cytokines, such as TGF-β, IFN-γ, IL-2, and IL-15, are able to promote tumor suppression. The multiple actions of cytokines within the cancer environment help to explain their dual role in tumor development.” (Page 6257, col. 1, para. 1).
Sheu teaches the claim limitation of the gene groups associated with cancer microenvironment comprise an antitumor cytokines group, and determining the first gene group expression levels for the subject comprises determining a gene group expression level for the antitumor cytokines group using a gene expression level obtained from the first RNA expression data for at least three genes in the antitumor cytokines group with “…cytokines, such as TGF-β, IFN-γ, IL-2, and IL-15, are able to promote tumor suppression. The multiple actions of cytokines within the cancer environment help to explain their dual role in tumor development.” (Page 6257, col. 1, para. 1)
Sheu does not explicitly teach the claim limitation of obtaining first RNA expression data for a first biological sample from a subject having, suspected of having, or at risk of having cancer; identifying, using the first gene group expression levels for the subject, at least one anti- cancer therapy to administer to the subject; and administering to the subject the at least one anti-cancer therapy identified using the first gene group expression levels for the subject of claims 21. However, these limitations are taught by Buerki and Joyce.
Sheu also does not teach wherein the antitumor cytokines group includes HMGB 1, TNF, IFNB1, IFNA2, CCL3, TNFSF10, and FASLG in claim 21. However, this limitation is taught by Garg.
Buerki teaches the claim limitation of obtaining first RNA expression data for a first biological sample from a subject having, suspected of having, or at risk of having cancer with “In some embodiments, the cancer is selected from the group consisting of a carcinoma, sarcoma, leukemia, lymphoma, myeloma, and a CNS tumor. In some embodiments, the cancer is selected from the group consisting of skin cancer, lung cancer, colon cancer, pancreatic cancer, prostate cancer, liver cancer, thyroid cancer, ovarian cancer, uterine cancer, breast cancer, cervical cancer, kidney cancer, epithelial carcinoma, squamous carcinoma, basal cell carcinoma, melanoma, papilloma, and adenomas. In some embodiments, the cancer is a prostate cancer. In some embodiments, the cancer is a pancreatic cancer. In some embodiments, the cancer is a thyroid cancer. In some embodiments, the cancer is a bladder cancer. In some embodiments, the cancer is a lung cancer.” (col. 68, para. 1) “…In some embodiments, assaying the expression level comprises detecting and/or quantifying the RNA or mRNA levels of the plurality of targets. In some embodiments, assaying the expression level comprises detecting and/or quantifying the protein level of the plurality of targets.” (col. 68, line 51).
Joyce teaches the claim limitation of identifying, using the first gene group expression levels for the subject, at least one anti- cancer therapy to administer to the subject with Table 1. Table 1 lists drugs and targets and mechanism of action (page 514).
Joyce teaches the claim limitation of administering to the subject the at least one anti-cancer therapy identified using the first gene group expression levels for the subject with “Various strategies have been adopted to break immune tolerance, including systemic administration of effector cytokines that enhance the immune response (e.g., IL-2, IL-12, IFN-γ).” (Page 517, col. 2, para. 1).
Garg teaches wherein the antitumor cytokines group includes HMGB 1, TNF, IFNB1, IFNA2, CCL3, TNFSF10, and FASLG with Table 1 (Page e1069938-3). Garg teaches HMGB1, TNF and IFNB1 gene in Table 1 (Page e1069938-3).
It would have been prima facia obvious to combine the teachings of Sheu and Buerki to arrive at the claimed invention. A person of ordinary skill in the art would have been motivated to modify the method of Sheu by obtaining RNA expression data for a first biological sample from a subject having, suspected of having, or at risk of having cancer as taught by Buerki for the benefit of identifying genes that are involved in cancer. Furthermore, there would have been a reasonable expectation of success, since both Sheu and Buerki teach methods that pertain to the analysis of RNA expression data.
It would have been prima facia obvious to combine the teachings of Sheu and Joyce to arrive at the claimed invention. A person of ordinary skill in the art would have been motivated to modify the method of Sheu to include identifying anti-cancer therapy and administering the therapy as taught by Joyce for the benefit of mitigating cancer progression. Furthermore, there would have been a reasonable expectation of success, since both Sheu and Joyce teach methods that pertain to the analysis of the tumor microenvironment.
It would have been prima facia obvious to combine the teachings of Sheu and Garg to arrive at the claimed invention. Garg’s analysis confirmed that ICD can serve as a platform for discovery of novel prognostic metagenes (Abstract). A person of ordinary skill in the art would have been motivated to modify the method of Sheu to include expression levels of HMGB1, TNF and IFNB1 as taught by Garg for the benefit of identifying the effects of these genes on cancer and for novel prognostic metagenes discoveries. Furthermore, there would have been a reasonable expectation of success, since both Sheu and Garg teach methods that pertain to the analysis of expression data.
Regarding claim 23, Sheu teaches the claim limitation of wherein the gene groups associated with cancer microenvironment further comprise a Th1 signature group, and determining the first gene group expression levels for the subject further comprises determining a gene group expression level for the Th1 signature group using a gene expression level obtained from the first RNA expression data for at least three genes in the Th1 signature group with “Th1 lymphocyte cells produce both IL-2 and IFN-γ and promote cell-mediated immune responses.” (page 6257, col. 1, para. 4) and Figure 2. Figure 2 depicts Role of intratumoral T cytokines in directing tumor progression versus antitumor immunity. Antitumorigenic cytokines (Th1) includes IL-2, IL-12, IL-18 and IFN-γ.
Regarding claims 24, Sheu teaches the claim limitation of wherein the gene groups associated with cancer microenvironment further comprise a M1 signatures group, and determining the first gene group expression levels for the subject further comprises determining a gene group expression level for the M1 signatures group using a gene expression level obtained from the first RNA expression data for at least three genes in the M1 signatures group with “The IL-1 family consists of pleiotropic proinflammatory and immunoregulatory cytokines, including IL-1α, IL-1β, and the IL-1 receptor antagonist (IL-1Rα).” (page 6260, col. 1, para. 3); “IL-1 and TNF-α are considered ‘alarm’ pro-inflammatory cytokines that are synthesized by macrophages soon after an inflammatory insult.” (page 6260, col. 1, para. 4) and “NF-κB activation in microenvironment cells (such as stromal fibroblasts, endothelial cells, and infiltrating leukocytes) leads to the secretion of pro-inflammatory cytokines (including TNF-α and others) that in turn activate NF-κB in premalignant cells or tumor cells.” (page 6258, col. 2, para. 2).
