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 .
Applicant’s amendment
Applicant’s amendment filed 2/12/2026 has been entered and received.
Claims 1-2, 13, 56, 63, 71 have been amended and claims 4-12, 14, 16-23, 25-27, 29-34, 36-43, 45-51, 53-55, 59-62, 64, 65, 69 and 70 have been cancelled.
Claims 1-3, 13, 15, 24, 28, 35, 44, 52, 56-58, 63, 66-68 and 71 are pending
Examiner Comment
In review of the file, the request for interview filed 12/15/2025 is acknowledged. It is noted that it was filed after the response filed 2/12/2025 and was intended to discuss the 101 rejection. Since a complete response was filed to first action on the merits, the examiner has provided an analysis of Applicants arguments without an interview.
Election/Restriction
Applicant’s election without traverse of Group II in the reply filed on 9/23/2021 was acknowledged. In prosecution and in view of the claim amendments, the restriction between groups I and II was withdrawn.
No new arguments nor comments have been provided in Applicant’s response for Group III.
Claims 1-3, 13, 15, 24, 28, 35, 44, 52, 56-58, 63, 66-68 and 71 are pending. Claim 71 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 9/23/2021.
The examiner has required restriction between product or apparatus claims and process claims, in this case the group directed to the method and not the product (claim 71) has been elected and not been amended consistent with the method for consideration of rejoinder.
Applicant is reminded that upon the cancellation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
Claims 1-3, 13, 15, 24, 28, 35, 44, 52, 56-58, 63, 66-68 drawn to a method of determining tumor burden in a sample by creating a library, providing a catch and determining reads to provide a value which excludes functional and germline alterations are currently under examination.
Priority
This application filed 8/28/2018, is Continuation of PCT/2017/019763 filed 2/7/217, which claims benefit to US provisional application 62/301534 filed 2/29/2016.
No comment on the summary of priority was made in Applicant’s response.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 2/12/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112
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, 13, 15, 24, 28, 35, 44, 47, 52, 56-58, 63, 66-68 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 is withdrawn.
The amendment to the claims and arguments for support of the specification and requirements of the claims to analyze tumor burden, ‘hybridize’ and analyze genomic regions is acknowledged. Examiner agrees that the metes and bounds of the claims are clear with respect to what a tumor member is directed to.
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 1-3, 13, 15, 24, 28, 35, 44, 47, 52, 56-58, 63, 66-68 stand rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
Claim analysis
Independent claims 1 and 2 have been amended and still are generally drawn to a method of determining tumor mutational burden in a sample. As amended, the claims require looking at any alteration for variation and correlating it to tumor burden by performing hybrid capture and sequencing what is captured. More specifically, the claims require that whole exome sequencing is not performed. The claims appear to imply and require that the sample is obtained from a subject with cancer, and the analysis requires steps of using hybrid capture and based on the examples the library is processed using NGS to obtain sequence reads from a predetermined set of genes. Dependent claims set forth the possible function that might be present such as alterations which ‘are associated with an effect on cell division, growth or survival, or are associated with cancer’. The claims as amended provide for a set of predetermined genes and read data from them for the evaluation of alterations where functional and germline alterations are subtracted from total count of alterations to provide for tumor mutational burden based on the remaining non-functional and non-germline alterations detected. Claims 1 and 2 do not require any specific number of predetermined sequences to be analyzed, as noted previously claim 3 has been amended to delete the limitation that the ‘predetermined set of genes does not comprise the entire genome’, and claim 44 provides for a ‘plurality’ or 50-500 or more genes be analyzed.
Response to Applicants arguments
Applicants provide a summary of the invention as providing a more accurate TMB measurement in genomic profiling. Applicants note that sample being analyzed is a tumor sample as amended, and that claims 1 and 2 provide a series of steps for evaluation TMB in the sample using hybrid capture without requiring whole exome sequencing. Applicants note the claims require performing hybrid capture and sequencing what is captured to evaluate the tumor burden from the sequence read data using alignment and assignment to quantify the TMB that might be present in the sample. Applicants note the memo of Aug 4, 2025 from the USPTO and argue the claims are not directed to a judicial exception or a mental process and that there is a practical application when viewed as a whole.
