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
Claim set received 08 May 2026 has been entered into the application.
Claims 2, 6-7, 10-11, 13-16, 27-42, 46-47, 49-54, 56-100, 102-108, and 110-117 are previously cancelled.
Claim 3 is cancelled.
Claims 1, 4-5, 8-9, 12, 17-21, 26, 43, 45, 48, and 55 are pending.
Election/Restrictions
Claims 101 and 109 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 15 September 2025.
Applicant has elected Group I.
Applicant elected cancer as a species, and elected ten microsatellite species from Table 5 [Specification 0041].
Thus, claims 1, 3-5, 8-9, 12, 17-21, 26, 43, 45, 48, and 55 are pending.
Priority
This Application is a 371 of PCT/US2021/038672 filed 23 June 2021 which claims benefit to U.S Provisional Application 63/044,029 filed 25 June 2020.
Information Disclosure Statement
It is noted that copies of NPL Citation No’s. 6-7 from the IDS filed 07 January 2025 (9 pages) were located. An updated 1449 has been provided.
The listing of references in the specification [pages 187-190] is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Rejections - 35 USC § 112
35 USC § 112(b)
The rejection of claim 1, 3-5, 8-9, 12, 17-21, 26, 43, 45, 48, and 55 under 35 U.S.C § 112(b) in the Office Action mailed 13 February 2026 is withdrawn in view of the amendments received 08 May 2026.
The rejection of claim 3 under 35 U.S.C § 112(b) in the Office Action mailed 13 February 2026 is withdrawn in view of the amendments received 08 May 2026 because claim 3 as cancelled.
Claim Rejections - 35 USC § 101
The instant rejection is maintained for reason for record in the Office Action mailed 13 February 2026 and modified in view of the amendments filed 08 May 2026. It is noted the amendments received 08 May 2026 are necessitated by new ground(s) of rejection.
The rejection of claim 3 under 35 U.S.C § 112(b) in the Office Action mailed 13 February 2026 is withdrawn in view of the amendments received 08 May 2026 because claim 3 as cancelled.
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 1, 4-5, 8-9, 12, 17-21, 26, 43, 45, 48, and 55 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
Following the flowchart of the MPEP 210
Step 1 - Process, Machine, Manufacture or Composition
Claims 1, 4-5, 8-9, 12, 17-21, 26, 43, 45, 48, and 55 are directed to a method, so a process.
Step 2A Prong One:
Law of Nature/Natural Phenomenon
Claim 1 recites the correlation between a patient’s cancer MSI statuses (i.e., patients nucleic acid variation) and patient’s cancers’ therapy administration response which encompasses a natural relationship between a patient’s MSI genotype and the patient’s response to the administration of a medication (i.e., checkpoint and non-checkpoint inhibitors). See MPEP 2106.04(b)(I)(i, v, and xi).
Identification of an Abstract Idea
Claim 1 recites:
(b) processing the microsatellite instability data to output a categorical measure of microsatellite instability high (MSI-H) or microsatellite stable (MSS)
This step can be performed in the human mind by organizing information (i.e., microsatellite instability data) to output measure of microsatellite instability high (MSI-H) or microsatellite stable (MSS) and is therefore an abstract idea.
processing step comprising applying a quantitative model relating the predictive capability of the markers in the set or a subset thereof to known MSI status
This step can encompasses using mathematical concepts (i.e., quantitative models [Spec page 172 78-81]) for processing microsatellite instability data to output a categorical measure which reads on abstract ideas. This step encompasses applying a mathematical model to microsatellite instability data to output a categorical measure reads on performing calculations microsatellite instability data to output a categorical measure which reads on abstract ideas. See MPEP 2106.04(a)(2)(I)(C). This step encompasses taking existing information (i.e., nucleic acid microsatellite data), manipulating the information via mathematical function/correlation (i.e., quantitative model), and organizing the data into a new form (i.e., output a categorical measure). See MPEP 2106.04(a)(2)(A)(iv)
wherein when the subject's cancer is determined to exhibit MSI-H, it is predicted that the cancer will respond to checkpoint inhibitor immunotherapy
This step can be performed in the human mind by observing and evaluating a subject’s cancer MSI-H status for predicting whether the cancer will respond to checkpoint inhibitor and is therefore an abstract idea.
when the subject's cancer is determined to exhibit MSS, it is predicted that the cancer is less likely to respond to checkpoint inhibitor immunotherapy
This step can be performed in the human mind by observing and evaluating a subject’s cancer MSS status for predicting whether the cancer will less likely respond to checkpoint inhibitor and is therefore an abstract idea.
