DETAILED ACTION
The Applicant’s response, received 29 September 2025, has been fully considered. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1-17, 21-30, 32, and 33 are pending.
Claims 12-14 are withdrawn.
Claims 1-11, 15-17, 21-30, 32, and 33 are rejected.
Priority
Claims 1-11, 15-17, 21-30, 32, and 33 are not given the benefit of priority to Provisional Application No. 62/746,997, filed 17 October 2018, because there is not support for the specific limitations regarding quality control (QC) testing on sequencing results and generating QC scores as recited in independent claim 1.
Claims 1-11, 15-17, 21-30, 32, and 33 are not given the benefit of priority to Provisional Application No. 62/804,458, filed 12 February 2019, because there is not support for the specific limitations regarding quality control (QC) testing on sequencing results and generating QC scores as recited in independent claim 1.
Claims 1-11, 15-17, 21-30, 32, and 33 are given the benefit of priority to Provisional Application No. 62/873,693, filed 12 July 2019.
Therefore, the effective filing date of the claimed invention is 12 July 2019.
Claim Objections
The objection to claim 1 in the Office action mailed 27 May 2025 is withdrawn in view of the amendment received 29 September 2025.
Claim Rejections - 35 USC § 112
The amendment received 29 September 2025 has been fully considered, however after further consideration, the rejection of claim 10 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, in the Office action mailed 27 May 2025 is maintained in view of the amendment and the Applicant’s arguments/remarks.
The rejection of claims 1-9, 11-17, 21-30, 32, and 33 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, in the Office action mailed 27 May 2025 is withdrawn in view of the amendment received 29 September 2025.
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 10 is 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 10 is indefinite for reciting “aligning each respective sequence read in the respective pluralities of sequence reads to a reference genome” because it is not clear if the microservice is to be programmed to identify mutations by aligning each sequence read, or if this is simply an intended use of the sequence reads.
Response to Arguments
The Applicant’s arguments/remarks received 29 September 2025 have been fully considered, and are persuasive in part, to the extent noted below.
The Applicant states on page 9 of the Remarks (para. 5) that as amended, the claims recite details of how the various microservices within the system are configured.
This argument is persuasive, to the extent that the rejection of claims 1-9, 11-17, 21-30, 32, and 33 is withdrawn, but not persuasive, to the extent that the rejection of claim 10 is maintained because the amendment and the argument/remarks do not remedy and/or address the rejection of claim 10 raised in the Office action mailed 27 May 2025.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-11, 15-17, 21-30, 32, and 33 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Specifically, claim 1 has been amended to recite as part of a 6th service providing a ‘match between the subject and one or more therapies, the match being based on at least the subjects TMB status’ which appears to be a new limitation not supported by the specification. More specifically, the specification and the art of record fails to provide any support or guidance to therapies associated with TMB status. In review of the specification support for ‘based on’ and correlated appears to supported for specific alterations such as CNV, alleles,… but there is no specific recitation of TMB and any appropriate therapy, and as required of the claim for any TMB status and any particular treatment. While the specification and the art of record supports that there are specific informative mutants which can be treated in particular or specific ways, there is no evidence nor guidance for a generic TMB status and any treatment as amended. While it is acknowledged the assessing TMB is not new and that the art in general supports it is a process that can be observed in some cancer states or progressions, there are no specific therapies provided in the instant specification for TMB status nor in art of record.
Providing evidence not present that this is known or amending the claims to be consistent with the art and generic guidance of the specification for known correlations could address the basis of the rejection.
Claim Rejections - 35 USC § 101
The amendment received 29 September 2025 has been fully considered, however after further consideration, the rejection of claims 1-11, 15-17, 21-30, 32, and 33 in the Office action mailed 27 May 2025 is maintained with modification in view of the amendment.
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 1-11, 15-17, 21-30, 32, and 33 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claims recite: (a) mathematical concepts, (e.g., mathematical relationships, formulas or equations, mathematical calculations); and (b) mental processes, i.e., concepts performed in the human mind, (e.g., observation, evaluation, judgement, opinion).
Claim Interpretations
Claims 1, 9, 28, 29, and 33 recite the term “microservice.” This term is interpreted to describe a program (i.e., a software program) that manipulates (i.e., processes) data to condition or shape the data to generate new interim data or to structure data in different structured formats for consumption by user application programs (substitute specification, page 27, ¶ [00159]). The limitations reciting “microservice configured to [action]” (e.g., receive, execute, generate, provide) are further interpreted as programming of the microservice, wherein one or more such microservices may be part of an order management system that orchestrates the sequence of events as needed at the appropriate time and in the appropriate order (e.g., substitute specification, page 98, para. [00452]).
Claim 15 recites the term “actionable oncology mutations.” This term is interpreted to mean gene variants that, if detected, would be expected to affect patients’ response to treatment, and therefore can influence treatment decisions (substitute specification, pages 47-48, ¶ [00231]). This term is interpreted to be synonymous with the term “tier 1 genes.”
Claim 16 recites the term “Tier 1 genes.” This term is interpreted to mean genes that can influence treatment decisions (substitute specification, pages 47-48, ¶ [00231]) and that are linked with response or resistance to targeted therapies, resistance to standard care, or toxicities associated with treatment (substitute specification, pages 47-48, ¶ [00231]). This term is interpreted to be synonymous with the term “actionable oncology mutations.”