Claims 22, 25-27 and 29-30 are rejected under 35 U.S.C. 103 as being unpatentable over Sheu ("Cytokine regulation networks in the cancer microenvironment." Front Biosci 13.13 (2008): 6255-6268., published 2008; cited on the 11/17/2025 “Notice of References Cited” form 892), in view of Buerki (US 11,035,005 B2; Date of Patent: Jun. 15, 2021; Prior Publication Data US 2014/0066323 A1: Mar. 6, 2014; cited on the 11/17/2025 “Notice of References Cited” form 892), Joyce ("Therapeutic targeting of the tumor microenvironment." Cancer cell 7.6 (2005): 513-520., published 2017; cited on the 11/17/2025 “Notice of References Cited” form 892) and Garg ("Immunological metagene signatures derived from immunogenic cancer cell death associate with improved survival of patients with lung, breast or ovarian malignancies: A large-scale meta-analysis." Oncoimmunology 5.2 (2016): e1069938.; cited on the attached “Notice of References Cited” form 892) as applied to claims 21 and 23-24 as discussed above; and in further view of Wu ("Tumor microenvironment and therapeutic response." Cancer letters 387 (2017): 61-68. Feb. 1, 2017.; cited on the 11/17/2025 “Notice of References Cited” form 892).
Sheu, Buerki, Joyce and Garg are applied to claims 21 and 23-24 as discussed above.
Sheu does not explicitly teach the claim limitation of obtaining second RNA expression data for a second biological sample from the subject, the second biological sample obtained from the subject after administration of the at least one anti- cancer therapy to the subject; determining, using the second RNA expression data, second gene group expression levels for the subject corresponding to respective gene groups in the set of gene groups; and determining, using the first gene group expression levels and the second gene group expression levels, efficacy of treating the subject using the at least one anti-cancer therapy of claim 22; wherein the gene groups associated with cancer malignancy comprise a proliferation rate group, and determining the first gene group expression levels for the subject further comprises determining a gene group expression level for the proliferation rate group using a gene expression level obtained from the first RNA expression data for at least three genes in the proliferation rate group of claim 25; determining, from among a plurality of molecular-functional (MF) profile types, an MF profile type with which to associate the subject based on the first gene group expression levels of claim 26; wherein the plurality of MF profile types include: a first MF profile type associated with inflamed and vascularized biological samples and/or inflamed and fibroblast-enriched biological samples; a second MF profile type associated with inflamed and non-vascularized biological samples and/or inflamed and non-fibroblast-enriched biological samples; a third MF profile type associated with non-inflamed and vascularized biological samples and/or non-inflamed and fibroblast-enriched biological samples; and a fourth MF profile type associated with non-inflamed and non-vascularized biological samples and/or non-inflamed and non-fibroblast-enriched biological samples of claim 27; of identifying the at least one anti-cancer therapy comprises identifying the at least one anti-cancer therapy from among a plurality of potential anti- cancer therapies using the determined MF profile type of claim 29; and wherein the at least one anti-cancer therapy comprises an anti-cancer therapeutic agent, the anti-cancer therapeutic agent selected from the group consisting of a small molecule, a polynucleotide, an expression vector, a subgenomic polynucleotide, a polypeptide, a peptide, a protein, a vector, and a eukaryotic cell of claim 30. However, these limitations are taught by Wu.
Regarding claim 22, Wu teaches the claim limitation of obtaining second RNA expression data for a second biological sample from the subject, the second biological sample obtained from the subject after administration of the at least one anti- cancer therapy to the subject; determining, using the second RNA expression data, second gene group expression levels for the subject corresponding to respective gene groups in the set of gene groups; and determining, using the first gene group expression levels and the second gene group expression levels, efficacy of treating the subject using the at least one anti-cancer therapy with “During cancer therapy, chemotherapeutic agents can elicit a misdirected tissue repair response orchestrated by TAMs [20], which may result in promotion of tumor growth and limitation of anti-tumor efficacy. In vitro and in vivo evidences have showed that TAMs mediate resistance to some chemotherapeutic agents (5-fluorouracil, doxorubicin, gemcitabine, paclitaxel, platinum compounds, etc.) as well as anti-VEGF treatment [21–26]. Moreover, TAMs acquire the ability to produce several suppressive cytokines such as IL-1β, IL-6, IL-10 and TGFβ, thus contributing to T-cell suppression in the TME [15].” (page 62, col. 1, para. 3); “The innate and adaptive immune system is a crucial component of the altered TME following therapy [69]. As mentioned above, TAM abundance may impede therapeutic responses. Diverse mechanisms are involved in the tumor-promoting function of TAMs after therapy: (1) chemotherapy (i.e., paclitaxel) or radiation treatment upregulates colony-stimulating factor 1 (CSF1), IL-34 and chemokine (C-C motif) ligand 2 (CCL2) in tumor cells, leading to increased recruitment of immunosuppressive TAMs and suppressed anti-tumor responses of CD8+ T cells (Fig. 1) [21,70]; (2) chemotherapy (i.e., cisplatin and carboplatin) increases the potency of tumor cells to induce IL-10-producing M2 macrophages [22], and macrophage-derived IL-10 inhibits IL-12 expression in dendritic cells, thus blocking activation of an effective adaptive response [71]; (3) TAMs enhance the tumor initiating capacity of cancer stem cells (CSCs) and protect CSCs from chemotherapy, thereby facilitating the therapeutic resistance [72]; (4) TAM-supplied cathepsins may blunt chemotherapeutic response of cancer cells [26]; and (5) TAMs induce upregulation of cytidine deaminase, which metabolizes