Claim 43 recites:
administering a cancer therapeutic to the subject selected based on the determined microsatellite instability statues, wherein the cancer therapeutic is a checkpoint inhibitor when the microsatellite instability status is MSI-H, and the cancer therapeutic is a non-checkpoint inhibitor when the microsatellite instability status is MSS
This step can be performed in the human mind by observing, comparing, and evaluating determined microsatellite instability data to administer a cancer therapeutic and is therefore an abstract idea. This step can be performed in the human mind by observing and evaluating the MSI-H status to administer a checkpoint inhibitor and is therefore an abstract idea. This step can be performed in the human mind by observing and evaluating the MSS status to administer a non-checkpoint inhibitor and is therefore an abstract idea.
Claims 4-5, 8-9, 12, 17-21, 26, 44, and 55 are further drawn to limitations that describe the abstract ideas of claim 1 and are therefore also abstract ideas.
Step 2A Prong Two - Consideration of Practical Application
Claims 1 does not recite any additional element which integrates the recited judicial exception into a practical application. It is noted that under Broadest Reasonable Interpretation (BRI), the recitation of the checkpoint and non-checkpoint inhibitors is interpreted as a prediction response to a specific medication and not administering steps, for example. Here, in the instant case, claim 1 merely set forth a method of data analysis for processing microsatellite instability data to output categorical measures (i.e., MSI-H and MSS) for predicting whether a subject’s cancer exhibits MSI-H and responds to checkpoint inhibitor immunotherapy and predicting whether subject’s cancer exhibits MSS and is less likely to respond to check point inhibitor therapy. As such, practicing the claims merely results processing information (i.e., microsatellite instability data) to output categorical measures (MSI-H and MSS). Such a result only produces information and does not provide for a practical application in the physical-world realm of physical things and acts, i.e., the claims do not utilize the data generated by the judicial exception to affect any type of change. See MPEP 2106.04(a)(2)(A)(iv). Furthermore, claim 1 requires a determined exhibition of MSI-H and/or MSS. However, claim 1 does not encompass any steps for determining exhibited MSI-H or MSS statuses such that the statuses are predictive cancer therapies (i.e., checkpoint inhibitors) responses which also does not provide further limitations (e.g., analysis steps) that integrate the recited judicial exception into a practical application. Therefore, the claim does not utilize the categorized information (i.e., microsatellite instability data) and the abstract ideas to construct a practical application such as treating a subject, transforming matter, or improving upon an existing technology.
Claim 43 recites a method for treating cancer in a subject comprising determining microsatellite instability in cells of a subject’s cancer by method of claim 1.
Additionally, claim 43 recites administering checkpoint inhibitor based on the determined microsatellite stability… when the microsatellite instability status is MSI-H administer a checkpoint inhibitor and/or when the microsatellite instability status is MSS administer a non-checkpoint inhibitor. However, the particular treatments (i.e., checkpoint inhibitors of claim 45 and non-checkpoint inhibitors of claim 48) of claim 43 are not integrated into a practical application because the limitations of claim 43 are conditional. The claim recites administering only based on microsatellite stability “when” MSI-H or MSS is determined. See MPEP 2111.04 Contingent Limitations. The clam does not recite concretely determining either MSI-H or MSS and then administering a treatment. The claim currently encompasses an embodiment where neither MSI-H or MSS are determined which would result in no treatment being administered. Therefore, this type of recitation is equivalent to the words "apply it". See MPEP 2106.05(f).
This judicial exception is not integrated into a practical application because the claims do not meet any of the following criteria:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field;
an additional element that applies or uses a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
an additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
an additional element effects a transformation or reduction of a particular article to a different state or thing; and
an additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception.
Step 2B - Consideration of Additional Elements and Significantly More
The claimed method also recites "additional elements" that are not limitations drawn to an abstract idea.
The recited additional element of data gathering (i.e., receiving microsatellite instability data) of claim 1 step (a) does not add significantly more than the recited judicial exception because receiving data that is subsequently analyzed by the abstract ideas is deemed an extra-solution activity. See MPEP 2106.05(g).