In response, the physical steps of the claim are acknowledged and address under 2B for additional elements. As provided in the record as evidence that hybrid capture was known and used to examine portions of a genome, Schrock et al. (2016) was provided for the use of hybrid capture of a sub-genomic region and sequence it for further characterization. What is left of the claim are the analysis of the data either broadly by ‘determining’ in claim 1 or in a series of generic steps of ‘aligning’, ‘assigning’ and ‘selecting’ in claim 2 prior to the same final ‘determining’ step provided in claim 1. The claims have been analyzed for what is recited and as a whole and were found to be steps of obtaining sequence data and subsequent steps to analyze the data. There are no specific hybrid probes, only that in part they provide less data than whole exome sequencing. Suggestions that it takes less time to use smaller portions of the genome versus the whole of exome are not surprising and consistent with looking at less data or sequence reads depending on how the sequencing is performed. Further, any increase in accuracy would seem to be derived from the probes used and that such probes being from informative portions of the genome versus surveying all exome sequences for possible alterations or mutations. The Aug memo is noted, however appears to be consistent with the analysis provided in the 101 rejection of record. As a whole, the claims generically indicate to provide probes for hybrid capture (which such were known) and to analyze generically in steps which align and assess differences to a reference as alterations or mutations in the final assessment of determining a ‘value’ represented by the number of alterations observed.
Accordingly, for the reasons above and of record, the rejection is maintained.
101 Analysis for completeness and clarity of the record.
For step 1 of the 101 analysis, as amended the claims are found to be directed to a statutory category of a process.
For step 2A of the 101 analysis, the judicial exception of the claims are the steps of analyzing possible alterations that may be present in the sequence data and correlating variations to tumor burden values. In review of the specification and recited steps, the aligning and comparing sequence to arrive at the identification of ‘alterations’ in sequences are instructional steps. The claim requires broad and generic steps for providing any sequence and ‘determining’ a value from any given sequence which then is representative of tumor burden. The judicial exception is a set of instructions for analysis of sequence data, and fall into the category of Mathematical Concepts to the extent that the tumor burden value is some form of a calculation, and also given the breadth to any sequence for analysis into the category of Mental Processes, that is concepts performed in the human mind (including an observation, evaluation, judgment, opinion) where here the claims encompass aligning two sequences and evaluating the differences as alteration and representative of tumor burden. Dependent claims set forth comparing a plurality, and as many as 500 predetermined sequences which appears to be a process of observation even with 500 or more sequences. Evaluating if a particular difference is present in a database or not also appears to be a step and task that can be performed by observational analysis, requiring simply to look up a potential variation and determining if it is listed in a dataset.
Recent guidance from the office requires that the judicial exception be evaluated under a second prong to determine whether the judicial exception is practically applied. In the instant case, the claims do not have an additional element to which the judicial exception is applied. The claims provide an additional element that provides sequence data, which is separate from the analysis step. While the claims have additional elements directed to the analysis performed with a processor, there is no evidence that the method provides any new or unique functionality to the processor. Additionally, the judicial exception requires steps recited at high level of generality and is not found to be a practical application of the judicial exception as broadly set forth.
For step 2B of the 101 analysis, each of the independent claims recites additional elements and are found to be the steps of obtaining sequence data. As such, and given the evidence of record the claims do not provide for any additional element to consider under step 2B which appears to provide for any improvement when viewed as the claim as a whole. For example, Schrock et al. (2016) provide for the use of hybrid capture of a sub-genomic region and sequence it for further characterization. While the claims encompass comparing a small number of sequences, to the extent that the steps of analysis can be done using a computer and known software it is noted that explaining the Alice framework, the Court wrote that "[i]n cases involving software innovations, [the step one] inquiry often turns on whether the claims focus on the specific asserted improvement in computer capabilities or, instead, on a process that qualifies as an abstract idea for which computers are invoked merely as a tool." The Court further noted that "[s]ince Alice, we have found software inventions to be patent-eligible where they have made non-abstract improvements to existing technological processes and computer technology." Moreover, these improvements must be specific -- "[a]n improved result, without more stated in the claim, is not enough to confer eligibility to an otherwise abstract idea . . . [t]o be patent-eligible, the claims must recite a specific means or method that solves a problem in an existing technological process."