the drug following its transport into the cancer cell, thus mediating acquired resistance to chemotherapy [73].” (page 64, col. 1, para. 1); “Several chemotherapeutic agents unexpectedly stimulate production of tumor-derived factors, which lead to expansion of MDSCs, critically causing refractoriness against the treatment. In breast cancer, chemokine (C-X-C motif) ligand 1/2 (CXCL1/2) production by cancer cells attract MDSCs, which secrete S100A8/ A9 that enhances cancer cell survival (Fig. 1). Anthracycline and cyclophosphamide trigger the production of tumor necrosis factor α (TNFα) from stromal cells, thus heightening the CXCL1/2 expression, amplifying the CXCL1/2-S100A8/A9 loop and causing chemoresistance [29]. In animal models and cancer patients, refractoriness to anti-angiogenic therapies based on inhibition of the VEGF pathway is associated with higher numbers of MDSCs or TAMs infiltrating tumor tissues [74,75]. The mechanisms of these myeloid cells facilitating tumor angiogenesis remain incompletely understood. It is conceivable that anti-VEGF treatment upregulates the alternative pro-angiogenic factors (prokineticin 1 and prokineticin 2) production from myeloid cells, unexpectedly leading to limitation of anti-angiogenic efficacy and tumor recurrence (Fig. 1) [76].” (page 64, col. 1, para. 2); and “There is a paracrine signaling network between the adaptive and innate immune systems that is associated with resistance to antitumor therapy. For instance, tumor-infiltrating T helper type 17 (Th17) cells and IL-17 induce the expression of CSF1 in stroma and this in turn attracts MDSCs, which drive anti-VEGF therapy resistance [77]. Chemotherapeutic agents (gemcitabine and 5-fluorouracil) can also activate MDSCs, leading to production of IL-1β, which induces a Th17 response and subsequently blunts the anti-cancer efficacy [78].” (page 64, col. 1, para. 3).
Regarding claim 25, Wu teaches the claim limitation of wherein the gene groups associated with cancer malignancy comprise a proliferation rate group, and determining the first gene group expression levels for the subject further comprises determining a gene group expression level for the proliferation rate group using a gene expression level obtained from the first RNA expression data for at least three genes in the proliferation rate group with “In short, IL-6 has been viewed as a major cytokine for the proliferation and survival of multiple myeloma cells.” (page 6261, col. 1, para. 2); “The IL-10 autocrine and/or paracrine loop may be important for tumor cell proliferation and survival (110), leading to the up-regulation of anti-apoptotic genes such as B-cell lymphoma 2 (BCL-2) or BCL-XL (111).” (page 6261, col. 2, para. 2); “IL-2 and IL-15 share a number of important properties, including the stimulation of the T-, NK-, and B cell proliferation/maturation (118).” (page 6262, col. 1, para. 2); “Stromal production of IL-15 may contribute to the proliferation of malignant cells in vivo, and IL-15 in turn is able to stimulate the growth of myeloma cells in a way independent of IL-6.” (page 6262, col. 1, para. 4)
Regarding claim 26, Wu teaches the claim limitation of determining, from among a plurality of molecular-functional (MF) profile types, an MF profile type with which to associate the subject based on the first gene group expression levels with the sections on “Vasculature” (page 61, col. 2, para. 1); “Cancer-associated fibroblasts” (page 61, col. 2, para. 2) to (page 62, col. 1, para. 1); “Immune cells” (page 62, col. 1, para. 3); “Tumor-associated endothelial cells” (page 62, col. 2, para. 1); and “Extracellular matrix” (page 62, col. 2, para. 2). Within each section, Wu discusses the genes that are expressed.
Regarding claim 27, Wu teaches the claim limitation of wherein the plurality of MF profile types include: a first MF profile type associated with inflamed and vascularized biological samples and/or inflamed and fibroblast-enriched biological samples; a second MF profile type associated with inflamed and non-vascularized biological samples and/or inflamed and non-fibroblast-enriched biological samples; a third MF profile type associated with non-inflamed and vascularized biological samples and/or non-inflamed and fibroblast-enriched biological samples; and a fourth MF profile type associated with non-inflamed and non-vascularized biological samples and/or non-inflamed and non-fibroblast-enriched biological samples with the sections on “Vasculature” (page 61, col. 2, para. 1); “Cancer-associated fibroblasts” (page 61, col. 2, para. 2) to (page 62, col. 1, para. 1); “Immune cells” (page 62, col. 1, para. 3); “Tumor-associated endothelial cells” (page 62, col. 2, para. 1); and “Extracellular matrix” (page 62, col. 2, para. 2).
Regarding claim 29, Wu teaches the claim limitation of identifying the at least one anti-cancer therapy comprises identifying the at least one anti-cancer therapy from among a plurality of potential anti- cancer therapies using the determined MF profile type with the sections on “Targeting stroma-derived paracrine factors” (Page 64, col. 2, para. 1); “Targeting tumor cell–extracellular matrix interactions” (Page 64, col. 2, para. 2); and “Targeting immune cells” (Page 64, col. 2, para. 3).
Regarding claim 30, Wu teaches the claim limitation of wherein the at least one anti-cancer therapy comprises an anti-cancer therapeutic agent, the anti-cancer therapeutic agent selected from the group consisting of a small molecule, a polynucleotide, an expression vector, a subgenomic polynucleotide, a polypeptide, a peptide, a protein, a vector, and a eukaryotic cell with “Preclinical work has demonstrated that small peptide CXCR4 antagonists (T140, TC14012, TN14003) effectively antagonize stromal protection of CLL cells from spontaneous or fludarabine-induced apoptosis [79]. Moreover, AMD3465, a nonpeptide small-molecule inhibitor of CXCR4, not only abrogates the protective effects of stromal cells on chemotherapy-induced apoptosis but also enhances the apoptogenic effects of sorafenib in AML cells, resulting in markedly reduced leukemia burden and prolonged survival of the animals [80].” (Page 64, col. 2, para. 1).