The recited additional element of administering medications of claim 43 does not add significantly more than the recited judicial exception because administering medications is deemed routine and conventional.
The recited additional element of medications of checkpoint inhibitors of claims 45 and non-checkpoint inhibitors of 48 does not add significantly more to the recited judicial exception because using medications to prevent and/or treat disease/conditions is deemed routine and conventional. See MPEP 2106.05(d)(II). To provide evidence of conventionality of using checkpoint inhibitors Xiao et al. (Xiao) disclose using immune checkpoint inhibitors ipilimumab, nivolumab, pembrolizumab, atezolizumab, and avelumab [Xiao, claim 50]. To provide conventionality of using non-checkpoint inhibitors, Xiao discloses using the non-checkpoint inhibitor therapies oxaliplatin [page 120 table 11] and trametinib and dabrafenib [page 121 00335]. (WO 2018/175501, Pub Date: 27 September 2018).
In conclusion, and when viewed as a whole, these additional claim element(s) do not provide meaningful limitation(s) to transform the abstract idea recited in the instantly presented claims into a patent eligible application of the abstract idea such that the claim(s) amounts to significantly more than the abstract idea itself. Therefore, the claim(s) are rejected under 35 U.S.C. 101 as being directed to non-statutory subject matter.
Response to Arguments
Applicant's arguments filed 13 February 2026 have been fully considered but they are not persuasive.
The Applicant points to the Office Action filed 13 February 2026 page 9 paragraphs 37-39 for guidance. The Applicant states the administrating a checkpoint inhibitor of claim 43 cannot be performed in human mind. Similarly, the Applicant states that administering a non-checkpoint into inhibitor not a step that can be performed in the human mind [remarks, page 15].
In response, and as noted in Step 2A Prong II of the 101 analyses above, the administration of the checkpoint and non-checkpoint inhibitors are based on conditional statements. Here, although the claim was amended, the claim language still encompasses the meaning as previous claim 43 of the claim set filed 15 September 2025. Thus, the previous rationale for the rejection remains applicable. As such, the particular treatments (i.e., checkpoint inhibitors of claim 45 and non-checkpoint inhibitors of claim 48) of claim 43 are not integrated into a practical application because the limitations of claim 43 are conditional. The claim recites administering only based on microsatellite stability “when” MSI-H or MSS” is determined. See MPEP 2111.04 Contingent Limitations. The clam does not recite concretely determining either MSI-H or MSS and then administering a treatment. The claim currently encompasses an embodiment where neither MSI-H or MSS are determined which would result in no treatment being administered. Therefore, this type of recitation remains equivalent to the words "apply it". See MPEP 2106.05(f).
This Applicant points to MPEP 2106.04(a)(2)(III) for guidance. The Office has not shown how the quantitative models of instant claim 1 are abstract ideas [remarks, page 15-16].
In response, and as noted in Step 2A Pong II above, the quantitative model for processing microsatellite instability data to output a categorical measure reads on abstract ideas (i.e., claim 4, quantitative models [Spec page 172 78-81]). This step encompasses applying a mathematical model to microsatellite instability data to output a categorical measure reads on performing calculations microsatellite instability data to output a categorical measure which reads on abstract ideas. See MPEP 2106.04(a)(2)(I)(C). This step encompasses taking existing information (i.e., nucleic acid microsatellite data), manipulating the information via mathematical function/correlation (i.e., quantitative model), and organizing the data into a new form (i.e., output a categorical measure). MPEP 2106.04(a)(2)(A)(iv).
The Applicant states the additional elements individually and in combination amount to significantly more and the claims provide an improvement to technology. The Applicant states the instant methods demonstrate that for at least 11 different cancer types, and as few one to seven tissue-specific markers can achieve 95% or greater sensitivity or specificity in diagnosing MSI (see e.g., par. [0005]). claimed methods provide an improvement to the technical field of determining MSI status, wherein MSI status can be determined by fewer markers than a person of skill in the art would expect from the prior art [remarks, page 16].
