DETAILED ACTION
Applicant’s response, filed 22 April 202, 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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 22 April 2025 has been entered.
Claim Status
Claims 1-21 are pending and examined herein.
Claims 1 and 13 are objected to.
Claims 1-21 are rejected.
Priority
Claims 1-21 are granted the claim to the benefit of priority to U.S. Provisional application 63/002824 filed 31 March 2020. Thus, the effective filling date of claims 1-21 is 31 March 2020.
Drawings
The drawings received 18 September 2023 are objected to because the reference number 408 is mentioned in the disclosure but is not included in Figure 4. The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they do not include the following reference sign(s) mentioned in the description: 408 (in Figure 4). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 1 and 13 are objected to because of the following informalities:
Claims 1 and 13 recite “no greater a second threshold amount” in lines 28-29 of claim 1 and lines 31-32 of claim 13 but should read “no greater than a second threshold amount”.
Claims 1 and 13 recite “the sample data” in line 43 of the claim and line 46 of claim 13 but should read “the sample”. Appropriate correction is required.
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 1-21 are 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.
(Step 1)
Claims 1-12 fall under the statutory category of a process and claims 13-21 fall under the statutory category of a machine.
(Step 2A prong 1)
Under the BRI, the instant claims recite judicial exceptions that are an abstract idea of the type that is in the grouping of a “mental process”, such as procedures for evaluating, analyzing or organizing information, and forming judgement or an opinion.
Independent claim 1 (a method) and claim 13 (a system) recite mental processes of “analyzing the sequencing data to determine a first subset of the sequencing reads that include one or more control regions…”, “determining a first number of sequencing reads of the first subset of sequencing reads that correspond to a first partition…”, “determining a second number of sequencing reads of the first subset of sequencing reads that correspond to a second partition…”, “generating MBD binding calibration data that indicates a first number of probabilities of additional nucleic acids being associated with the first partition and a second number of probabilities…”, “analyzing the sequencing data to determine a second subset of the sequencing reads that include one or more classification regions…”, “determining partition data for the second subset of the sequencing reads based on partition tags included in the second subset of the sequencing reads…”, “determining CG region data that indicates a number of CG regions of individual nucleic acids that correspond to the individual sequencing reads of the second subset of sequencing reads”, and “determining an amount of methylation of the number of CG regions in individual classification regions of the one or more classification regions based on an analysis of the partition data and the CG region data in relation to the MBD calibration data”.
Claim 1 recites mathematical concepts of “determining an estimate for tumor fraction of the sample data by maximizing a likelihood of the estimate of the tumor fraction based on the amounts of methylation of the one or more classification regions, the estimate for tumor fraction indicating a number of nucleic acids included in the sample derived from a tumor”.
Dependent claims 2 and 14 recite a mental process of “analyzing the sequencing data to determine a third subset of the sequencing reads that include one or more additional control regions…”, “determining a third number of sequencing reads of the third subset of sequencing reads that correspond to the first partition…”, “determining a fourth number of sequencing reads of the third subset of sequencing reads that correspond to the second partition…”, and “determining a third number of probabilities of the additional nucleic acids being associated with the first partition and a fourth number of probabilities of the additional nucleic acids being associated with the second partition wherein…”. Dependent claims 3 and 15 recite a mental process and a mathematical concept of “determining a respective likelihood for a plurality of candidate amounts of methylation of the number of CG regions in the individual classification regions of the one or more classification regions based on…”. Dependent claims 4 and 16 recite a mental process of “performing an alignment process to determine amounts of homology between…” and “determining, based on the alignment process, the first subset of sequencing reads by determining…”. Dependent claims 5 and 17 recite a mental process of “performing an alignment process to determine amounts of homology between…” and “determining, based on the alignment process, the second subset of sequencing reads by…”. Dependent claims 7 and 19 recite a mental process of “determining the one or more classification regions by determining a first plurality of classification regions having at least a first threshold methylation rate in tumor cells” and “determining a second plurality of classification regions having no greater than a second threshold…”. Dependent claim 8 and 20 recites a mental process and mathematical concept of “determining a first likelihood of a candidate estimate of the tumor fraction for the sample based on…” and “determining a second likelihood of the candidate estimate of the tumor fraction for the sample based on…”. Dependent claims 9 and 21 recite a mental process and mathematical concept of “determining a probability of a presence of a tumor in the subject from which the sample is derived based on the tumor fraction”. Dependent claim 12 recites a mental process of “determining that the first portion of the plurality of nucleic acids is associated with the first partition of the plurality of partitions”, “determining that the first subset of the second portion of the plurality of nucleic acids is associated with an additional partition of the plurality of partitions”, and “determining that the second subset of the second portion of the plurality of nucleic acids is associated with the second partition”.
The claims recite analyzing/evaluating sequencing data to determine subsets of data, determining numbers of reads corresponding to a partition that was based on methylated regions, generating MBD calibration data based on the number of first and second reads, analyzing a second subset, determining partition data in a second subset, determining CG region data, and determining an amount of methylation of the number of CG regions in individual classification regions. The human mind is capable of analyzing data, organizing data, and making judgments on the data which the human mind is capable of performing. The claims recite a mathematical concept of determining an estimate of the tumor fraction of sample data by maximizing a likelihood of the estimate of the tumor fraction based on the amounts of methylation, determining likelihoods, and determining probabilities through mathematical calculations using numerical data (as shown in [0095]-[0100] and [0119]-[0128] of the instant disclosure). Dependent claims 6 and 18 further limit the mental process/mathematical concept recited in the independent claim but do not change their nature as a mental process/mathematical concept.