It would have been prima facia obvious to combine the teachings of Sheu and Wu to arrive at the claimed invention. A person of ordinary skill in the art would have been motivated to modify the method of Sheu to include obtaining a second RNA expression data from the subject after administration of the anti-cancer therapy as taught by Wu for the benefit of comparing RNA expression data prior to and after the administration of the anticancer therapy for the purpose of accessing the effectiveness of the therapy. A person of ordinary skill in the art would have also been motivated to modify the method of Sheu to include determining a gene group expression level for the proliferation rate group as taught by Wu for the benefit of determining the genes that contribute to the proliferation of malignant cells. A person of ordinary skill in the art would have also been motivated to modify the method of Sheu to include determining molecular-functional (MF) profile types as taught by Wu for the benefit of determining the effects of MF profiles types on therapy response. A person of ordinary skill in the art would have also been motivated to modify the method of Sheu to include AMD3465, a nonpeptide small-molecule inhibitor of CXCR4 as the anti-cancer therapeutic agent as taught by Wu because the agent not only abrogates the protective effects of stromal cells on chemotherapy-induced apoptosis but also enhances the apoptogenic effects of sorafenib in AML cells (Page 64, col. 2, para. 1). Furthermore, there would have been a reasonable expectation of success, since both Sheu and Wu teach methods that pertain to the analysis of genes in the tumor microenvironment.
Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over Sheu ("Cytokine regulation networks in the cancer microenvironment." Front Biosci 13.13 (2008): 6255-6268., published 2008; cited on the 11/17/2025 “Notice of References Cited” form 892), in view of Buerki (US 11,035,005 B2; Date of Patent: Jun. 15, 2021; Prior Publication Data US 2014/0066323 A1: Mar. 6, 2014; cited on the 11/17/2025 “Notice of References Cited” form 892), Joyce ("Therapeutic targeting of the tumor microenvironment." Cancer cell 7.6 (2005): 513-520., published 2017; cited on the 11/17/2025 “Notice of References Cited” form 892) and Garg ("Immunological metagene signatures derived from immunogenic cancer cell death associate with improved survival of patients with lung, breast or ovarian malignancies: A large-scale meta-analysis." Oncoimmunology 5.2 (2016): e1069938.; cited on the attached “Notice of References Cited” form 892) as applied to claims 21 and 23-24 as discussed above; and in further view of Merico (Enrichment Map: A Network-Based Method for Gene-Set Enrichment Visualization and Interpretation. PLoS ONE 5(11): e13984, Nov. 15, 2010; published 2010; cited on the 08/04/2022 IDS Document)
Sheu, Buerki, Joyce and Garg are applied to claims 21 and 23-24 as discussed above.
Regarding claim 28, Merico teaches the claim limitation of determining the first gene group expression levels corresponding to the respective gene groups in the set of gene groups is performed using a gene set enrichment analysis (GSEA) technique with “Here, we analyzed the changes in gene expression associated with estrogen treatment of a breast cancer cell line (MCF7) at 24 hours of culture [33]. Enrichment results were generated after scoring genes for differential expression using the t-test statistic, comparing the estrogen-treated versus the untreated samples. GSEA was then used to find enriched GO gene-sets in up- or down-regulated genes.” (page 3, col. 2, para. 2).
It would have been prima facia obvious to combine the teachings of Sheu and Merico to arrive at the claimed invention. A person of ordinary skill in the art would have been motivated to modify the method of Sheu to include using a gene set enrichment analysis (GSEA) technique as taught by Merico to help functionally characterize large gene lists (Abstract, Background). Furthermore, there would have been a reasonable expectation of success, since both Sheu and Merico teach methods that pertain to the analysis of the genetic data involved in cancer.
Claims 31, 33-34, 36 and 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Sheu ("Cytokine regulation networks in the cancer microenvironment." Front Biosci 13.13 (2008): 6255-6268., published 2008; cited on the 11/17/2025 “Notice of References Cited” form 892), in view of Buerki (US 11,035,005 B2; Date of Patent: Jun. 15, 2021; Prior Publication Data US 2014/0066323 A1: Mar. 6, 2014; cited on the 11/17/2025 “Notice of References Cited” form 892), Joyce ("Therapeutic targeting of the tumor microenvironment." Cancer cell 7.6 (2005): 513-520., published 2017; cited on the 11/17/2025 “Notice of References Cited” form 892) and Mager ("Cytokine-induced modulation of colorectal cancer." Frontiers in oncology 6 (2016): 96.; cited on the attached “Notice of References Cited” form 892).
Regarding independent claim 31, Sheu teaches the claim limitation of determining, using the first RNA expression data, first gene group expression levels for the subject corresponding to respective gene groups in a set of gene groups, the set of gene groups comprising gene groups associated with cancer malignancy and different gene groups associated with cancer microenvironment with “IL-8 (CXCL-8), a CXC chemokine, is produced by a variety of human carcinoma cells. In the pancreatic tumor microenvironment, IL-8 mRNA can be enhanced by TNF-α, LIF, IL-1β, IL-6, IL-8, or IFN-β, suggesting a pivotal role in the progression of cancers.” (Page 6260, col. 1, para. 3); “Moreover, cutaneous melanomas expressing both IL-15 and IL-15R mRNA have been correlated with increased malignancy (132).” (Page 6262, col. 2, para. 1) and “…cytokines, such as TGF-β, IFN-γ, IL-2, and IL-15, are able to promote tumor suppression. The multiple actions of cytokines within the cancer environment help to explain their dual role in tumor development.” (Page 6257, col. 1, para. 1).
Sheu teaches the claim limitation of the gene groups associated with cancer microenvironment comprise an antitumor cytokines group, and determining the first gene group expression levels for the subject comprises determining a gene group expression level for the antitumor cytokines group using a gene expression level obtained from the first RNA expression data for at least three genes in the antitumor cytokines group with “…cytokines, such as TGF-β, IFN-γ, IL-2, and IL-15, are able to promote tumor suppression. The multiple actions of cytokines within the cancer environment help to explain their dual role in tumor development.” (Page 6257, col. 1, para. 1)
Sheu does not explicitly teach the claim limitation of obtaining first RNA expression data for a first biological sample from a subject having, suspected of having, or at risk of having cancer; identifying, using the first gene group expression levels for the subject, at least one anti- cancer therapy to administer to the subject; and administering to the subject the at least one anti-cancer therapy identified using the first gene group expression levels for the subject of claims 31. However, these limitations are taught by Buerki and Joyce.
