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 .
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 claims 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.
Status of Claims
Applicant’s amendments to claims filed 06/10/2026 in response to the Non-Final Rejection mailed 03/10/2026 are acknowledged.
Claims 12, 15, and 48 are amended.
Claims 9-10, 25, and 32 have been canceled.
New claims 100-102 are acknowledged.
Claims 12, 15, 17, 21, 27, 33, 36, 40, 44-45, 48, 58, 72-74, 81, and 100-103 are pending and under examination.
Response to Remarks filed 06/10/2026
The amendments and arguments presented in the papers filed 06/10/2026 ("Remarks”) have been thoroughly considered. The issues raised in the Office action dated 03/10/2026 listed below have been reconsidered as indicated.
a) The objections to the specification regarding the use of trade names or marks are withdrawn in view of the amendments to the specification.
b) The 35 USC 112(b) indefiniteness rejections of claims 9-10, 12, 15, 17, 21, 25, 27, 32-33, 36, 40, 44-45, 48, 58, 72-74 and 81 have been withdrawn in view of the amendments to claim 12 and as moot in view of the cancellation of claims 9-10, 25, and 32.
c) The rejection of claims 9 and 10 under 35 U.S.C. 101 are withdrawn as moot in view of the cancellation of the claims.
d) The rejection of claims 9, 10, and 12 under 35 U.S.C. 102(a)(2) as being anticipated by Park (US20220316012; WO2021086068) is withdrawn as moot in view of the cancellation of claims 9 and 10 and in view of the amendments to claim 12.
e) The rejection of claims 12, 15, 17, 21, 27, 33, 36, 40, 44-45, 48, 58, 72-74 and 81 under 35 U.S.C. 103 as being unpatentable over Park in view of Otto (US20170356053) and Swanton (US20210147934) are withdrawn in view of amendments to the claims.
f) The rejection of claims 25 and 32 under 35 U.S.C. 103 as being unpatentable over Park in view of Otto, Swanton, and further in view of Melendez are withdrawn as moot in view of the cancellation of the claims.
New and modified grounds of rejection necessitated by amendment are detailed below and this action is made FINAL.
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.
Claims 12, 15, 17, 21, 27, 33, 36, 40, 44-45, 48, 58, 72-74, 81, and 100-103 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 12 recites the limitation “detecting a presence of a somatic loss of heterozygosity (LOH) of one or more HLA-I genes in a sample comprising nucleic acid from an individual having a squamous cell cancer or a NSCLC”. It is unclear if the sample is required to be from a cancerous tissue, cell or other source from the individual or can instead be from any source from the individual including non-cancerous tissues, cells or other source.
Claim 12 recites the limitations “(b) identifying the individual, based on the presence of the somatic LOH of one or more HLA-I genes detected in the sample, as a candidate to receive a treatment that comprises an immune checkpoint inhibitor.” The claim is indefinite. The claim does not clearly set forth what defines or an individual as a candidate. It is unclear what criteria would determine a “candidate” beyond detecting a presence of somatic LOH of one or more HLA-I genes. It is unclear if a candidate would be expected to have a particular response to receiving a treatment that comprises an immune checkpoint inhibitor.
Claim 12 recites the limitation “(c) administering to the individual an effective amount of a treatment that comprises an immune checkpoint inhibitor”. Step (c) does not require a candidate from step (b) but is directed to the “individual”. Step (c) therefore does not require administering a treatment to an individual identified as a candidate or exclude administering a treatment to an individual with an absence of a somatic loss of heterozygosity (LOH) of one or more HLA-I genes.
Claims 15, 17, 21, 27, 33, 36, 40, 44-45, 48, 58, 72-74, 81, and 100-103 are similarly indefinite because they directly or indirectly depend from claim 12.
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.
Claims 12, 15, 17, 21, 27, 33, 36, 40, 44-45, 48, 58, 72-74, 81, and 100-103 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 a law of nature.
