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. Claims 9-10, 12, 15,17, 21, 25, 27, 32-33, 36, 40, 44-45, 48, 58, 72-74, and 81 are pending and currently under examination. Priority This application 18/570,006 filed on 12/13/2023 is a 371 national phase of PCT/ US2022/073166 filed on 06/24/2022 , and claims the benefit of provisional U.S. Patent Application No. 63/215,356 , filed on 06/25/2021 . The priority date of independent claim s 9 and 10 and independent claim 12 and its dependent claims is determined to be 06/25/2021 , the filing date of provisional U.S. Patent Application No. 63/215,356 . Specification The use of terms which are trade names or marks used in commerce (including IIlumina ® , PacBio® , Roche 454 TM among others), has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. Claim Interpretation Claim 15 include s the term “optionally” to describe “ ligating one or more adaptors onto one or more nucleic acids from the plurality of nucleic acids ”. Claim scope is not limited by claim language that makes optional but does not require specific structural features. MPEP 2111.04. Claim 32 recites “ the squamous cell cancer or NSCLC has a tumor mutational burden ”. Other claims, including claim 12, which claim 32 depends from , recites the limitation “TMB”. It is suggested that terms be used consistently throughout the claims. 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. 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. Claim s 9-10, 12, 15,17, 21, 25, 27, 32-33, 36, 40, 44-45, 48, 58, 72-74, and 81 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. Claim 9 recites the limitation “ (b) responsive to said knowledge, administering to the individual an effective amount of a treatment that comprises an immune checkpoint inhibitor ”. It is unclear what steps are taken to determine the appropriate immune checkpoint inhibitor treatment or what correlation there is between treatment selection and “( i ) a somatic LOH of one or more HLA-I genes, or ( ii) a somatic LOH of one or more HLA-I genes and a high TMB”. Claims 9, 10, 12, 15 recite the limitation “ a sample ” from an individual . It is unclear what criteria define a sample from an individual. It is unclear if the sample is intended to be a cell type, tissue, or other source from the individual. Claims 15,17, 21, 25, 27, 32-33, 36, 40, 44-45, 48, 58, 72-74, and 81 are similarly indefinite because they directly or indirectly depend from claim 12. Claim 10 recites the limitation “ responsive to acquiring knowledge --- administering to the individual an effective amount of a treatment that comprises an immune checkpoint inhibitor ”. It is unclear what steps are taken to determine the appropriate immune checkpoint inhibitor treatment or what correlation there is between treatment selection and “( i ) a somatic LOH of one or more HLA-I genes, or ( ii) a somatic LOH of one or more HLA-I genes and a high TMB”. Claim 12 recites the limitation “ administering to the individual an effective amount of a treatment that comprises an immune checkpoint inhibitor ”. It is unclear what steps are taken to determine the appropriate immune checkpoint inhibitor treatment or what correlation there is between treatment selection and “( i ) a somatic LOH of one or more HLA-I genes, or ( ii) a somatic LOH of one or more HLA-I genes and a high TMB”. Claim Rejections - 35 USC § 101 35 U.S.C. 101 reads as follows: Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title. Claim FILLIN "Pluralize the word 'Claim' if necessary and then identify the claim(s) being rejected." 9 and 10 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. 35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p] henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106, part II. Based upon consideration of the claims as a whole, as well as consideration of elements/steps recited in addition to the judicial exception, the present claims fail to meet the elements required for patent eligibility. Step 1 The claimed invention is directed to the statutory category of a process. Step 2A, Prong One The claims are taken to be directed to an abstract idea, a judicial exception. Claim 9 i s directed to a method comprising “ acquiring knowledge of: ( i ) a somatic LOH of one or more HLA-I genes, or (ii) a somatic LOH of one or more HLA-I genes and a high TMB, in a sample from an individual having a squamous cell cancer or a NSCLC ” . This limitation is an abstract mental process (see MPEP 2106.04(a)(2)(III)). As written, the acquiring knowledge step e ncompasses the mental step of reading a report of patient data . Claim 10 is directed to a method comprising “responsive to acquiring knowledge of: ( i ) a somatic LOH of one or more HLA-I genes, or (ii) a somatic LOH of one or more HLA-I genes and a high TMB, in a sample from an individual having a squamous cell cancer or a NSCLC, administering --- ”. This limitation is an abstract mental process (see MPEP 2106.04(a)(2)(III)). As written, the acquiring knowledge step e ncompasses the mental step of reading a report of patient data . Furthermore, “responsive to” encompasses evaluating and making a mental judgment based on reading a report. Step 2A, Prong Two The exception is not integrated into a practical application of the exception. The claims do not recite any additional elements that integrate the exception into a practical a pplication of the exception. While claims 9 and 10 additionally recite the active step of ” a dministering to the individual an effective amount of a treatment that comprises an immune checkpoint inhibitor”, the treatment steps do not integrat e the