Sheu also does not teach the gene groups associated with cancer microenvironment comprise a M1 signatures group, and determining the first gene group expression levels for the subject comprises determining a gene group expression level for the M1 signatures group using a gene expression level obtained from the first RNA expression data for at least three genes in the M1 signatures group, wherein the M1 signatures group includes NOS2, IL12A, IL12B, IL23A, TNF, IL1B, and SOCS3 in claim 31. However, this limitation is taught by Mager.
Buerki teaches the claim limitation of obtaining first RNA expression data for a first biological sample from a subject having, suspected of having, or at risk of having cancer with “In some embodiments, the cancer is selected from the group consisting of a carcinoma, sarcoma, leukemia, lymphoma, myeloma, and a CNS tumor. In some embodiments, the cancer is selected from the group consisting of skin cancer, lung cancer, colon cancer, pancreatic cancer, prostate cancer, liver cancer, thyroid cancer, ovarian cancer, uterine cancer, breast cancer, cervical cancer, kidney cancer, epithelial carcinoma, squamous carcinoma, basal cell carcinoma, melanoma, papilloma, and adenomas. In some embodiments, the cancer is a prostate cancer. In some embodiments, the cancer is a pancreatic cancer. In some embodiments, the cancer is a thyroid cancer. In some embodiments, the cancer is a bladder cancer. In some embodiments, the cancer is a lung cancer.” (col. 68, para. 1) “…In some embodiments, assaying the expression level comprises detecting and/or quantifying the RNA or mRNA levels of the plurality of targets. In some embodiments, assaying the expression level comprises detecting and/or quantifying the protein level of the plurality of targets.” (col. 68, line 51).
Joyce teaches the claim limitation of identifying, using the first gene group expression levels for the subject, at least one anti- cancer therapy to administer to the subject with Table 1. Table 1 lists drugs and targets and mechanism of action (page 514).
Joyce teaches the claim limitation of administering to the subject the at least one anti-cancer therapy identified using the first gene group expression levels for the subject with “Various strategies have been adopted to break immune tolerance, including systemic administration of effector cytokines that enhance the immune response (e.g., IL-2, IL-12, IFN-γ).” (Page 517, col. 2, para. 1).
Mager teaches the gene groups associated with cancer microenvironment comprise a M1 signatures group, and determining the first gene group expression levels for the subject comprises determining a gene group expression level for the M1 signatures group using a gene expression level obtained from the first RNA expression data for at least three genes in the M1 signatures group, wherein the M1 signatures group includes NOS2, IL12A, IL12B, IL23A, TNF, IL1B, and SOCS3 with “Bioactive IL-23 is a heterodimeric complex consisting of IL-23p19 (encoded by IL23A) and IL-12p40 (encoded by IL12B), which are specific for IL-23 or shared with IL-12, respectively. In the serum of CRC patients, IL-23 levels are increased and positively correlate with VEGF. In primary CRC tissue, IL23A and IL12B transcripts are overexpressed, whereas IL12A mRNA is not upregulated. Moreover, high IL-23 levels together with low SOCS3 expression in primary tumor tissue were predictive of a higher rate of CRC metastasis” (page 7, col. 2, para. 2) and “Active IL-12 is constituted of two subunits, IL-12p35 and IL-12p40 that are encoded by IL12A and IL12B, respectively.” (page 5, col. 1, para. 1).
It would have been prima facia obvious to combine the teachings of Sheu and Buerki to arrive at the claimed invention. A person of ordinary skill in the art would have been motivated to modify the method of Sheu by obtaining RNA expression data for a first biological sample from a subject having, suspected of having, or at risk of having cancer as taught by Buerki for the benefit of identifying genes that are involved in cancer. Furthermore, there would have been a reasonable expectation of success, since both Sheu and Buerki teach methods that pertain to the analysis of RNA expression data.
It would have been prima facia obvious to combine the teachings of Sheu and Joyce to arrive at the claimed invention. A person of ordinary skill in the art would have been motivated to modify the method of Sheu to include identifying anti-cancer therapy and administering the therapy as taught by Joyce for the benefit of mitigating cancer progression. Furthermore, there would have been a reasonable expectation of success, since both Sheu and Joyce teach methods that pertain to the analysis of the tumor microenvironment.
It would have been prima facia obvious to combine the teachings of Sheu and Mager to arrive at the claimed invention. A person of ordinary skill in the art would have been motivated to modify the method of Sheu to include expression levels of NOS2, IL12A, IL12B, IL23A, TNF, IL1B or SOCS3 as taught by Mager for the benefit of identifying the effects of these genes on cancer to better design therapeutic approaches. Furthermore, there would have been a reasonable expectation of success, since both Sheu and Mager teach methods that pertain to the analysis of expression data and cancer.
Regarding claim 33, Sheu teaches the claim limitation of wherein the gene groups associated with cancer microenvironment further comprise a Th1 signature group, and determining the first gene group expression levels for the subject further comprises determining a gene group expression level for the Th1 signature group using a gene expression level obtained from the first RNA expression data for at least three genes in the Th1 signature group with “Th1 lymphocyte cells produce both IL-2 and IFN-γ and promote cell-mediated immune responses.” (page 6257, col. 1, para. 4) and Figure 2. Figure 2 depicts Role of intratumoral T cytokines in directing tumor progression versus antitumor immunity. Antitumorigenic cytokines (Th1) includes IL-2, IL-12, IL-18 and IFN-γ.