Claim 1 recites the term “data consume.” This term is interpreted to mean a process of transforming raw data into processed information that is suitable for use in a subsequent process step (substitute specification, page 2, ¶¶ [0006] & [0009]; page 10, ¶ [0010]; page 12, ¶ [0042]; page 14, ¶¶ [0048] - [0051]; page 32, ¶ [00173]; page 33, ¶ [00179]; page 35, ¶ [00183]; and page 57, ¶ [00269]).
Subject matter eligibility evaluation in accordance with MPEP 2106.
Eligibility Step 1: Step 1 of the eligibility analysis asks: Is the claim to a process, machine, manufacture or composition of matter?
Claims 1-11, 15-17, 21-30, 32, and 33 are directed to a system (i.e., a machine or manufacture) for conducting genomic sequencing.
Therefore, these claims are encompassed by the categories of statutory subject matter, i.e., each claim as a whole falls within one or more statutory categories, and thus satisfy the subject matter eligibility requirements under step 1.
[Step 1: YES]
Eligibility Step 2A: First it is determined in Prong One whether a claim recites a judicial exception, and if so, then it is determined in Prong Two whether the recited judicial exception is integrated into a practical application of that exception.
Eligibility Step 2A Prong One: In determining whether a claim is directed to a judicial exception, examination is performed that analyzes whether the claim recites a judicial exception, i.e., whether a law of nature, natural phenomenon, or abstract idea is set forth or described in the claim.
Independent claim 1 recites the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas:
a first microservice (i.e., a software program) configured to receive… (i.e., generate a data product) (i.e., mental processes);
a second microservice (i.e., a software program) configured to execute… (i.e., generate a data product) (i.e., mental processes);
a third microservice (i.e., a software program) configured to execute… (i.e., generate a data product) (i.e., mental processes);
a fourth microservice (i.e., a software program) configured to execute (i.e., generate a data product) (i.e., mental processes) quality control (QC) testing on the germline sequencing results to generate a germline QC score and on the somatic sequencing results to generate a somatic QC score (i.e., mental processes and mathematical concepts);
a fifth microservice (i.e., a software program) configured to generate (i.e., generate a data product) (i.e., mental processes) at least one clinical report, wherein the clinical report comprises a tumor mutational burden (TMB) status associated with the subject, wherein the TMB status is based at least in part on the identified sequences of nucleotides in the germline specimen and identified sequences of nucleotides in the somatic specimen (i.e., mental processes and mathematical concepts), and wherein the TMB status is calculated from:
(i) mutations in the germline sequencing results and a panel size of the targeted-panel when the germline QC score is above a passing threshold and the somatic QC score is below a passing threshold (i.e., mental processes and mathematical concepts);
(ii) mutations in the somatic sequencing results and the panel size of the targeted-panel when the somatic QC score is above the passing threshold and the germline QC score is below the passing threshold (i.e., mental processes and mathematical concepts); and
(iii) mutations in the somatic sequencing results, mutations in the germline sequencing results, and the panel size of the targeted-panel when the somatic QC score is above the passing threshold and the germline QC score is above the passing threshold (i.e., mental processes and mathematical concepts); and
a sixth microservice (i.e., a software program) configured to provide (i.e., generate a data product) (i.e., mental processes) at least one clinical report to the physician, the at least one clinical report comprising the subject's TMB status and a match between the subject and one or more therapies, the match being based on at least the subject’s TMB status (i.e., mental processes);
each microservice includes a data consume definition (i.e., mental processes); and
each microservice generates a data product (i.e., mental processes).
Dependent claims 9-11, 21-30, and 33 further recite the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas, as noted below:
Dependent claim 9 further recites:
a seventh microservice (i.e., a software program) configured to execute (i.e., generate a data product) (i.e., mental processes);
Dependent claim 10 further recites:
wherein mutations are identified by aligning each respective sequence read in the respective pluralities of sequence reads to a reference genome (i.e., mental processes).
Dependent claim 11 further recites:
wherein the TMB status is calculated from mutations identified in the subject's DNA (i.e., mental processes and mathematical concepts).
Dependent claim 21 further recites:
wherein the TMB status is determined as TMB-high when the subject's TMB is greater than 9 mutations per megabase (i.e., mental processes and mathematical concepts).
Dependent claim 22 further recites:
wherein the TMB status is determined as TMB-low when the subject's TMB is less than 9 mutations per megabase (i.e., mental processes and mathematical concepts).
Dependent claim 23 further recites:
wherein the mutations are identified from only non-synonymous mutations comprising fusions, non-silent somatic coding mutations, missense, insertions, deletions, and stop-loss variants (i.e., mental processes).
Dependent claim 24 further recites:
wherein the somatic QC score passing threshold is based at least in part on mutations having coverage greater than 100x and an allelic fraction greater than 5% (i.e., mental processes and mathematical concepts).
Dependent claim 25 further recites:
wherein the germline QC score passing threshold is based at least in part on mutations having coverage greater than 100x and an allelic fraction greater than 5% (i.e., mental processes and mathematical concepts).
Dependent claim 26 further recites:
wherein the germline QC score passing threshold is not met when a germline specimen is not available to the system (i.e., mental processes).
Dependent claim 27 further recites:
wherein the somatic QC score passing threshold is not met when a somatic specimen is not available to the system (i.e., mental processes).