In response, the argument is not persuasive because in view light of the specification the claims are merely drawn to gathering and analyzing information (i.e., nucleic acid microsatellite data using conventional clinical and data analysis techniques (i.e., quantitative models) and displaying the result (i.e., cancer exhibiting MSI-H and MSS statuses). See MPEP 2106.05(a)(II)(iii). Furthermore, claim 1 is drawn to analyzing DNA to provide sequence information for detecting allelic variants (i., microsatellite statuses). See MPEP 2106.05(d)(II)(v). Here, the claims are drawn to nucleic acid analysis for detecting genetic variants (i.e., MSI-H or MSS) for administering a cancer therapeutic with no indication in the instant specification that claimed method identifies a technical problem and explains the details of an unconventional technical solution expressed in the claim, or identifies technical improvements realized by the claim over the prior art (i.e., using MSI biomarkers for predicting response to checkpoint immunotherapy) for administering a cancer therapeutic.
Claim Rejections - 35 USC § 103
The instant rejection is maintained for reason for record in the Office Action mailed 13 February 2026 and modified in view of the amendments filed 08 May 2026. It is noted the amendments received 08 May 2026 are necessitated by new ground(s) of rejection.
The rejection of claim(s) 1, 9, 12, 26, 43-45, 48, and 55 under 35 U.S.C. 103 as being unpatentable over Xiao et al. (WO 2018/175501, Pub Date: 27 September 2018) in view of Van Velzen et al. (Cancer treatment reviews, 2020-06, Vol.86, p.102024, Article 102024) in the Office Action mailed 13 February 2026 is withdrawn in view of the amendments filed 08 May 2026.
The rejection of claim(s) 3-4 under 35 U.S.C. 103 as being unpatentable over Xiao in view of Van Velzen, as applied to claims 1, 9, 12, 26, 43-45, 48, and 55, and in further view of Johnson et al. (Patent Pub: US 2019/0108312, Pub Date: 11 April 2019) in the Office Action mailed 13 February 2026 is withdrawn in view of the amendments filed 08 May 2026.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 4, 26, 43-45, 48, and 55 are rejected under 35 U.S.C. 103 as being unpatentable over Xiao et al. (WO 2018/175501, Pub Date: 27 September 2018) in view of Van Velzen et al. (Cancer treatment reviews, 2020-06, Vol.86, p.102024, Article 102024) in view of Johnson et al. (Patent Pub: US 2019/0108312, Pub Date: 11 April 2019).
Claim 1 (a) receiving microsatellite instability data for a defined set of microsatellites repeat marker sequences in cells of the subject's cancer.
Claim 1 (b) processing the microsatellite instability data to output a categorical measure of microsatellite instability high (MSI-H) or microsatellite stable (MSS).
Claim 1 (b) recites the processing step comprising applying a quantitative model relating the predictive capability of the markers in the set or a subset thereof to known MSI status;
Claim 1 recites when the subject's cancer is determined to exhibit MSI-H, it is predicted that the cancer will respond to checkpoint inhibitor immunotherapy.
Claim 1 recites when the subject's cancer is determined to exhibit MSS, it is predicted that the cancer is less likely to have a decreased response to checkpoint inhibitor immunotherapy as compared to a subject determined to exhibit MSI-H.
Xiao et al. (Xiao) disclose using sample from cancer patients [Xiao, claim 21]. Xiao discloses the cancer can be Non-Small Cell Lung Cancer (NSCLC) [Xiao, claims 23 and 61]. Xiao discloses using 11,348 patients sequenced tumor data [Xiao, page 158 para 00457]. Xiao teaches determining profiles using an immunoassay [Xiao, claim 43] [Instant Specification top of page 4 para 0016]. Xiao discloses using a 592-gene sequencing panel of the genes of tables 7-10 [Xiao, page 158 para 00457; Tables 7-10 pages 112-119]. Xiao discloses using a MISA algorithm to identify 8,921 microsatellite locations by analyzing 592 microsatellite loci target NGS panel and finding 7,317 target microsatellite loci [Xiao, page 159 para 00463]. Xiao discloses examining the 7,317 target microsatellite loci and comparing them to reference genome hg19 [Xiao, page 220 para 00464], as in instant claim 1 step (a). Here, although Xiao does not explicitly disclose “receiving” microsatellite instability data, Xiao discloses examining the microsatellite data from patient tumor samples and analyzing the data with a MSIA algorithm which suggests that microsatellite data of a patient’s cancer was received/inputted into a system for subsequent analysis.