Regarding claim 34, Sheu teaches the claim limitation of wherein the gene groups associated with cancer microenvironment further comprise an antitumor cytokines group, and determining the first gene group expression levels for the subject further comprises determining a gene group expression level for the an antitumor cytokines using a gene expression level obtained from the first RNA expression data for at least three genes in the an antitumor cytokines group with “The IL-1 family consists of pleiotropic proinflammatory and immunoregulatory cytokines, including IL-1α, IL-1β, and the IL-1 receptor antagonist (IL-1Rα).” (page 6260, col. 1, para. 3); “IL-1 and TNF-α are considered ‘alarm’ pro-inflammatory cytokines that are synthesized by macrophages soon after an inflammatory insult.” (page 6260, col. 1, para. 4) and “NF-κB activation in microenvironment cells (such as stromal fibroblasts, endothelial cells, and infiltrating leukocytes) leads to the secretion of pro-inflammatory cytokines (including TNF-α and others) that in turn activate NF-κB in premalignant cells or tumor cells.” (page 6258, col. 2, para. 2) and in Figure 2 (page 6257). Fig. 2 depicts antitumorigenic cytokines.
Regarding independent claims 36, Sheu teaches the claim limitation of determining, using the first RNA expression data, first gene group expression levels for the subject corresponding to respective gene groups in a set of gene groups, the set of gene groups comprising gene groups associated with cancer malignancy and different gene groups associated with cancer microenvironment with “IL-8 (CXCL-8), a CXC chemokine, is produced by a variety of human carcinoma cells. In the pancreatic tumor microenvironment, IL-8 mRNA can be enhanced by TNF-α, LIF, IL-1β, IL-6, IL-8, or IFN-β, suggesting a pivotal role in the progression of cancers.” (Page 6260, col. 1, para. 3); “Moreover, cutaneous melanomas expressing both IL-15 and IL-15R mRNA have been correlated with increased malignancy (132).” (Page 6262, col. 2, para. 1) and “…cytokines, such as TGF-β, IFN-γ, IL-2, and IL-15, are able to promote tumor suppression. The multiple actions of cytokines within the cancer environment help to explain their dual role in tumor development.” (Page 6257, col. 1, para. 1).
Sheu teaches the claim limitation of the gene groups associated with cancer microenvironment comprise an angiogenesis group, and determining the first gene group expression levels for the subject comprises determining a gene group expression level for the angiogenesis group using a gene expression level obtained from the first RNA expression data for at least three genes in the angiogenesis group with “…cytokines, such as TGF-β, IFN-γ, IL-2, and IL-15, are able to promote tumor suppression. The multiple actions of cytokines within the cancer environment help to explain their dual role in tumor development.” (Page 6257, col. 1, para. 1) and high concentrations of CXCL12 are able to induce angiogenesis (page 6259, col. 2, para. 2) and IL-23 signaling leads to up-regulation of MMPs, increased angiogenesis, and decreased recruitment of CD8+ T cells to tumors (page 6260, col. 2, para. 2).
Sheu does not explicitly teach the claim limitation of obtaining first RNA expression data for a first biological sample from a subject having, suspected of having, or at risk of having cancer; identifying, using the first gene group expression levels for the subject, at least one anti- cancer therapy to administer to the subject; and administering to the subject the at least one anti-cancer therapy identified using the first gene group expression levels for the subject of claims 36. However, these limitations are taught by Buerki and Joyce.
Sheu teaches that high concentrations of CXCL12 are able to induce angiogenesis (page 6259, col. 2, para. 2) and IL-23 signaling leads to up-regulation of MMPs, increased angiogenesis, and decreased recruitment of CD8+ T cells to tumors (page 6260, col. 2, para. 2), but does not teach wherein the angiogenesis group includes VEGFA, VEGFB, VEGFC, PDGFC, CXCL8, CXCR2, FLT1, PIGF, CXCL5, KDR, ANGPT1, ANGPT2, TEK, VWF, CDH5, NOS3, VCAM1, MMRN1, LDHA, HIF1A, EPAS1, CA9, SPP1, LOX, SLC2A1, and LAMP3 in claim 36. However, this limitation is taught by Mager.
Buerki teaches the claim limitation of obtaining first RNA expression data for a first biological sample from a subject having, suspected of having, or at risk of having cancer with “In some embodiments, the cancer is selected from the group consisting of a carcinoma, sarcoma, leukemia, lymphoma, myeloma, and a CNS tumor. In some embodiments, the cancer is selected from the group consisting of skin cancer, lung cancer, colon cancer, pancreatic cancer, prostate cancer, liver cancer, thyroid cancer, ovarian cancer, uterine cancer, breast cancer, cervical cancer, kidney cancer, epithelial carcinoma, squamous carcinoma, basal cell carcinoma, melanoma, papilloma, and adenomas. In some embodiments, the cancer is a prostate cancer. In some embodiments, the cancer is a pancreatic cancer. In some embodiments, the cancer is a thyroid cancer. In some embodiments, the cancer is a bladder cancer. In some embodiments, the cancer is a lung cancer.” (col. 68, para. 1) “…In some embodiments, assaying the expression level comprises detecting and/or quantifying the RNA or mRNA levels of the plurality of targets. In some embodiments, assaying the expression level comprises detecting and/or quantifying the protein level of the plurality of targets.” (col. 68, line 51).
Joyce teaches the claim limitation of identifying, using the first gene group expression levels for the subject, at least one anti- cancer therapy to administer to the subject with Table 1. Table 1 lists drugs and targets and mechanism of action (page 514).
Joyce teaches the claim limitation of administering to the subject the at least one anti-cancer therapy identified using the first gene group expression levels for the subject with “Various strategies have been adopted to break immune tolerance, including systemic administration of effector cytokines that enhance the immune response (e.g., IL-2, IL-12, IFN-γ).” (Page 517, col. 2, para. 1).
Mager teaches determining a gene group expression level for the angiogenesis group using a gene expression level obtained from the first RNA expression data for at least three genes in the angiogenesis group, wherein the angiogenesis group includes VEGFA, VEGFB, VEGFC, PDGFC, CXCL8, CXCR2, FLT1, PIGF, CXCL5, KDR, ANGPT1, ANGPT2, TEK, VWF, CDH5, NOS3, VCAM1, MMRN1, LDHA, HIF1A, EPAS1, CA9, SPP1, LOX, SLC2A1, and LAMP3 with “Various cells, such as TAMs, CAFs, tumor cells, platelets, and mast cells, produce VEGF (6). There are several different molecules comprising the VEGF family, namely VEGF-A, VEGF-B, VEGF-C, and VEGF-D, as well as different isoforms of VEGF-A and VEGF-B with potentially different function. Their mode of action has already been reviewed in detail elsewhere (263). Of note, VEGFA, VEGFB, VEGFC, and VEGFD expression is modulated during the adenoma–carcinoma sequence in CRC. For instance, VEGFA is upregulated in adenomas and carcinomas, whereas VEGFD is more abundant in normal tissues.” (page 10, col. 1, para. 2).