Dependent claim 28 further recites:
wherein the first microservice is initiated when the system receives the order from the physician (i.e., mental processes);
the second microservice is initiated when the first microservice terminates (i.e., mental processes);
the third microservice is initiated when the first microservice terminates (i.e., mental processes);
the fourth microservice is initiated when both the second and third microservices terminate (i.e., mental processes);
the fifth microservice is initiated when the fourth microservice terminates (i.e., mental processes); and
the sixth microservice is initiated when the fifth microservice terminates (i.e., mental processes).
Dependent claim 29 further recites:
wherein the first microservice is initiated when the system receives the order from the physician (i.e., mental processes);
the second microservice is initiated when the first microservice terminates (i.e., mental processes);
the third microservice is initiated when the first microservice terminates (i.e., mental processes);
the fourth microservice is initiated when both the second and third microservices terminate (i.e., mental processes);
the seventh microservice is initiated when the fourth microservice terminates (i.e., mental processes);
the fifth microservice is initiated when the seventh microservice terminates (i.e., mental processes);
the sixth microservice is initiated when the fifth microservice terminates (i.e., mental processes).
Dependent claim 30 further recites:
wherein the at least one clinical report comprises listing immune checkpoint blockade inhibitors as a treatment when the TMB status is TMB-high (i.e., mental processes).
Dependent claim 33 further recites:
wherein the second microservice (i.e., a software program) is configured to output… (i.e., generate a data product) (i.e., mental processes); and
wherein the third microservice (i.e., a software program) is configured to output… (i.e., generate a data product) (i.e., mental processes).
The abstract ideas recited in the claims are evaluated under the broadest reasonable interpretation (BRI) of the claim limitations when read in light of and consistent with the specification. As noted in the foregoing section, the claims are determined to contain limitations that can practically be performed in the human mind with the aid of a pen and paper (e.g., configuring microservices) and therefore recite judicial exceptions from the mental process grouping of abstract ideas. Additionally, the recited limitations that are identified as judicial exceptions from the mathematical concepts grouping of abstract ideas (e.g., calculating a TMB score) are abstract ideas irrespective of whether or not the limitations are practical to perform in the human mind.
Generating data products for use by other applications comprises processing information that can be practically be performed in the human mind with or without a physical aid and/or operated on mathematically (see MPEP 2106.04(a)(2)).
Therefore, claims 1-11, 15-17, 21-30, 32, and 33 recite an abstract idea.
[Step 2A Prong One: YES]
Eligibility Step 2A Prong Two: In determining whether a claim is directed to a judicial exception, further examination is performed that analyzes if the claim recites additional elements that when examined as a whole integrates the judicial exception(s) into a practical application (MPEP 2106.04(d)). A claim that integrates a judicial exception into a practical application will apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception. The claimed additional elements are analyzed to determine if the abstract idea is integrated into a practical application (MPEP 2106.04(d)(I); MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the abstract idea, the claim fails to integrate the abstract idea into a practical application (MPEP 2106.04(d)(III)).
The judicial exceptions identified in Eligibility Step 2A Prong One are not integrated into a practical application because of the reasons noted below.
Dependent claims 10, 11, 21-27, and 30 do not recite any elements in addition to the judicial exception, and thus are part of the judicial exception.
The additional elements in independent claim 1 include:
one or more computers in communication;
receive data;
output data;
a germline specimen and a somatic specimen;
next generation sequencing (NGS) of a subject’s germline and somatic specimen; and
a targeted panel (i.e., to identify sequences of nucleotides in the germline specimen and in the somatic specimen); and
the plurality of microservices operate independent of the other system resources.
The additional elements in dependent claims 2-9, 15-17, 28, 29, 32, and 33 include:
wherein the germline sequencing results and the somatic sequencing results include respective pluralities of sequence reads generated from short-read, paired-end NGS (claim 2);
wherein the targeted-panel comprises a plurality of probes; wherein each probe in the plurality of probes uniquely targets a respective portion of a reference genome; and wherein each sequence read in the respective pluralities of sequence reads corresponds to at least one probe in the plurality of probes (claim 3);
wherein the respective pluralities of sequence reads have an average depth of at least 50X across the plurality of probes (claim 4);
wherein the respective pluralities of sequence reads have an average depth of at least 400X across the plurality of probes (claim 5);
wherein the plurality of probes includes probes for at least three hundred different genes selected from a predetermined group of genes (claim 6);
wherein the somatic specimen comprises macro dissected formalin fixed paraffin embedded (FFPE) tissue sections, surgical biopsy, skin biopsy, punch biopsy, prostate biopsy, bone biopsy, bone marrow biopsy, needle biopsy, CT-guided biopsy, ultrasound-guided biopsy, fine needle aspiration, aspiration biopsy, fresh tissue or blood samples, and the germline specimen comprises blood or saliva from the subject (claim 7);
wherein the somatic specimen is of a breast tumor, a glioblastoma, a prostate tumor, a pancreatic tumor, a kidney tumor, a colorectal tumor, an ovarian tumor, an endometrial tumor, a breast tumor, or a combination thereof (claim 8);
a germline specimen and a targeted gene panel (i.e., to identify somatic sequences of nucleotides to generate somatic sequencing results) (claim 9);
cell-free next generation sequencing of a subject’s germline specimen (claim 9);
wherein the NGS is conducted using a gene panel focused on actionable oncology mutations as the targeted panel (claim 15); 1
wherein the NGS is conducted using a gene panel targeting Tier 1 genes as the targeted panel (claim 16);
wherein the NGS is conducted on at least one of the PIK3CA gene, the CDKN2A gene, the PTEN gene, or the EGFR gene (claim 17);
wherein the targeted-panel includes a plurality of probes configured to target specific genes (claim 32);
receive data (claims 28 and 29); and
output data (claims 9, 28, 29, and 33).