Xiao discloses a process for using NGS for the 592-gene panels and examining and comparing the 7,317 target microsatellite loci to human reference genome hg19. Xiao discloses examining microsatellite loci data and comparing the data to thresholds and calibrating the data based on comparison of total number of altered loci per patient to MSI-F for maximizing sensitivity while maintaining an appropriately high specificity, positive predictive value (PPV), and negative predictive value (NPV). [Xiao, page 220 para 00464]. Xiao discloses classifying cancers as MSS, MSI-Low, or MSI-H based on the calibrated thresholds of altered microsatellite loci [Xiao, page 220 para 00465], as in instant claim 1 (b) processing the microsatellite instability data to output a categorical measure of microsatellite instability high (MSI-H) or microsatellite stable (MSS).
Xiao discloses identifying a potential benefit from an immune checkpoint when the biological sample is MSI-High [Xiao, claim 47]. Xiao [disclosure page 132, para 00359 above para 00360] discloses “The indication whether each treatment is likely to benefit the patient, not benefit the patient, or has indeterminate benefit may be weighted. For example, a potential benefit may be a strong potential benefit or a lesser potential benefit. Such weighting can be based on any appropriate criteria, e.g., the strength of the evidence of the biomarker treatment association, or the results of the profiling, e.g., a degree of over- or under expression.” Here, under Broadest Reasonable Interpretation (BRI), the term “potential benefit” is interpreted as a response or “therapy response” because, as noted in the example above, the treatment is likely to have benefit, have intermediate benefit, or have no benefit which reads on whether the patients’ cancer’s response to the therapy (i.e., checkpoint and/or non-checkpoint inhibitor) is objectively (i.e., use of clinical/laboratory methods) beneficial or not. Xiao discloses monitoring the effectiveness of treatment using complete response (CR), partial response, stable disease (SD), and progressive disease (PD) categories. Xiao discloses identifying the biological sample as microsatellite stable (MSS) if the number of altered microsatellite loci are below a threshold [Xiao, claim 30]. Additionally, the specification discloses molecular profiling results in a complete or partial response [specification, page 76 0253], as instant claim 1 step (b) when the subject's cancer is determined to exhibit MSI-H, it is predicted that the cancer will respond to checkpoint inhibitor immunotherapy.
Dependent claims 26, 43-45, and 48.
Xiao discloses examining the 7,317 target microsatellite loci and comparing them to reference genome hg19 [Xiao, page 220 para 00464], as in claim 26.
Xiao discloses identifying the biological sample status as MSI-H [Xiao, claim 1 step (d)]. Xiao discloses identifying at least one therapy based on the MSI status [Xiao, claim 81 steps (i-ii)]. Xiao discloses the therapy is an immune checkpoint inhibitor [Xiao, claim 52]. Xiao discloses identifying the biological sample as microsatellite stable (MSS) [Xiao, claim 30]. Xiao discloses using the non-checkpoint inhibitor therapies: oxaliplatin [page 120 table 11] and trametinib and dabrafenib [page 121 00335]. Xiao discloses administering at least one therapy [Xiao, claim 59], as in instant claim 43. Therefore, it is obvious that if MSI-H status was determined a checkpoint inhibitor would be administered. It is further obvious that if MSS status was determined a non-checkpoint inhibitor could be utilized.
Xiao discloses the molecular profile can comprise PD-L1 [Xiao, claim 42], as in instant claim 44.
Xiao discloses the immune checkpoint inhibitor therapy is selected from ipilimumab, nivolumab, pembrolizumab, atezolizumab, and avelumab [Xiao, claim 50], as in instant claim 45.
Xiao discloses using the non-checkpoint inhibitor therapies: oxaliplatin [page 120 table 11] and trametinib and dabrafenib [page 121 00335], as in instant claim 48.
Xiao does not teach:
Xiao does not teach claim 1 (b) the processing step comprising applying a quantitative model relating the predictive capability of the markers in the set or a subset thereof to known MSI status.
Xiao does not teach claim 1 (b) when the subject's cancer is determined to exhibit MSS, it is predicted that the cancer is likely to have a decreased response to checkpoint inhibitor immunotherapy as compared to a subject determined to exhibit MSI-H.
Xiao does not teach claim 4.