It would have been prima facia obvious to combine the teachings of Sheu and Buerki to arrive at the claimed invention. A person of ordinary skill in the art would have been motivated to modify the method of Sheu by obtaining RNA expression data for a first biological sample from a subject having, suspected of having, or at risk of having cancer as taught by Buerki for the benefit of identifying genes that are involved in cancer. Furthermore, there would have been a reasonable expectation of success, since both Sheu and Buerki teach methods that pertain to the analysis of RNA expression data.
It would have been prima facia obvious to combine the teachings of Sheu and Joyce to arrive at the claimed invention. A person of ordinary skill in the art would have been motivated to modify the method of Sheu to include identifying anti-cancer therapy and administering the therapy as taught by Joyce for the benefit of mitigating cancer progression. Furthermore, there would have been a reasonable expectation of success, since both Sheu and Joyce teach methods that pertain to the analysis of the tumor microenvironment.
It would have been prima facia obvious to combine the teachings of Sheu and Mager to arrive at the claimed invention. A person of ordinary skill in the art would have been motivated to modify the method of Sheu to include the expression levels of VEGFA, VEGFB and VEGFC as taught by Mager for the benefit of identifying the effects of these genes on cancer to better design therapeutic approaches. Furthermore, there would have been a reasonable on cancer to expectation of success, since both Sheu and Mager teach methods that pertain to the analysis of expression data and cancer.
Regarding claim 38, Sheu teaches the claim limitation of wherein the gene groups associated with cancer microenvironment further comprise a Th1 signature group, and determining the first gene group expression levels for the subject further comprises determining a gene group expression level for the Th1 signature group using a gene expression level obtained from the first RNA expression data for at least three genes in the Th1 signature group with “Th1 lymphocyte cells produce both IL-2 and IFN-γ and promote cell-mediated immune responses.” (page 6257, col. 1, para. 4) and Figure 2. Figure 2 depicts Role of intratumoral T cytokines in directing tumor progression versus antitumor immunity. Antitumorigenic cytokines (Th1) includes IL-2, IL-12, IL-18 and IFN-γ.
Regarding claim 39, Sheu teaches the claim limitation of wherein the gene groups associated with cancer microenvironment further comprise a M1 signatures group, and determining the first gene group expression levels for the subject further comprises determining a gene group expression level for the M1 signatures group using a gene expression level obtained from the first RNA expression data for at least three genes in the M1 signatures group with “The IL-1 family consists of pleiotropic proinflammatory and immunoregulatory cytokines, including IL-1α, IL-1β, and the IL-1 receptor antagonist (IL-1Rα).” (page 6260, col. 1, para. 3); “IL-1 and TNF-α are considered ‘alarm’ pro-inflammatory cytokines that are synthesized by macrophages soon after an inflammatory insult.” (page 6260, col. 1, para. 4) and “NF-κB activation in microenvironment cells (such as stromal fibroblasts, endothelial cells, and infiltrating leukocytes) leads to the secretion of pro-inflammatory cytokines (including TNF-α and others) that in turn activate NF-κB in premalignant cells or tumor cells.” (page 6258, col. 2, para. 2).
Claims 32, 35, 37, and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Sheu ("Cytokine regulation networks in the cancer microenvironment." Front Biosci 13.13 (2008): 6255-6268., published 2008; cited on the 11/17/2025 “Notice of References Cited” form 892), in view of Buerki (US 11,035,005 B2; Date of Patent: Jun. 15, 2021; Prior Publication Data US 2014/0066323 A1: Mar. 6, 2014; cited on the 11/17/2025 “Notice of References Cited” form 892), Joyce ("Therapeutic targeting of the tumor microenvironment." Cancer cell 7.6 (2005): 513-520., published 2017; cited on the 11/17/2025 “Notice of References Cited” form 892) and Mager ("Cytokine-induced modulation of colorectal cancer." Frontiers in oncology 6 (2016): 96.; cited on the attached “Notice of References Cited” form 892). as applied to claims 31, 33-34, 36 and 38-39 as discussed above; and in further view of Wu ("Tumor microenvironment and therapeutic response." Cancer letters 387 (2017): 61-68. Feb. 1, 2017.; cited on the 11/17/2025 “Notice of References Cited” form 892).
Sheu, Buerki, Joyce and Mager are applied to claims 31, 33-34, 36 and 38-39 as discussed above.
Sheu does not explicitly teach the claim limitation of obtaining second RNA expression data for a second biological sample from the subject, the second biological sample obtained from the subject after administration of the at least one anti- cancer therapy to the subject; determining, using the second RNA expression data, second gene group expression levels for the subject corresponding to respective gene groups in the set of gene groups; and determining, using the first gene group expression levels and the second gene group expression levels, efficacy of treating the subject using the at least one anti-cancer therapy of claims 32, and 37; wherein the gene groups associated with cancer malignancy comprise a proliferation rate group, and determining the first gene group expression levels for the subject further comprises determining a gene group expression level for the proliferation rate group using a gene expression level obtained from the first RNA expression data for at least three genes in the proliferation rate group of claims 35 and 40. However, these limitations are taught by Wu.