The additional element of one or more computers in communication (claim 1) invokes a computer and/or computer-related components merely as tools for use in the claimed process, and therefore is not an improvement to computer functionality itself, or an improvement to any other technology or technical field, and thus, does not integrate the judicial exceptions into a practical application (MPEP 2106.04(d)(1)).
The additional elements of receive data (claims 28 and 29) and/or output data (claims 9, 28, 29, and 33) are merely pre-solution and post-solution activities for use in the claimed process – a nominal addition to the claims that does not meaningfully limit the claims, and therefore does not add more than insignificant extra-solution activity to the judicial exceptions (MPEP 2106.05(g)).
The additional elements of a germline specimen and a somatic specimen (claims 1, 7, 8, and 9); next generation sequencing (NGS) of a subject’s germline and somatic specimen (claim 1); short-read, paired-end NGS sequencing (claim 2); cell-free next generation sequencing of a subject’s germline specimen (claim 9); a targeted panel (claims 1, 3, and 9); a gene panel as the targeted-panel (claims 15, 16, 17, and 32); and probes (claims 3, 4, 5, 6, and 32); are steps and/or components of the steps of gathering the data for use in the claimed process, and thus amount to insignificant extra-solution activities (MPEP 2106.05(g)), and also do not amount to more than generally linking the use of a judicial exception(s) to a particular technological environment (MPEP 2106.05(h)).
Thus, the additionally recited elements merely invoke a computer as a tool, and/or amount to mere data gathering, and/or amount to merely indicating a field of use or technological environment in which to apply a judicial exception, and/or amount to insignificant extra-solution activities, and as such, when all limitations in claims 1-11, 15-17, 21-30, 32, and 33 have been considered as a whole, the claims are deemed to not recite any additional elements that would integrate a judicial exception into a practical application (MPEP 2106.04(d)).
[Step 2A Prong Two: NO]
Eligibility Step 2B: Because the claims recite an abstract idea, and do not integrate that abstract idea into a practical application, the claims are probed for a specific inventive concept. The judicial exception alone cannot provide that inventive concept or practical application (MPEP 2106.05). Identifying whether the additional elements beyond the abstract idea amount to such an inventive concept requires considering the additional elements individually and in combination to determine if they amount to significantly more than the judicial exception (MPEP 2106.05A i-vi).
The claims do not include any additional elements that are sufficient to amount to significantly more than the judicial exception(s) because of the reasons noted below.
Dependent claims 10, 11, 21-27, and 30 do not recite any elements in addition to the judicial exception(s). The additional elements recited in independent claim 1 and dependent claims 2-9, 15-17, 28, 29, 32, and 33 are identified above, and carried over from Step 2A: Prong Two along with their conclusions for analysis at Step 2B. Any additional element or combination of elements that was considered to be insignificant extra-solution activity at Step 2A: Prong Two was re-evaluated at Step 2B, because if such re-evaluation finds that the element is unconventional or otherwise more than what is well-understood, routine, conventional activity in the field, this finding may indicate that the additional element is no longer considered to be insignificant; and all additional elements and combination of elements were evaluated to determine whether any additional elements or combination of elements are other than what is well-understood, routine, conventional activity in the field, or simply append well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, per MPEP 2106.05(d).
The additional elements of one or more computers in communication (claim 1), and receive (claims 28 and 29) and/or output data (claims 9, 28, 29, and 33) are conventional computer components and/or functions (see MPEP at 2106.05(b) and 2106.05(d)(II) regarding conventionality of computer components and computer processes).
The additional element of the plurality of microservices operate independent of the other system resources (claim 1) is conventional. Evidence for the conventionality is shown by Dragoni et al. (arXiv:1606.04036v4 [cs.SE], 2017, https://doi.org/10.48550/arXiv.1606.04036, pp. 1-17, newly cited). Dragoni et al. reviews microservices: yesterday, today, and tomorrow (Title; and Abstract) and shows that a microservice is a cohesive, independent process interacting via messages, and from a technical point of view, should be independent components conceptually deployed in isolation and equipped with dedicated memory persistence tools (e.g., databases) and since all of the components of a microservice architecture are microservices, its distinguishing behavior derives from the composition and coordination of its components via messages (page 2, Definition 2). Dragoni et al. further shows that a microservice architecture is a distributed application where all of its modules are microservices (page 2, Definition 3). Dragoni et al. further shows that microservices are a trend in software architecture, and manage growing complexity by functionally decomposing large systems into a set of independent services, and each service in microservice architecture is operationally independent from other services and the only form of communication between services is through their published interfaces (page 6, para. 4; and page 7, para. 3).