Claim 12 is directed to a method comprising “(a) detecting a presence of a somatic loss of heterozygosity (LOH) of one or more HLA-I genes in a sample comprising nucleic acid from an individual having a squamous cell cancer or a NSCLC” and “(b) identifying the individual, based on the presence of the somatic LOH of one or more HLA-I genes detected in the sample, as a candidate to receive a treatment that comprises an immune checkpoint inhibitor". The claim is directed to a process that involves the judicial exceptions of a law of nature/natural phenomenon (i.e. the natural correlation between the presence of the somatic LOH of one or more HLA-I genes in a sample from an individual and the status of the individual as a candidate to receive a treatment that comprises an immune checkpoint inhibitor). A correlation that preexists in the human is an unpatentable phenomenon.
Claims 15, 17, 21, 27, 33, 36, 40, 44-45, 48, 58, 72-74, 81, and 100-103 directly or indirectly depend from claim 12, and are similarly directed to a natural phenomenon.
Claim 12 also recites the limitation “wherein identifying the individual as a candidate to receive a treatment that comprises an immune checkpoint inhibitor is based on the presence of the somatic LOH of one or more HLA-I genes and the high TMB detected in the sample”. The claim is directed to a process that involves the judicial exceptions of a law of nature/natural phenomenon (i.e. the natural correlation between the presence of the somatic LOH of one or more HLA-I genes and high TMB in a sample from an individual and the status of the individual as a candidate to receive a treatment that comprises an immune checkpoint inhibitor). A correlation that preexists in the human is an unpatentable phenomenon.
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 application of the exception.
While claim 12 additionally recites the active step of “administering to the individual an effective amount of a treatment that comprises an immune checkpoint inhibitor”, the treatment steps do not integrate the judicial exception into a practical application. The steps do not recite any particular treatment that integrates the exception into a new and useful end or directed to a particular condition. Instead, the step recites treatment at a high level of generality(See MPEP 2106.04(d)(2)). Immune checkpoint inhibitors represent a massive genus not limited to a particular type of treatment. Furthermore, the step as written does not require the administering of treatment to an individual identified as a candidate.
Dependent claim 15 additionally recites the steps “amplifying nucleic acids --, capturing a plurality of nucleic acids --- with a bait molecule; sequencing the captured nucleic acids ---; fitting --- values associated with one or more of the plurality of sequence reads to a model; and based on the model, detecting the somatic LOH --- and a relative binding propensity”, these are not integrations of the exception into a practical application. Rather, these steps are data-gathering required to perform the method.
Claims 100 and 101 additionally recite steps “ligating one or more adaptors---” and “detecting a presence of a high tumor mutational burden (TMB)---”. These steps are not integrations of the exception into a practical application. Rather, these steps are data gathering required to perform the method.
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 “amplifying nucleic acids --, capturing a plurality of nucleic acids --- with a bait molecule; sequencing the captured nucleic acids ---; fitting --- values associated with one or more of the plurality of sequence reads to a model; and based on the model, detecting the somatic LOH --- and a relative binding propensity”; “ligating one or more adaptors---” and “detecting a presence of a high tumor mutational burden (TMB)---” are techniques that are routine, conventional, and well-known in the art as demonstrated in the 103 rejections documented below. Additionally, steps directed to “administering” a treatment are cited at a high level of generality and do not require a particular treatment.
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 § 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, 17, 21, 27, 33, 36, 40, 44-45, 48, 58, 72-74, 81, and 101 are rejected under 35 U.S.C. 103 as being unpatentable over Park et al. (US20220316012).
The following are new rejections necessitated by amendments
Regarding claim 12, Park teaches methods for predicting response to immunotherapy, the method comprising obtaining a biological sample (a sample comprising nucleic acid ) from a patient (para 10), preferably, a non-small cell lung cancer patient (para 37). Park teaches calculating a haplotype-specific copy number of the HLA locus using LOH HLA (paras 143, 176) and discriminating somatic mutations (para 135), which reads on “(a) detecting a presence of a somatic loss of heterozygosity (LOH) of one or more HLA-I genes in a sample”.
Park further teaches that individuals with HLA LOH respond to immune checkpoint inhibitor treatment, i.e. show a therapeutic effect (Figs. 5 and 14B), which reads on (b) “identifying the individual, based on the presence of the somatic LOH of one or more HLA-I genes detected in the sample, as a candidate to receive a treatment that comprises an immune checkpoint inhibitor”.