judicial exception into a practical application. The claims do not include a step of administering a particular agent to the subject to treat a particular disease after determining that the subject having a disease will be responsive to that particular agent. See MPEP 2106.04(d)(2) . Furthermore claims 9 and 10 direct that the administering occurs “responsive to said knowledge”. Such limitation amounts to no more than a mere instruction to apply the treatment (See MPEP 2106.05(f)). Step 2B The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception. The claim does not add a specific limitation other than what is well-understood, routine, and conventional in the field. Steps directed to “administering” immune checkpoint inhibitors are techniques that are routine, conventional, and well-known in the art as demonstrated in the 102 and 103 rejection s documented below. Furthermore, the courts have recognized the following laboratory techniques as well-understood, routine, conventional activities in the life science arts when they are claimed in a merely generic manner or as insignificant extra-solution activity: Detecting DNA or enzymes in a sample, Sequenom , 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017); Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs. Ltd., 818 F.3d at 1377; 118 USPQ2d at 1546; For these reasons, the claims are rejected under section 101 as being directed to non-statutory subject matter. Claim Rejections - 35 USC § 102 In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless – (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention. (a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention. Claim(s) 9, 10, and 12 is/are rejected under 35 U.S.C. 102 FILLIN "Insert either \“(a)(1)\” or \“(a)(2)\” or both. If paragraph (a)(2) of 35 U.S.C. 102 is applicable, use form paragraph 7.15.01.aia, 7.15.02.aia or 7.15.03.aia where applicable." \d "[ 2 ]" (a)(2) as being FILLIN "Insert either—clearly anticipated—or—anticipated—with an explanation at the end of the paragraph." \d "[ 3 ]" anticipated by FILLIN "Insert the prior art relied upon." \d "[ 4 ]" Park et al. (US20220316012 , published 10/16/2022, filed 10/29/2020 ; WO2021086068 published 05/06/2021 ) . Regarding claim 9 , Park teaches determining NSCLC patients with HLA LOH and high TMB (Fig. 5) (acquiring knowledge), and using that information (responsive to the knowledge) to select an appropriate treatment ( a (ICI) n effective amount of a treatment ) (Abstract), including an immune checkpoint inhibitor (para 5). Park further teaches that somatic mutations can be discriminated (para 135), and further that somatic mutations are important in determining response to ICIs (para 223). Regarding claim 10 , Park teaches determining NSCLC patients with HLA LOH and high TMB (Fig. 5) (acquiring knowledge), and using that information (responsive to the knowledge) to select an appropriate treatment ( an effective amount of a treatment ) (Abstract), including an immune checkpoint inhibitor (para 5). Park further teaches that somatic mutations can be discriminated (para 135), and further that somatic mutations are important in determining response to ICIs (para 223). Regarding claim 12 , , Park teaches determining NSCLC patients with HLA LOH and high TMB (Fig. 5) (acquiring knowledge), and using that information (responsive to the knowledge) to select an appropriate treatment ( an effective amount of a treatment ) (Abstract), including an immune checkpoint inhibitor (para 5). Park further teaches that somatic mutations can be discriminated (para 135), and further that somatic mutations are important in determining response to ICIs (para 223). Claim Rejections - 35 USC § 103 In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action: A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made. Claims 12, 15, 17, 21,27, 33, 36, 40, 44-45, 48, 58, 72-74 and 81 are rejected under 35 U.S.C. 103 as being unpatentable over Park et al. (US20220316012 ) in view of Otto et al. ( US 20170356053 ) and Swanton et al. (US 20210147934 ) . The teachings of Park as they relate to claim 1 2 are stated in the 102 rejection above in this office action. Regarding claim 15, Park teaches detecting HLA LOH frequencies, but does not teach the claim ed method of claim 15. Otto is directed to a method of analyzing nucleic acids from tumor samples , including NSCLC (paras 3 and 727). Otto teaches a method for hybridization of sample nucleic acid to a bait set to evaluate a region of interest (para 5, Fig. 1 ) . Otto teaches performing the method on exemplary genes including HLA-A (Table 5B), and that the method may be used to assess loss-of-heterozygosity (LOH) (para 363, 780). The method compri ses : p roviding a plurality of nucleic acids (para 536), amplifying each member of the plurality of selected members (para 8), contacting the library with a bait set ( i.e. a bait molecule (paras 520, 681), to provide a plurality of selected members (para 8). The bait set hybridizes with a sequence or allele (para 137-1 40 ). The method further comprises sequencing with next generation sequencing (para 292). Otto states that use of the bait hybridization for sequencing allows specific targets to be selected for sequencing and allows the level and depth of sequence coverage to be adjusted (para 512), enabling the method to achieve a sequencing depth necessary for assessing loss of heterozygosity (para 363). N either Park nor Otto teach fitting, by one or more processors, one or more values associated with one or more of the plurality of sequence reads to a model; and based on the model, detecting the somatic