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. Status of the Claims Claims 1, 3-6, and 9-10 are examined herein. Claim Objections Claims 1, 3-6, and 9-10 are objected to because: Claims 1, 3, 4, 6, and 9-10 contain abbreviations CM, TIM-3, PD-1, TIGIT, 4-1BB, GITR, ICOS, and OX40. These should be completely spelled out in its first occurrence. Claim 5 recites peripheral-blood, should be blood or peripheral blood. Appropriate correction is required. Claim Rejections - 35 USC § 112 The following is a quotation of the first paragraph of 35 U.S.C. 112(a): (a) IN GENERAL. —The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention. The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112: The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention. Claims 1, 3-6, and 9-10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, as failing to comply with the written description requirement. The claim(s) 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, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection. Claims 1, 3-6, and 9-10 are directed to determining expression levels of markers and their combinations: CD69, CM, CD8, CD40L, CD86, TIM-3, CD4, CD69, TIGIT, HLA-DR, CD25, CD71, 4-1BB, GITR, ICOS, OX40, and PD-1 for making a decision on administering an anticancer agent when the measured expression levels are lower than a corresponding predetermined reference value. State of the prior art & level of predictability in the art. Prior art is silent on using the recited markers and their combinations for making a decision on administering an anticancer agent when the measured expression levels are lower than their corresponding predetermined reference values. The level of predictability in the art of biomarkers is low. Level of one of ordinary skill is high with an ordinary practitioner possessing a PhD and related post-doctoral research experience. Amount of direction and examples provided by the inventor – the specification is silent with respect to expression levels of CD69, CM, CD8, CD40L, CD86, TIM-3, CD4, CD69, TIGIT, HLA-DR, CD25, CD71, 4-1BB, GITR, ICOS, OX40, and PD-1 markers expressed in lung cancer patients at lower levels than the corresponding predetermined reference values. The disclosed data are presented in Fig. 1-5 and Examples 1 and 2, but none of the figures or the examples disclose the expression levels of CD69, CM, CD8, CD40L, CD86, TIM-3, CD4, CD69, TIGIT, HLA-DR, CD25, CD71, 4-1BB, GITR, ICOS, OX40, and PD-1 markers. Figure 1: Correlation between the percentage of PD-1+ Tim3+ CD8+ T cells or CM CD8+ T cells among total peripheral blood CD8+ CD3+ T cells and TLS-B cell density in the corresponding tumors. Fig. 1 fails to disclose the comparison of the marker’s expression levels in normal and cancer patients. Figure 2: Correlations between TLS-B cell density and marker expression on TIL CD4+ T cells. Fig. 2 fails to disclose the comparison of the marker’s expression levels in normal and cancer patients. Figure 3: Correlation between TLS-B cell density and specific CD4+ T cell markers in tumors. Fig. 3 fails to disclose the comparison of the marker’s expression levels in normal and cancer patients. Figure 4: Decreased frequencies of CD4+FoxP3+ Tregs in TLS- Bhigh tumors. Fig. 4 fails to disclose the comparison of the marker’s expression levels in normal and cancer patients. Figure 5: High density of TLS-B cells cancels out the negative impact of high Treg density on overall survival. Fig. 5 fails to disclose the marker’s expression levels. Example 1: Determination of the TLS status from peripheral blood (pg. 31, starts on line 15). The results shown in Fig. 1 and table 1 fail to disclose the comparison of the marker’s expression levels in normal and cancer patients. Example 2: Determination of the TLS status based on the quantification of selective tumor-infiltrating CD4+ T cell subsets of NSCLC patients (pg. 33, starts on line 21). The results: A high density of TLS-B cells is associated with a specific intratumor CD4+ T cell gene expression signature - pg. 35, line 21. Data not shown in the specification, fig. 2, or fig. 3. The results of Example 2 fail to disclose the comparison of the marker’s expression levels in normal and cancer patients. Therefore, based on the above findings, one of ordinary skill in the art would conclude that Applicant did not have possession of the claimed invention. Claims 1, 3-6, and 9-10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, as failing to comply with the enablement requirement. The claims contain 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. Enablement requires that the specification teach those in the art to make and use the invention without undue experimentation. Claims 1 and 3-5 recite determining in a sample obtained from said patient expression levels of TIM-3, CD8, and CD4; claims 6 and 9-10 recite determining in a sample obtained from said patient expression levels of TIM-3 and CD4; and then administering an anti-cancer agent to a subject identified as having an expression level lower than a corresponding predetermined reference value. The limitation of having an expression level lower than a corresponding predetermined reference value contradicts the following prior art teachings: Klippel et al . (PGPub 20210171629) teach “TIM3 expression has been associated with many types of chronic diseases, including cancer (e.g., melanoma, lung, liver, ovarian, etc.). High TIM3 expression has been detected in tumor infiltrating lymphocytes (TILs) and some tumors from patients with advanced melanoma, non-small cell lung cancer, or follicular B-cell non-Hodgkin lymphoma” ([0004]). Klippel teaches high TIM-3 expression associated with non-small cell lung cancer. Therefore, there is a contradiction between instant disclosure and the prior art teaching. The specification fails to address this discrepancy. Rittershaus et al . (U.S. Pat. No 5426029) teach that expression levels of CD4 marker in sera of patients with lung cancer either overlap or are higher than those of normal individuals (Col. 19, par. 1 and Fig. 1). This is another contradiction between instant disclosure and the prior art. The specification discloses lower CD4 levels in lung cancer patients and fails to address this discrepancy. Freeman et al . (AU2020204366) teach treating cancer with an anti-PD-l antibody molecule (pg. 37, line 8) and the subject has, or is identified as having, a tumor