Regarding claims 32 and 37, Wu teaches the claim limitation of obtaining second RNA expression data for a second biological sample from the subject, the second biological sample obtained from the subject after administration of the at least one anti- cancer therapy to the subject; determining, using the second RNA expression data, second gene group expression levels for the subject corresponding to respective gene groups in the set of gene groups; and determining, using the first gene group expression levels and the second gene group expression levels, efficacy of treating the subject using the at least one anti-cancer therapy with “During cancer therapy, chemotherapeutic agents can elicit a misdirected tissue repair response orchestrated by TAMs [20], which may result in promotion of tumor growth and limitation of anti-tumor efficacy. In vitro and in vivo evidences have showed that TAMs mediate resistance to some chemotherapeutic agents (5-fluorouracil, doxorubicin, gemcitabine, paclitaxel, platinum compounds, etc.) as well as anti-VEGF treatment [21–26]. Moreover, TAMs acquire the ability to produce several suppressive cytokines such as IL-1β, IL-6, IL-10 and TGFβ, thus contributing to T-cell suppression in the TME [15].” (page 62, col. 1, para. 3); “The innate and adaptive immune system is a crucial component of the altered TME following therapy [69]. As mentioned above, TAM abundance may impede therapeutic responses. Diverse mechanisms are involved in the tumor-promoting function of TAMs after therapy: (1) chemotherapy (i.e., paclitaxel) or radiation treatment upregulates colony-stimulating factor 1 (CSF1), IL-34 and chemokine (C-C motif) ligand 2 (CCL2) in tumor cells, leading to increased recruitment of immunosuppressive TAMs and suppressed anti-tumor responses of CD8+ T cells (Fig. 1) [21,70]; (2) chemotherapy (i.e., cisplatin and carboplatin) increases the potency of tumor cells to induce IL-10-producing M2 macrophages [22], and macrophage-derived IL-10 inhibits IL-12 expression in dendritic cells, thus blocking activation of an effective adaptive response [71]; (3) TAMs enhance the tumor initiating capacity of cancer stem cells (CSCs) and protect CSCs from chemotherapy, thereby facilitating the therapeutic resistance [72]; (4) TAM-supplied cathepsins may blunt chemotherapeutic response of cancer cells [26]; and (5) TAMs induce upregulation of cytidine deaminase, which metabolizes the drug following its transport into the cancer cell, thus mediating acquired resistance to chemotherapy [73].” (page 64, col. 1, para. 1); “Several chemotherapeutic agents unexpectedly stimulate production of tumor-derived factors, which lead to expansion of MDSCs, critically causing refractoriness against the treatment. In breast cancer, chemokine (C-X-C motif) ligand 1/2 (CXCL1/2) production by cancer cells attract MDSCs, which secrete S100A8/ A9 that enhances cancer cell survival (Fig. 1). Anthracycline and cyclophosphamide trigger the production of tumor necrosis factor α (TNFα) from stromal cells, thus heightening the CXCL1/2 expression, amplifying the CXCL1/2-S100A8/A9 loop and causing chemoresistance [29]. In animal models and cancer patients, refractoriness to anti-angiogenic therapies based on inhibition of the VEGF pathway is associated with higher numbers of MDSCs or TAMs infiltrating tumor tissues [74,75]. The mechanisms of these myeloid cells facilitating tumor angiogenesis remain incompletely understood. It is conceivable that anti-VEGF treatment upregulates the alternative pro-angiogenic factors (prokineticin 1 and prokineticin 2) production from myeloid cells, unexpectedly leading to limitation of anti-angiogenic efficacy and tumor recurrence (Fig. 1) [76].” (page 64, col. 1, para. 2); and “There is a paracrine signaling network between the adaptive and innate immune systems that is associated with resistance to antitumor therapy. For instance, tumor-infiltrating T helper type 17 (Th17) cells and IL-17 induce the expression of CSF1 in stroma and this in turn attracts MDSCs, which drive anti-VEGF therapy resistance [77]. Chemotherapeutic agents (gemcitabine and 5-fluorouracil) can also activate MDSCs, leading to production of IL-1β, which induces a Th17 response and subsequently blunts the anti-cancer efficacy [78].” (page 64, col. 1, para. 3).
Regarding claims 35 and 40, Wu teaches the claim limitation of wherein the gene groups associated with cancer malignancy comprise a proliferation rate group, and determining the first gene group expression levels for the subject further comprises determining a gene group expression level for the proliferation rate group using a gene expression level obtained from the first RNA expression data for at least three genes in the proliferation rate group with “In short, IL-6 has been viewed as a major cytokine for the proliferation and survival of multiple myeloma cells.” (page 6261, col. 1, para. 2); “The IL-10 autocrine and/or paracrine loop may be important for tumor cell proliferation and survival (110), leading to the up-regulation of anti-apoptotic genes such as B-cell lymphoma 2 (BCL-2) or BCL-XL (111).” (page 6261, col. 2, para. 2); “IL-2 and IL-15 share a number of important properties, including the stimulation of the T-, NK-, and B cell proliferation/maturation (118).” (page 6262, col. 1, para. 2); “Stromal production of IL-15 may contribute to the proliferation of malignant cells in vivo, and IL-15 in turn is able to stimulate the growth of myeloma cells in a way independent of IL-6.” (page 6262, col. 1, para. 4)
It would have been prima facia obvious to combine the teachings of Sheu and Wu to arrive at the claimed invention. A person of ordinary skill in the art would have been motivated to modify the method of Sheu to include obtaining a second RNA expression data from the subject after administration of the anti-cancer therapy as taught by Wu for the benefit of comparing RNA expression data prior to and after the administration of the anticancer therapy for the purpose of accessing the effectiveness of the therapy. A person of ordinary skill in the art would have also been motivated to modify the method of Sheu to include determining a gene group expression level for the proliferation rate group as taught by Wu for the benefit of determining the genes that contribute to the proliferation of malignant cells. Furthermore, there would have been a reasonable expectation of success, since both Sheu and Wu teach methods that pertain to the analysis of genes in the tumor microenvironment.
Response to 35 USC § 103 Remarks received 03/17/2026
Applicant amended claims 21 and 31-40.
It is noted that applicant’s remarks are based on amened claims.
Applicant’s remarks, see pages 10-12, filed 03/17/2026, with respect to the rejection(s) of claim(s) 21-40 under 35 USC § 103 have been fully considered and are persuasive. Therefore, the rejections have been withdrawn. However, upon further consideration, a new ground of rejection is made in view of claim amendments.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/K.K./Examiner, Art Unit 1686
/LARRY D RIGGS II/Supervisory Patent Examiner, Art Unit 1686
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