Park teaches a patient group predicted to show a therapeutic effect can be selected and an appropriate treatment can be administered (Abstract) and teaches a cancer treatment may be an immune checkpoint inhibitor (para 46), which reads on (c) “administering to the individual an effective amount of a treatment that comprises an immune checkpoint inhibitor”.
Park does not explicitly teach “identifying the individual, based on the presence of the somatic LOH of one or more HLA-I genes detected in the sample, as a candidate to receive a treatment” as recited in claim 12.
However, 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 modify the teachings of Park to arrive at the instantly claimed invention. Park teaches individuals with the presence of HLA LOH that respond to ICI treatment. One of skill in the art would have been motivated to provide ICI treatment by the therapeutic response of HLA LOH individuals to ICI treatment. Park states that there is no association between HLA LOH alone and an improved response to anti-PD-L1 agent (para 183) compared to HLA intact individuals but does teach that individuals with HLA LOH respond to ICI treatment, thereby identifying them as candidates for treatment. 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 (para 143, 176).
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 carcinoma (para 131).
Regarding claim 45, Park teaches the cancer can be NSCLC (Fig. 5, para 139), which reads on limitation (c): “the squamous cell lung cancer is a non-small cell lung cancer (NSCLC)”.
Regarding claim 48, Park teaches analyzing data from NSCLC patients prior to immunotherapy (para 9), which reads on limitation (c): “the squamous cell cancer or NSCLC was not previously treated with an immune checkpoint inhibitor”.
Regarding claim 58, Park teaches an immune checkpoint inhibitor may be an anti-CTLA-4 inhibitor (para 47), which reads on limitation (d) wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor.
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) “the sample is from a tumor biopsy”.
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).
Regarding claim 101, Park teaches detecting an HLA-corrected TMB (para 149). Park teaches in patients without HLA LOH, NeoAgl and NeoAgC are set to 0 (paras 152-153) for the corrected TMB (Equation 1). Thus, TMB is only ‘corrected’ when a patient has HLA LOH. Park further teaches an association between corrected TMB and response to ICIs in HLA (para 186). Park teaches classifying patients in the high TMB group using a corrected TMB applied to HLA LOH samples (i.e. patients with LOH for HLA genes) (para 188). Park teaches individuals with high HLA-corrected TMB (and lost HLA genes that respond to ICI treatment (Fig. 17A), thus identifying a individuals with high TMB and HLA LOH as candidates to receive a treatment that comprises an immune checkpoint inhibitor.
Claims 15, 21 and 100 are rejected under 35 U.S.C. 103 as being unpatentable over Park et al. (US20220316012) as applied to claims 12, 17, 21, 27, 33, 36, 40, 44-45, 48, 58, 72-74, 81, and 101 above, and further in view of Otto et al. (US20170356053) and Swanton et al. (US20210147934).
The following are new rejections necessitated by amendments
Regarding claim 15, Park teaches detecting HLA LOH frequencies (paras 141, 143, 175). Park further teaches obtaining a nucleic acid sample and amplifying target nucleic acids (para 36); preparing a library, sequencing, and analyzing the reads (para 135).
However, Park does not teach the method recited in claim 15 for detecting somatic LOH of one or more HLA-I genes.
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 comprises: providing 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 137-140). 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).
Neither 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 role 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 21, Otto teaches the method comprises sequencing with next generation sequencing (para 292).
Regarding claim 100, Otto teaches ligating adaptor sequences to 5′ or 3′ end of the nucleic acids in each member of the plurality of members (nucleic acids) (paras 283-285) and amplifying each member of the plurality with a primer specific for the adaptor sequence (paras 286-290), which reads on ligating adaptors before amplifying nucleic acids.
Claims 102 and 103 are rejected under 35 U.S.C. 103 as being unpatentable over Park et al. (US20220316012) as applied to claims 12, 17, 21, 27, 33, 36, 40, 44-45, 48, 58, 72-74, 81, and 101 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 claims 102 and 103, Regarding claims 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), and report TMB as a number of mutations (para 132 for example) but does not define TMB in terms of 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 therapy (p. 661, Abstract). Meléndez teaches that NSCLC patients whose tumors had a high (≥10 mut/Mb) TMB responded well to treatment with immune checkpoint inhibitors (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 with Meléndez to arrive at the instantly claimed invention. The modification would have entailed substituting 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
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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/JESSICA GRAY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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