LOH of one or more HLA-I genes and a relative binding propensity for an HLA allele of the HLA-I gene. Swanton is directed to a method for analyzing HLA alleles in tumors . Swanton teaches determining the HLA profile of an individual using sequencing and processing using a prediction algorithm, i.e. fitting to a model (para 43). Swanton further states that the sequence information may be obtained by standard nucleic acid sequencing methods (para 41). Swanton does not explicitly teach using processors to detect somatic HLA LOH, but states that determining HLA LOH uses four computational steps (para 351) . Swanton further teaches that the determination of HLA LOH is determined in tumor BAM files (i.e. reads from somatic cells) vs. germline (paras 351-352). Swanton also teaches binding predictions by particular HLA alleles using algorithms (para 75). It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Park with Otto and Swanton to arrive at the instantly claimed invention. The modification would have first entailed using the method of Otto to obtain information regarding HLA alleles in a sample from NSCLC patients. One would have been motivated to do so for the added benefits of depth, sensitivity and accuracy as taught by Otto (para 1418, 1434). The modification would further have entailed using the method of Swanton to analyze the reads of Otto to produce the data for Park to interpret. Park teaches the importance of systematically determining the roll of HLA in tumors (para 5) and provides a method for a simple convenient and accurate determination of HLA specific copy number loss (para 7) as well as established methods for predicting binding of alleles, an important factor for interpreting allele data. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art. Regarding claim 17 , Park teaches calculating copy number of the HLA locus (pa r a 143 , 176 ) . Regarding claim 21 , Otto teaches t he method comprises sequencing with next generation sequencing (para 292). Regarding claim 27, Park teaches NSCLC patients who are PD-L1 positive (Fig. 5). Regarding claim 33 , Park teaches NSCLC patients that do not comprise a mutation in EGFR (Fig. 5 and Table 1). Regarding claim 36 , Park teaches analyzing NSCLC patients with advanced NCSLC (para 213). Regarding claim 40 , Park teaches the cancer can be lung cancer (para 37). Regarding claim 44 , Park teaches the cancer can be lung squamous cell carcinom a (para 131). Regarding claim 45 , Park teaches the cancer can be NSCLC (Fig. 5, para 139), which reads on limitation (c). Regarding claim 48 , Park teaches analyzing data from NSCLC patients prior to immunotherapy (para 9), which reads on limitation (e). Regarding claim 58 , Park teaches an immune checkpoint inhibito r may be an anti-CTLA-4 inhibitor (para 47), which reads on limitation (d). Regarding claim 72 , Park teaches collecting biopsy tissue samples from NSCLC patients (para 129). Regarding claim 73 , Park teaches collecting biopsy tissue samples, which comprise cells, from NSCLC patients (para 129). Regarding claim 74 , Park teaches collecting biopsy tissue samples from \NSCLC patients (para 129), which reads on limitation (b). Regarding claim 81 , Park teaches taking samples from patients (para 129), and refers to cancer immunotherapy in the context of the method as activating the immune system of a human body (para 4). Claim(s) 25 and 32 is/are rejected under 35 U.S.C. 103 as being unpatentable over Park et al. (US20220316012 ) in view of Otto et al. (US 20170356053 ) and Swanton et al. (US 20210147934 ) as applied to claim s 15,17,21,27,33,36,40,44-45,48,58,72-74 and 81 above, and further in view of Meléndez et al. (Methods of measurement for tumor mutational burden in tumor tissue. Trans Lung Cancer Res. 2018 Dec;7(6):661-667; on IDS dated 05/01/2024). Regarding claim s 25 and 32 , Park teaches classifying the patients as a “high TMB group” or a “low TMB group” using a determined TMB cutoff (para 51) but does not define TMB in terms of mut/Mb . Neither Park, Otto or Swanton teach a high TMB comprises a TMB of at least about 10 mutations/ megabase (mut/Mb) (claim 25), or the squamous cell cancer or NSCLC has a tumor mutational burden of at least about 10 mut/Mb. Meléndez teaches methods for measuring TMB, and states that high tumor mutational burden (TMB) has been identified as a genetic signature that is associated with a favorable outcome for immune checkpoint inhibitor therap y (p. 661, Abstract). Meléndez teaches that NSCLC patients whose tumors had a high (≥10 mut/Mb) TMB responded well to treatment with immune checkpoint inhibitor s (p. 662, col. 2). It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Park, Otto and Swanton with Meléndez to arrive at the instantly claimed invention. The modification would have entailed s ubstituting previously known definition of high TMB taught by Meléndez as the high TMB definition of Park. One would have been motivated by the convenience of using a recognized standard. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art. Conclusion Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT JESSICA GRAY whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (571)272-0116 . The examiner can normally be reached FILLIN "Work Schedule?" \* MERGEFORMAT Monday-Friday 8-5 with second Fridays off . 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, FILLIN "SPE Name?" \* MERGEFORMAT WINSTON SHEN can be reached at FILLIN "SPE Phone?" \* MERGEFORMAT (571)272-3157 . 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. /JESSICA GRAY/ Examiner, Art Unit 1682 /WU CHENG W SHEN/ Supervisory Patent Examiner, Art Unit 1682