As indicated in the summary of the judicial exception above and in view of the teachings of the specification, the steps are drawn to analysis of sequence data. While the instruction are could be stored on a medium and could be implemented on a computer, together the steps do not appear to result in significantly more than a means to compare sequences. The judicial exception of the method as claimed can be performed by hand and in light of the teaching of the specification on a computer. In review of the instant specification the methods do not appear to require a special type of processor and can be performed on a general purpose computer. Dependent claims set forth additional steps which are more specifically define the considerations and steps of calculating, and comparing, and do not add additional elements which result in significantly more to the claimed method for the analysis.
Response to Applicant’s arguments
Applicants provide an overview of the present invention and argue that surveying a small fraction of the genome can serve as an effective means to assess tumor burden versus assaying the whole genome. Applicants argue that assessing TMB is valuable comparing Gubin et al, Le et al and Snyder et al for providing several disadvantages in WGS. Noting the lcaim amendments and the guidance of the specification, applicants explain what the invention is directed to and that examples provide evidence for measurement of mutational burden in targeted samples and the identification of functional alterations at the same time.
Providing an overview of MPEP 2106 Applicants argue for step 1, that the claims are directed to a statutory category.
In response, Examiner agrees that as amended, the claims are directed to a process.
For step 2A prong 1, Applicants argue that the claims do not recite an abstract idea, and are directed to evaluating a tumor mutational burden in a sample. As amended, it noted that claims provide physical steps and steps in which certain types of sequence reads for functional variants and germline alterations are to be excluded in the analysis which is now performed on at least one processor.
In response, the additional elements have been noted (and evaluated more fully in prong 2), however the judicial exception of evaluating sequence read data has been found to fall into the category of a mental process providing only instructions to evaluate potential different in sequence data as an abstract step. There is no necessary complexity or amount required of the claims such that the analysis appears to be simply comparing sequences and counting variants as a way to assess tumor burden. It is noted that originally the claims did not require a processor, and now with amendment, the indication to perform the analysis using a processor and evidence of record is not sufficient to make the claim patent eligible, and simply indicate to use a computer in the analysis steps.
For step 2A, prong 2, Applicants argue that there are several elements that result in substantial improvements in the technology of evaluating tumor mutation burden noting the guidance of the specification, and require excluding functional alterations which allow for accurate measurements of TMB for immunotherapies and improvements.
In response, a review of the relevant art demonstrates that the study of TMB was known, and that mutational load correlates with the response of certain types of cancer to immunotherapy (see for example Gubin et al. (2015) and Le et al. (2015)). The evidence of record does not appear to support an improvement by excluding any specific types of sequences as a variety of possible antigens may serve as targets. For TMB analysis in general, Gubin et al. clearly demonstrate that mutational load correlates with the response and that mutational load it-self was a better indicator of response to a variety of immunotherapies demonstrating an acknowledgement of TMB importance in cancer treatment with immunotherapeutic approaches.
For step 2B, Applicants argue that combination of steps is not conventional, and note that Gubin fails to exclude certain sequences in the analysis, and generally include alterations associated with progression. Applicants argue that the claims comprise several inventive steps that provide for an inventive concept by picking a predetermined set of genes associated with cell division, growth or survival or are associated with cancer.