Van Velzen
Van Velzen et al. (Van Velzen) teaches immune checkpoint blockades are therapeutic options for lung cancer [page 1 right col middle para]. Van Velzen teaches an MSI assessment of 171 patients showed that 4/7 (57.1%) of MSI-H patients responded to the checkpoint inhibitor pembrolizumab, whereas 15/167 (9.0%) of MSS/MSS-L patients responded to checkpoint inhibitor pembrolizumab [page 3 right col top para], as in claim 1 step (b) when the subject's cancer is determined to exhibit MSS, it is predicted that the cancer is less likely to have a decreased response to checkpoint inhibitor immunotherapy as compared to a subject determined to exhibit exhibited MSI-H statuses. Here, because Van Velzen teaches 9.0% of patients with MSS/MSI-L statuses responded to the checkpoint inhibitor pembrolizumab while 57.1% of patients with MSI-H statuses responded to the checkpoint inhibitor pembrolizumab, it teaches that patients with MSS statuses were less likely to respond the checkpoint inhibitor(s) immunotherapy as compared to exhibited MSI-H statuses.
Johnson
Johnson et al. (Johnson) disclose using a background model for determining microsatellite instability that determines microsatellite instability characterization associated with at least one cancer condition for a user based on between the microsatellite instability parameter and the microsatellite instability threshold [Johnson, claim 1]. Johnson discloses background models can be based on neural network, regression, decision tree, random forest [Johnson, para 0034]. Johnson discloses background model is used to determines loci associated with MSI and samples associated with MSI can be compared to (e.g., VAF files) [Johnson, page 5 right col para 0041]. Johnson discloses the VAF files identifying loci most enriched for length polymorphisms, such as with VAFs in excess of background relative to a reference population (i.e., relating the predictive capability of the markers in the set or a subset thereof to known MSI status) [Johnson, page 5 right col para 0040], as instant claim 1 (b) the processing step comprising applying a quantitative model relating the predictive capability of the markers in the set or a subset thereof to known MSI status.
Johnson discloses using machine learning algorithms, neural networks, random-forest, decision trees, and logistic regression as background models [disclosure, page 4 para 0034]. Xiao discloses distinct cancer lineages using sensitivity, specificity, positive predictive value, negative predictive value, or any combination thereof [Xiao, claim 24], as in instant claim 4. Therefore, it is obvious that Johnson and Xiao disclose a claimed step using a quantitative model that can comprise a regression model, decision-tree model, machine-learning algorithm, neural network and evaluate test characteristics such as sensitivity, accuracy, correlation, probability, specificity, false-positive rate, false negative rate, positive predictive value, negative predictive value.
It would obvious to one of ordinary skill in the art by the effective filing date of the claimed invention to modify the methods Xiao in view of Van Velzen because Van Velzen teaches processing microsatellite data for determining microsatellite instability statuses and administering checkpoint inhibitors. One of ordinary skill in the art would be motivated to combine Xiao in view of Van Velzen because Van Velzen teaches a study that evaluated the efficacy and safety of using checkpoint inhibitor (i.e, pembrolizumab) in cancer patients with MSI-H and MSS/MSS-L statuses that resulted in cancers that exhibited MSS status had a lesser or decreased response to pembrolizumab compared to MSI-H status patients. Thus, one of ordinary skill in the art would expect a reasonable success combining the checkpoint inhibitor responses of Van Velzen with the microsatellite processing of Xiao to construct a claimed step for determining if MSS status cancer patients are less likely to respond to checkpoint inhibitors because Van Velzen provides studies that illustrate that using checkpoints inhibitor against MSS status patients is not an effective treatment which could lead to the administration of alternative immunotherapies in order to increase MSS/therapy response rate/percentage. Therefore, combining the microsatellite instability processing methods of Xiao in view of the checkpoint inhibitor responses of Van Velzen would yield a predictable method for predicting whether a subject’s cancer MSI status will respond and/or is less likely to respond to checkpoint inhibitor immunotherapy.