The additional elements of next generation sequencing (NGS) of a subject’s germline and somatic specimen (claim 1); short-read, paired-end sequencing (claim 2); and using gene probes (claims 3, 4, 5, 6, and 32); are conventional. Evidence for the conventionality is shown by Shendure et al. (Nature Biotechnology, 2008, Vol. 26, No. 10, pp. 1135-1145, as cited in the Office action mailed 12 October 2023). Shendure et al. reviews DNA sequencing technologies, paired ends, and short read lengths (page 1140, Table 1). Shendure et al. further shows that probes can be used to precisely identify variant positions (page 1137, Box 2, para. 1); and sequencing for somatic or germline variation discovery in individuals (page 1143, Box 4).
The additional element of cell-free next generation sequencing (claim 9) is conventional. Evidence for the conventionality is shown by Bennett et al. (Oncotarget, 2016, Vol. 7, No. 43, pp. 71013-71035, as cited in the Office action mailed 12 October 2023). Bennett et al. reviews the use of cell-free DNA and next-generation sequencing in personalized medicine for cancer (Title; and Abstract).
The additional element of using a targeted gene panel for genomic sequencing (claims 1, 3, 9, 15, 16, 17, and 32), is conventional. Evidence for the conventionality is shown by Buttner et al. (European Society for Medical Oncology, 2019 (Published online 24 January 2019), Vol 4:e000442, doi:10.1136/esmoopen-2018-000442, pp. 1-12, as cited in the Office action mailed 12 October 2023). Buttner et al. shows that a quantitative measure of the total number of mutations in tumor tissue of patients can be assessed by large targeted gene panel sequencing (Abstract; and page 1, column 2, para. 3). Buttner et al. further shows examples of next-generation sequencing gene panels in development of currently available to assess tumor mutational burden (page 5, Table 2).
Therefore, when taken alone, all additional elements in claims 1-11, 15-17, 21-30, 32, and 33 do not amount to significantly more than the above-identified judicial exception(s). Even when evaluated as a combination, the additional elements fail to transform the exception(s) into a patent-eligible application of that exception. Thus, claims 1-11, 15-17, 21-30, 32, and 33 are deemed to not contribute an inventive concept, i.e., amount to significantly more than the judicial exceptions (MPEP 2106.05(II)).
[Step 2B: NO]
Response to Arguments
The Applicant’s arguments received 29 September 2025 have been fully considered, but are not persuasive.
The Applicant summarizes the eligibility analysis process at Step 2A on page 10 (para. 1) of the Remarks, and summarizes instant claim limitations that were identified as judicial exceptions in the Office action mailed 27 May 2025 (para. 2), and summarizes the memorandum titled “Reminders on evaluating subject matter eligibility of claims under 35 U.S.C. 101” (the “August 4 Memo”) on page 10 (paras. 3-4) and page 11 (para. 1) of the Remarks. The Applicant further states (para. 2) that the features that the Office identifies as mathematical concepts are analogous to features that the memorandum indicates do not recite a judicial exception, and are distinct from features that the memorandum indicates do recite a judicial exception, and that the instant claims do not require any specific mathematical calculations and do not refer to any mathematical calculations by name. The Applicant further states (para. 3) that the claimed fourth microservice, for example, is configured to execute QC testing on the germline sequencing results to generate a germline QC score and on the somatic sequencing results to generate a somatic QC score, and nowhere does the claim recite any specific mathematical calculations that the fourth microservice implements to generate the QC score, and the claim does not refer to any mathematical calculations by name. The Applicant further states (para. 4) that the claimed fifth microservice, for example, is configured to generate a clinical report that includes a TMB status based at least in part on identified sequences, and that the claim sets forth three inputs from which the TMB status is calculated depending on the relationship between the QC scores and thresholds (numbered (i) to (iii) in the claims), but it does not specify any particular algorithm or identify any particular mathematical calculations that must be performed to generate the TMB status. Finally, the Applicant states (para. 5) that thus, by the reasoning set forth in the memorandum, even if the claimed fourth and fifth microservices may involve a broad array of techniques or activities that may involve or rely upon mathematical concepts, because the claim does not set forth or describe any mathematical relationships, calculations, formulas, or equations using words or mathematical symbols, the claims are not directed to mathematical concepts.
These arguments are not persuasive, because first, the fourth microservice limitation reciting “generate a germline QC score…and…generate a somatic QC score” at least describe mathematical concepts, not least because determining a quality control score involves converting a quality predictor value (that is generated using a statistical model) for each base into a score reflecting the probability of an incorrect base call (which requires using a mathematical equation). Second, in the fifth microservice limitation, the claim recites “wherein the TMB status is calculated…” and further recites using threshold values as criteria for the calculation, which are at least describing mathematical relationships. Third, the “August 4 Memo” is not intended to announce any new USPTO practice or procedure and is meant to be consistent with existing USPTO guidance, which was adhered to during the examination of the instant claims.
The Applicant provides a summary of the Step 2A Prong Two analysis in the Office action mailed 27 May 2025 on page 11 (para. 6) and page 12 (para. 1) of the Remarks, and states (para. 2) that as an initial matter, the Applicant notes that the Office’s listing is incomplete, e.g., subtracting the alleged mental processes or mathematical concepts identified above from the claim, it can be seen that the claim does not merely recite NGS; the claim further recites executing the NGS of the subject’s somatic and germline specimens, respectively, to identify sequences of nucleotides in the somatic and germline specimens, respectively, using the targeted-panel to generate somatic and germline sequencing results, respectively. The Applicant further states that as these features were not identified by the Office as judicial exceptions, they must be considered at Step 2Am, Prong Two and Step 2B, and as noted in the foregoing arguments, the features identified by the Office as allegedly mathematical concepts must be considered as additional features as well, as those features do not recite any such mathematical concepts. The Applicant further states (para. 3) that contrary to the Office’s allegations, the claimed features regarding microservices being configured to execute NGS on a subject’s germline and somatic specimens to identify sequences of nucleotides using a targeted-panel to generate germline sequencing results integrate the alleged judicial exceptions into a practical application thereof, and amount to significantly more than the alleged judicial exceptions.