based on PD- Ll , CD8, and/or lFNy markers. Specifically, “the methods described herein further include identifying a subject based on having a high percentage of cells that are positive for all of PD-L1, CD8, and IFNy . In some embodiments, the subject has, or is identified as having, one, two or more of PD- Ll , CD8, and/or IFNy , and one or more of a lung cancer” (pg. 39, lines 7-10). The high percentage of cells positive for CD8 taught by Freeman is another contradiction not addressed by instant disclosure. Kowanetz et al . (WO 2016183326) teach a method for selecting a therapy for a patient suffering from a non-small cell lung cancer (pg. 3, lines 32-33) and that “the tumor sample obtained from the patient comprises an increased number of CD8+ T-cells relative to a reference tumor sample” (pg. 4, lines 3-4). The increased number of CD8+ T-cells from the patient is another contradiction between instant disclosure and the prior art teaching. The specification discloses lower CD8 levels in lung cancer patients and fails to address this discrepancy. In light of the discrepancies between the disclosure and the prior art, the experimentation needed to practice the invention would have to involve undue experimentation. Based on the above findings, one of ordinary skill in the art would conclude that the specification fails to teach the skilled artisan how to make and use the claimed invention without undue experimentation. The following is a quotation of 35 U.S.C. 112(b): (b) CONCLUSION. —The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention. The following is a quotation of 35 U.S.C. 112 (pre-AIA), second paragraph: The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention. Claims 1, 3, 4, 6, and 9-10 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claims 1 and 6 recite “an expression level” twice in each claim. It is unclear if the claims are referring to an additional expression level or the expression level already recited in each claim. Claims 1 and 6 recite “treating the patient” and “administering an anti-cancer agent to a subject”. The relation between the patient and a subject is unclear. Claims 1 and 6 recite “determining an expression level of a marker and administering an anti-cancer agent to a subject identified as having an expression level lower than a corresponding predetermined reference value” for a patient already suffering from a lung cancer. Even before any expression level is determined, it is known that the patient is already suffering from a lung cancer and therefore needs an anti-cancer treatment. The significance of determining an expression level of a marker in administering an anti-cancer agent is unclear. The determined expression levels are not used in any claim to further specify or fine-tune the treatment that the patient should be receiving. Claims 1, 3, 4, 6, and 9-10 recite markers identifiers followed by plus sign. The plus sign is used to designate a cell phenotype, wherein the phenotype identifier by itself is not a measure of a quantity, while the claims recite markers and quantitative comparisons with reference levels. It is unclear what is actually recited in the claims. Subject Matter Free of the Prior Art Claims 1, 3-6, and 9-10 are free of the prior art. Please, see 112(a) and 112(b) rejections above for details. The prior art does not teach determining expression levels of markers and their combinations: CD69, CM, CD8, CD40L, CD86, TIM-3, CD4, CD69, TIGIT, HLA-DR, CD25, CD71, 4-1BB, GITR, ICOS, OX40, and PD-1 for making a decision on administering an anticancer agent when the measured expression levels are lower than their corresponding predetermined reference values. The closest prior art: Klippel et al . (PGPub 20210171629) teach “TIM3 expression has been associated with many types of chronic diseases, including cancer (e.g., melanoma, lung, liver, ovarian, etc.). High TIM3 expression has been detected in tumor infiltrating lymphocytes (TILs) and some tumors from patients with advanced melanoma, non-small cell lung cancer, or follicular B-cell non-Hodgkin lymphoma” ([0004]). The reference fails to teaches lower TIM-3 expression levels associated with lung cancer. Rittershaus et al . (U.S. Pat. No 5426029) teach that expression levels of CD4 marker in sera of patients with lung cancer overlap or higher than those of normal individuals (Col. 19, par. 1 and Fig. 1). The reference fails to teaches lower CD4 expression levels associated with lung cancer. Freeman et al . (AU2020204366) teach treating cancer with an anti-PD-l antibody molecule (pg. 37, line 8) and the subject has, or is identified as having, a tumor based on PD- Ll , CD8, and/or lFNy markers. Specifically, “the methods described herein further include identifying a subject based on having a high percentage of cells that are positive for all of PD-L1, CD8, and IFNy . In some embodiments, the subject has, or is identified as having, one, two or more of PD- Ll , CD8, and/or IFNy , and one or more of a lung cancer” (pg. 39, lines 7-10). The reference fails to teaches lower CD8 expression levels associated with lung cancer. Kowanetz et al . (WO 2016183326) teach a method for selecting a therapy for a patient suffering from a non-small cell lung cancer (pg. 3, lines 32-33) and that “the tumor sample obtained from the patient comprises an increased number of CD8+ T-cells relative to a reference tumor sample” (pg. 4, lines 3-4). The reference fails to teaches lower CD8 expression levels associated with lung cancer. Conclusion Any inquiry concerning this communication or earlier communications from the examiner should be directed to Alexander Volkov whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (571) 272-1899 . The examiner can normally be reached FILLIN "Work Schedule?" \* MERGEFORMAT M-F 9:00AM-5:00PM (EST) . If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, FILLIN "SPE Name?" \* MERGEFORMAT Bao-Thuy Nguyen can be reached on FILLIN "SPE Phone?" \* MERGEFORMAT (571) 272-0824 . The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center for authorized users only. Should you have questions about access to Patent Center, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). 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) Form at https://www.uspto.gov/patents/uspto-automated- interview-request-air-form. /ALEXANDER ALEXANDROVIC VOLKOV/ Examiner, Art Unit 1677 /REBECCA M GIERE/ Primary Examiner, Art Unit 1677