It would be obvious to one of ordinary skill in the art by the effective filing date of the claimed invention to modify the methods of Xiao in view of Van Velzen in view of Johnson because Johnson also discloses methods detecting microsatellite instability associated with cancer [Johnson, claim 1] but discloses processing microsatellite data using machine learning models (i.e., algorithms, neural networks, random-forest, decision trees, and logistic regression for detecting microsatellite instability [Johnson, claim 1 and page 4 right col para 0034]]). Furthermore, one of ordinary skill in the art would be motivated to combine Xiao in view of Van Velzen in view of Johnson because Johnson discloses its embodied method (i.e., model processing using machine learning algorithms, neural networks, random-forest, decision trees, and logistic regression for detecting microsatellite instability [Johnson, claim 1 and page 4 right col para 0034]) can be performed asynchronously (e.g., sequentially) and/or concurrently (e.g., in parallel; concurrently on different threads for parallel computing) to improve computer/computational processing in microsatellite instability detection [Johnson, page 3 left col para 0022]). Thus, one of ordinary skill in the art would expect a reasonable success incorporating the quantitative models and asynchronous and concurrent model processing of Johnson with the processing microsatellite instability data categorical measures (i.e., microsatellite instability high (MSI-H) or microsatellite stable (MSS)) methods of Xiao and the efficacy and safety evaluations of Van Velzen to construct a computationally improved method for determining if a subject’s cancer microsatellite instability status will respond to a immunotherapy (i.e., checkpoint inhibitors) because Johnson also discloses the microsatellite instability detection method can be used for facilitating in the treatment of a patient with at least one cancer [Johnson, claim 20] and discloses their method can be performed asynchronously and/or concurrently to improve computer processing of microsatellite stability data. Therefore, incorporating/combining the MSI status identification and immunotherapy administration methods of Xiao in view of the response evaluations of Van Velzen in view of the quantitative models and asynchronous and concurrent model processing of Johnson would yield a predictable improved method for evaluating test characteristics for predicting whether a subject's cancer MSI status will or is likely to have a decreased respond to checkpoint inhibitor immunotherapies as compared to another MSI status.
Response to Arguments
Applicant's arguments filed 13 February 2026 have been fully considered but they are not persuasive.
The Applicant states the instant application provides significant enhanced methodologies for diagnosing MSI. The Applicant points to the disclosure of Xiao [para 00386 and 00436] for guidance. The Applicant states the instant methods can use only one biomarker for MSI-H for diagnosis of LUSC. The Applicant states Xiao is silent regarding tissue-specific loci, and in fact teaches away from the instant methods. The cancer-agnostic approach of Xiao would fail for many cancer types which are successfully diagnosed using the claimed methods, as the instant application specifically identifies tissue type specific markers that work best in tumors originating from particular organ systems. Thus, the one size-fits-all approach of Xiao could not lead to the methods as claimed herein. The Applicant states Van Velzen allegedly teaches that patients with MSS statuses are less likely to respond to checkpoint inhibitor therapies compared to patients with MSI-H statuses. However, the Applicant states the teachings of Van Velzen do not cure the deficiencies in Xiao as described above [remarks, pages 16-17].
In response, the argument is not persuasive because as noted above Xiao in view of Velzen in view of Johnson now teach the method of claim 1. Additionally, as noted above, Xiao discloses/reads on the limitations of claim 1. Regarding Xiao not disclosing any biomarkers Xiao discloses loci comprises 10 loci [Xiao, claim 9]. Xiao discloses molecular profile can contain the gene/loci for PIK3Rl [disclosure, page 125]. It is also noted that claim 1 does not require any specific biomarkers/genes. It is noted that claim 1 would need to be amended to encompass a specific gene/biomarker. With respect to Velzen, Velzen teaches immune checkpoint blockades are therapeutic options for lung cancer [page 1 right col middle para]. Van Velzen teaches an MSI assessment of 171 patients showed that 4/7 (57.1%) of MSI-H patients responded to the checkpoint inhibitor pembrolizumab, whereas 15/167 (9.0%) of MSS/MSS-L patients responded to checkpoint inhibitor pembrolizumab [page 3 right col top para] which reads on claim 1 step (b) when the subject's cancer is determined to exhibit MSS, it is predicted that the cancer is less likely to respond to checkpoint inhibitor immunotherapy as compared MSI-H.
Conclusion
Claims 1, 4-5, 8-9, 12, 17-21, 26, 43, 45, 48, and 55 are rejected.
No claims are allowed.
Finality
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.
Inquiries
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/J.C.P./ Examiner, Art Unit 1687
/Anna Skibinsky/
Primary Examiner, AU 1635
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