These arguments are not persuasive, because first, the claim limitations identified as mathematical concepts in the above rejection and discussed in the foregoing response to arguments, are judicial exceptions for the reasons explained above, and are therefore not additional elements. Second, in the Office action mailed 27 May 2025, independent claim 1 in addition to certain dependent claims were rejected under 35 U.S.C. 112(b) as indefinite for reciting a system as well as method steps of using the system, i.e., “executing sequencing” and furthermore, the limitations reciting “microservice for [action]” (e.g., for receiving, for executing, for generating, for providing) were interpreted as programming of the microservice that generates for consumption by other programs, i.e., data output from one microservice becomes data input to another microservice, as noted in rejection under 35 U.S.C. 101 in the Office action mailed 27 May 2025 and in the above rejection. Third, it is not clear from the Applicant’s foregoing argument as to whether the Applicant is arguing that the microservice is somehow configured to control the sequencer machine, as opposed to merely generating a data output, e.g., a notification or prompt indicating that the next step in an order management process should/should not begin, i.e., the sequencing of a patient’s DNA sample. Nonetheless, the configuration of a microservice (i.e., the abstract idea) is not sufficient to integrate the recited judicial exceptions into a practical application at Eligibility Step 2A Prong Two and/or is not sufficient to amount to significantly more than the recited judicial exceptions at Eligibility Step 2B.
The Applicant summarizes the eligibility analysis process at Step 2A Prong Two on page 12 (para. 4) and states (para. 5; and at page 13, para. 1) that the Office alleges that the additional features are insignificant because they do not amount to more than generally linking the use of a judicial exception to a particular technological environment and they are part of the data gathering process used in the recited judicial exception. The Applicant further states that this is a mischaracterization and misapplication of the factors that Office examination policy requires to be considered, as an additional feature is not considered to be insignificant if it is any part of a data gathering process used in an alleged judicial exception; instead, it is only considered insignificant if it subsumes all uses of the recited judicial exception and is only tangentially related to the invention. The Applicant further states (para. 2) that in other words, if the additional element imposes meaningful limits on the claim, and if the judicial exception can be performed without using the particular type of data gathering reflected in the additional element, Office examination policy indicates that the additional element renders the claim patent-eligible under § 101. The Applicant further summarizes (para. 3) claim 1 limitations regarding NGS that are an additional element.
These arguments are not persuasive, because first, a claim that integrates a judicial exception into a practical application at Eligibility Step 2A Prong Two will recite an additional element or combination of additional elements that will apply, rely on, or use the judicial exception(s) in a manner that imposes a meaningful limit on the judicial exception, e.g., as indicated in subsection I. at 2106.04(d) in the MPEP. As noted and discussed in the above rejection, when all limitations in claims 1-11, 15-17, 21-30, 32, and 33 have been considered as a whole (i.e., the analysis takes into consideration all the claim limitations and how those limitations interact and impact each other when evaluating whether the exception is integrated into a practical application), they are deemed to not recite any additional elements that would integrate a judicial exception into a practical application. Second, a conclusion of whether a claim is eligible at Step 2B requires that all relevant considerations be evaluated, which comprises steps of: (1) carrying over the identification of any additional element(s) in the claim from Step 2A Prong Two; (2) carrying over the conclusions from Step 2A Prong Two on the considerations discussed in MPEP §§ 2106.05(a) - (c), (e) (f) and (h); (3) re-evaluating any additional element or combination of elements that was considered to be insignificant extra-solution activity per MPEP § 2106.05(g), because if such re-evaluation finds that the element is unconventional or otherwise more than what is well-understood, routine, conventional activity in the field, this finding may indicate that the additional element is no longer considered to be insignificant; and (4) evaluating whether any additional element or combination of elements are other than what is well-understood, routine, conventional activity in the field, or simply append well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, per MPEP § 2106.05(d). As noted and discussed in the above rejection, when all additional elements in claims 1-11, 15-17, 21-30, 32, and 33 have been evaluated individually and in combination at Eligibility Step 2B, they are deemed to not contribute an inventive concept, i.e., amount to significantly more than the judicial exceptions (MPEP 2106.05(II)). Third, the next generation sequencing (NGS) steps in independent claim 1 are steps of gathering the data used to generate the clinical report comprising the calculated tumor mutational burden (TMB) status and a match between the subject and one or more therapies, the match being based on at least the subject’s TMB status, and therefore the NGS limitations are additional elements that do not meaningfully limit the judicial exceptions, because these (and the other identified additional elements) do not apply, rely on, or use the judicial exception(s) in a manner that imposes a meaningful limit on the judicial exception.