In response, for Step 2B the combination of additional elements are analyzed not the steps of analysis set forth in the judicial exception. While it is acknowledged that some research in cancer focuses on alterations that result in the progression of cancer, the teaching of Gubin et al clearly provide that TMB alone, i.e. independent of gene and the gene function, correlates with response and is subject to analysis and application in potential therapies. More importantly, it is recognized and suggested that a variety of genes can be the target for immunotherapy, and that the field is still unsettled and empirical for results. For example, Snyder et al. (2014) provides data that suggests a need for an expanded definition of the previous categories of driver and passenger mutations in view of evidence that exonic missense mutations in general confer increased MHC class I binding and confirm the hypothesis that some mutations formerly categorized as passengers may in fact represent “immune determinants.” It appears that broadly providing for the use of hybrid capture and sequence analysis were technique known and used, and with respect to specific targets provide for ‘passenger’ genes that were not considered functional variants and drivers in the oncogenic process, but may serve as neo-antigens in immunotherapy in the treatment of cancer.
Therefore, for the reasons above and of record, the rejection is maintained.
As noted previously, one way to overcome a rejection for non-patent-eligible subject matter is to persuasively argue that the claimed subject matter is not directed to a judicial exception. Another way for the applicants to overcome the rejection is to persuasively argue that the claims contain elements in addition to the judicial exception that either individually or as an ordered combination are not well understood, routine, or conventional. Another way for the applicants to overcome the rejection is to persuasively argue that the claims as a whole result in an improvement to a technology. Persuasive evidence for an improvement to a technology could be a comparison of results of the claimed subject matter with results of the prior art, or arguments based on scientific reasoning that the claimed subject matter inherently results an improvement over the prior art. The applicants should show why the claims require the improvement in all embodiments.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
An updated search of the art demonstrates that exome capture techniques do not provides whole exome mapping as demonstrated by Hodges et al. (2007) who analyze genome-wide in situ exon capture for selective resequencing that not 100% of the exons targeted are captured and not all exons need to be captured. While assays to target exons and the general ability of sequence read in an assessment for personalized medicine is possible, the art of record fails to provide correlating germline and alterations with known function with evaluating tumor burden as the instant claims require. More generally the evidence of record demonstrates that assessment of tumor burden can be performed. Aggarwal et al. and Wange et al for example demonstrate a correlation with response to a variety of immunotherapies as potential targets. As a whole, they provide the basis that use of TMB can be used as a clinically actionable biomarker for immunotherapy. Similar to the previously art that was provided to demonstrate that tumor burden was positively associated with immunotherapy as evidenced by Gubin et al. (2015), Snyder et al. (2014), and Le et al. (2015) which an increased mutational burden in samples would correlate with a benefit from treatments such as CTLA-4 blockade, and demonstrate that there was a significant difference in mutational load between patients with a long-term clinical benefit and those with a minimal benefit or no benefit, and that high numbers of somatic mutations and potential mutation-associated neoantigens were associated with longer progression-free survival and with a trend toward objective response, and results that suggest that the evaluation of tumor genomes can help guide immunotherapy.
The art of record supports the view that the number and type of alterations may prove to be valuable for judging the potential usefulness of immune checkpoint inhibitors, even in mismatch repair–proficient cancers. Most importantly, our results show an approach for the treatment of a specific class of tumors that is based solely on genetic status — that is, without regard to the underlying tumor type. The references above and of record demonstrate the TMB is correlated with assessment of cancer, however the source of sequence to exclude from the analysis is not consistent with the instant claims to exclude functional variants from the assessment of tumor burden, and appears to provide any sequence can be used, and more particularly provides for targets which are encompassed by the claims as functional variants. Further, the art of record generally attempts to identify alterations that cause or correlate to tumor progression and even when looking at alterations generally do not actively exclude the alterations listed in the instant claims.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Joseph T Woitach whose telephone number is (571)272-0739. The examiner can normally be reached Mon-Fri; 8:00-4:00.
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, Karlheinz R Skowronek can be reached at 571 272-9047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Joseph Woitach/Primary Examiner, Art Unit 1687
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