The Applicant states on page 13 (para. 4) that the relevant questions under Step 2A, Prong Two are: (1) does NGS of the subject’s germline/somatic specimen to identify sequences of nucleotides in the germline/somatic specimen using the targeted-panel impose meaningful limits on the claim? And (2) is NGS of the subject’s germline/somatic specimen to identify the sequences required by all uses of a microservice for generating a data product. The Applicant states (para. 5, and page 14, paras. 1-3) that the answer to the first question is yes, and further states (page 14, paras. 4-6, and page 15, para. 1) that the answer to the second question is no, because it is possible to generate a generic data product without the use of any type of gene sequencing, let along NGS, and let alone NGS on a subject’s germline and somatic specimens using a targeted panel to generate germline and somatic sequencing results, and the Applicant expands on this answer (page 14, para. 6) by stating that the second microservice generates NGS results for the germline specimen (and thus does not rely on the somatic specimen), whereas the third microservice generates NGS results for the somatic specimen (and thus does not rely on the germline specimen), and (page 15, para. 1) because the use of both germline and somatic specimens is not required by all uses of NGS, NGS is not required by all uses of gene sequencing, and gene sequencing is not required by all uses of a microservice to generate a data product, the additional elements are much more than mere necessary data gathering and outputting.
These arguments are not persuasive, because first, with regard to the Applicant’s first question in the foregoing argument and the Applicant’s corresponding answer, the claim limitation(s) reciting next-generation sequencing of the subject’s germline/somatic specimen do not impose a meaningful limit on the claim(s) for the reasons given in the foregoing responses to arguments and in the above rejection. Second, with regard to the Applicant’s second question in the foregoing argument and the Applicant’s corresponding answer, it is noted that at MPEP 2106.05(g) (Insignificant Extra-Solution Activity) one of the several examples of activities that the courts have found to be insignificant extra-solution activity includes performing clinical tests on individuals to obtain input for an equation, which is analogous to performing genomic sequencing on a subject’s DNA sample to obtain sequencing data for use in determining a tumor mutational burden (TMB) status for determining matching therapies that are presented in a clinical report, as recited in independent claim 1.
The Applicant states on page 15 (para. 2) that claim 1 has been amended to further recite the clinical report comprising a match between the subject and a therapy, the match being based on at least the subject’s TMB status, and that these additional features provide for improvements in the technological fields of genomic sequencing and cancer treatment. The Applicant points to the Applicant’s own specification (Remarks, para. 3) for descriptions of generating a therapy match between a patient and therapies (e.g., Specification at paras. [0259], [0327], [0353], [0354], and [0359] – [0360]). Finally, the Applicant states (para. 4) that in addition to the features that impose meaningful limits on the claim, the claims recite additional features that effect an improvement in a technology or technological field, and therefore (para. 5) independent claim 1 recites additional features that are sufficient to incorporate the alleged judicial exception into a practical application thereof, and the claims are patent-eligible for at least this reason.
These arguments are not persuasive, because first, the limitations reciting a clinical report comprising a match between the subject and a therapy, the match being based on at least the subject’s TMB status, are limitations comprising judicial exceptions that are identified at Eligibility Step 2A Prong One in the above rejection, and thus, instant claimed advantage of an improvement in a technology or technological field is a purported improvement to the abstract idea (data analysis), and not an improvement to computer functionality itself, or an improvement to another technology or technical field. Second, and as noted in the responses to the foregoing arguments and as noted and discussed in the above rejection, the instant claims do not recite any additional elements that apply, rely on, or use the judicial exception(s) in a manner that imposes a meaningful limit on the judicial exception.
The Applicant summarizes the eligibility analysis process at Step 2B on page 15 (bottom) and page 16 (para. 1) of the Remarks, and states (para. 2) that in support of the Office’s conclusion that a plurality of microservices operating independent of the other system resources…is conventional, the Office refers to the 2017 article “Microservices: yesterday, today, and tomorrow” by the author Dragoni. The Applicant points out that Dragoni states that microservices are a new trend in software architecture, and the Applicant subsequently states that if microservices in general were a new trend around the effective filing date of the instant application, then it does not follow that a plurality of microservices operating independent of other system resources was well-understood, routine, or conventional, and further states that the Office in particular relies on Dragoni’s definition of a microservice, however, Dragoni expressly notes that there is a lack of consensus as to how to define a microservice.
These arguments are not persuasive, because first, the microservices (i.e., software programs) limitations are identified as judicial exceptions from the mental processes grouping of abstract ideas in the above rejection, and therefore are not limitations that are reevaluated at Step 2B (i.e., the microservice limitations are not additional elements), and therefore are not required to show conventionality, however the additional element(s) in the limitation “the plurality of microservices operate independent of the other system resources” is the “…independent of the other system resources” aspect of the limitation. The Dragoni reference, for its part, is used to show conventionality of computer technology equipped for a plurality of software programs to run independent of the other system resources (e.g., distributed computing), and the reference was particularly chosen in order to provide context for the instant claim limitations reciting a particular type of software architecture, i.e., microservices. Second, and although a moot point for the reasons provided in this response to arguments, Dragoni shows that the term “microservices” was first introduced in 2011 (well before the effective filing date of the claimed invention) and that until then, the software architecture approach had been known under different names (Dragoni, page 6, para. 3).
The Applicant states on page 16 (bottom) that in support of the Office’s conclusion that next generation sequencing (NGS) of a subject’s germline and somatic specimen… [is] conventional, the Office refers to the article “Next-generation DNA sequencing” by the author Shendure. The Applicant further states on page 17 (para. 1) of the Remarks that the Shendure reference does not support the Office’s conclusion. The Applicant further states (para. 2) that at best, Shendure sets forth various suggestions and predictions about what may, at some point in Shendure’s future, become more common.
These arguments are not persuasive, because first, the publication date of Shendure is 2008 (well in advance of the 12 July 2019 effective filing date of the claimed invention). Second, the selection of the Shendure reference was intentional so as to show conventionality of particular applications of next-generation sequencing that predated the effective filing date of the claimed invention by at least a decade (e.g., see Table 2 of the reference). Third, a well-understood, routine, and conventional practice in the writing of review articles for scientific and technical journals is to review the past and present state of the art by synthesizing existing research, identifying gaps, highlighting trends, offering critical evaluations, and discussing future directions, none of which would disqualify the Shendure reference from showing conventionality of the additional elements reevaluated at Step 2B in the above rejection. Fourth, Shendure clearly states that over the past three years (i.e., 2005-2008), massively parallel DNA sequencing platforms have become widely available, reducing the cost of DNA sequencing by over two orders of magnitude, and democratizing the field by putting the sequencing capacity of a major genome center in the hands of individual investigators (Abstract).
The Applicant states on page 17 (para. 3) that the Dragoni and Shendure references do not demonstrate that the additional elements are widely prevalent or in common use in the relevant field, comparable to the types of activity or elements that are so well-known that they do not need to be described in detail in a patent application to satisfy 35 U.S.C. 112(a). The Applicant further states (para. 4) that because the Office has not provided evidence that supports a conclusion that NGS as it is particularly recited in the Applicant’s claims is well-understood, routine, and conventional, the balance of the factors set forth in Office examination policy is in favor of a finding that the additional features are significant.
These arguments are not persuasive, at least because of the reasons already given in response to the foregoing arguments.
The Applicant further states on page 17 (para. 5) that the claims as amended recite features related to a therapy match for the subject, which effect an improvement in a technology or technological field, and in addition, this improvement is sufficient to amount to significantly more than the alleged judicial exception.
These arguments are not persuasive, at least because of the reasons already given in response to the foregoing arguments.
The Applicant states on page 18 (para. 1) that independent claim 1 recites additional features that are sufficient to amount to significantly more than the alleged judicial exception, and that the claims are patent-eligible for at least this reason.
These arguments are not persuasive, at least because of the reasons already given in response to the foregoing arguments.
The Applicant states on page 18 (para. 2) that to ensure completeness of record, the Applicant maintains and repeats the previously presented arguments that the additional features further improve the technology of gene sequencing and provide technical solutions to problems arising in the technical field of NGS. The Applicant further states that the Office’s response to these arguments is first to flatly deny that there is any such improvement, second to allege that the Colley application (incorporated by reference into this application) only provides a “wide-ranging review,” and third to simply repeat the conclusory allegation that the claims have been properly considered.
The Applicant’s effort to ensure completeness of record is noted, however the arguments are not persuasive, because first, the Office has not “flatly” denied anything, but rather presented a detailed analysis of the instant claims in accordance with the MPEP at 2106. Second, the Office did not assert that the Colley application “only provides a ‘wide-ranging review,’” but rather, the Office action mailed 27 May 2025 (at paragraph [96]) pointed out that the Colley application is directed to adaptive order fulfillment and tracking methods and systems, and the field of the disclosure is complex medical testing order processing and management methods and systems and more specifically adaptive order processing systems for generating customized complex orders including items to be facilitated by many different system resources, managing those resources to complete order items and ultimately generate order reports and to enable visualization of real time and historical order status (Colley, substitute specification, page 15, para. [0046]), and more specifically to systems and methods for automated quality assurance testing of structured clinical data and ensuring accurate data entry into one or more computer systems (Ibid., para. [00114]) and extraction and analysis of data embedded in patient health records (Ibid., e.g., paras. [00121], [00137], [00138], [00152], [00166], [00187]). The fact that Colley provides a wide-ranging review (Colley, substitute specification, throughout) of aspects of the human genome and methods for generating and analyzing genome data, does not provide support for the Applicant’s assertion that the instant claims improve the technology of gene sequencing. Third, and as noted above, the instant application and instant claims have been properly considered.
The Applicant states on page 18 (para. 3) that the recently-issued “August 4 Memo” noted above indicates that the Office’s response is incomplete. The Applicant further summarizes aspects of the Memorandum, and further states that the Applicant requests that the Office reconsider the previous arguments regarding improvements to gene sequencing and solutions to problems arising in the technical field of NGS with the above guidance (i.e., the Memorandum) in mind, and further states that the preponderance of the evidence of record supports a finding that the claims are patent-eligible.
These statements/arguments are not persuasive, because the “August 4 Memo” is not intended to announce any new USPTO practice or procedure and is meant to be consistent with existing USPTO guidance, which was adhered to during the examination of the instant claims.
The Applicant states on page 18 (para. 4) of the Remarks that because the Applicant’s independent claims recite a technical solution to a technological problem, the claims both integrate the alleged judicial exception into a practical application thereof and amount to significantly more than the judicial exception, and accordingly (para. 5) requests reconsideration and withdrawal of the rejection under 35 U.S.C. 101.
These arguments are not persuasive, at least for the reasons provided in the foregoing responses to arguments and in the above rejection.
Conclusion
No claims are allowed. I
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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/S.W.B./Examiner, Art Unit 1687
/Joseph Woitach/Primary Examiner, Art Unit 1687