(Step 2A prong 2)
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). Integration into a practical application is evaluated by identifying whether there are any additional elements recited in the claim and evaluating those additional elements to determine whether they integrate the exception into a practical application.
The additional element in claim 1 and 13 of performing judicial exceptions in a generic computer environment and the additional element in claim 13 of a computer readable media storing instructions that cause a generic computer to perform judicial exceptions does not integrate the judicial exception into a practical application because this is simply applying the judicial exception to a generic computer without an improvement to computer technology. These additional elements only interact with the judicial exceptions by utilizing a computer as a tool to perform the judicial exceptions.
The additional element in claim 1 and 13 of obtaining sequencing data comprising sequence reads indicating a nucleotide sequence of a nucleic acid included in a cfDNA sample and indicating a methyl binding domain (MBD) partition of a plurality of MBD partitions, the MBD partition indicating an amount of methylation of cytosine-guanin (CG) regions of the nucleotide sequence, wherein individual CG regions of the nucleic acid sequence include at least a threshold number of cytosine-guanine pairs and the additional element in claim 10 of wherein the sample includes a first number of nucleic acids derived from blood or tissue of a subject and a second number of synthetic nucleic acid that include nucleotide sequences that correspond to the one or more control regions do not integrate the judicial exception into a practical application because this is adding insignificant extra solution activity of data gathering. This step of obtaining sequencing data is interpreted as a computer receiving already generated sequencing data and the further limiting of the sample is interpreted as limiting the content of the already generated sequencing data being received. This additional element interacts with the judicial exceptions only by providing data to be processed by the judicial exceptions. It is noted that the content of the data does not change the active step of obtaining data in a computer environment and the content of the data is part of the abstract idea.
The additional elements in claim 11 of performing methyl capture and performing elations to partition sequences do not integrate the judicial exception into a practical application because this is adding insignificant extra solution activity of data gathering. These additional elements interacts with the judicial exceptions only by providing data to be processed by the judicial exceptions.
The additional element in claim 12 of attaching barcodes to nucleic acids to identify different partitions does not integrate the judicial exception into a practical application because this is adding insignificant extra solution activity of data gathering. This additional element interacts with the judicial exceptions only by providing data to be processed by the judicial exceptions.
Thus, the additional elements do not integrate the judicial exceptions into a practical application.
(Step 2B)
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because:
The additional element in claim 1 and 13 of performing judicial exceptions in a generic computer and the additional element in claim 13 of a computer readable media storing instructions that cause a generic computer to perform judicial exceptions is conventional as shown by MPEP 2106.05(b) and 2106.05(d)(II).
The additional element in claim 1 and 13 of obtaining sequencing data comprising sequence reads indicating a nucleotide sequence of a nucleic acid included in a cfDNA sample and indicating a methyl binding domain (MBD) partition of a plurality of MBD partitions, the MBD partition indicating an amount of methylation of cytosine-guanin (CG) regions of the nucleotide sequence, wherein individual CG regions of the nucleic acid sequence include at least a threshold number of cytosine-guanine pairs and the additional element in claim 10 of wherein the sample includes a first number of nucleic acids derived from blood or tissue of a subject and a second number of synthetic nucleic acid that include nucleotide sequences that correspond to the one or more control regions are conventional as shown by MPEP 2106.05(b) and 2106.05(d)(II). This step of obtaining sequencing data is interpreted as a computer receiving already generated sequencing data and the further limiting of the sample is interpreted as limiting the content of the already generated sequencing data being received. It is noted that the content of the data does not change the active step of obtaining data in a computer environment.
The additional element in claim 11 of performing methyl capture and elution is conventional as shown on page 227 and 230 of Hsu et al. (Molecular Toxicology Protocols (2020): 225-234; newly cited) which shows the use of a commercially available kit (Methyl Miner kit) to perform a MBD capture assay and shows elution at different salt concentrations to analyze different methylation densities, as shown on page 233 of Brinkman et al. (Methods 52.3 (2010): 232-236; newly cited) which shows a Methyl capture assay which utilizes different salt concentrations for eluting sequences different methylation densities, and as shown on page 2 of De Meyer et al. (PloS one 8.3 (2013): e59068; newly cited) which shows several commercially available MBD capture assay kits and elution protocols.
The additional element in claim 12 of attaching barcodes to nucleic acids is conventional as shown by Plongthongkum et al. (Nature Reviews Genetics 15.10 (2014): 647-661; newly cited) which reviews profiling of DNA methylation modifications and shows attaching barcodes to nucleic acids.
Thus, the additional elements do not amount to significantly more than the judicial exception.
Response to Arguments
Applicant's arguments filed 22 April 2025 have been fully considered but they are not persuasive.
Applicant argues the recited claims make use of calibration sequences having known methylation states in order to obtain information about the methylation states of the cfDNA in the patient samples being analyzed. Such calibration sequences may be added exogenously to a sample or be endogenous to the sample. This feature of the claims is not routine. Applicant further argues that the calibration data is used, in part, to determine the tumor fraction present in the patient sample, an integration of the abstract calculation and the non-routine steps into a practical application. (Reply p. 12).
These arguments have been fully considered but found to be not persuasive. The MPEP states at 2106.05(d) “another consideration when determining whether a claim recites significantly more than a judicial exception is whether the additional element(s) are well-understood, routine, conventional activities previously known to the industry” which shows that that the analysis of conventionality is reserved for additional elements (i.e., not judicial exceptions). The claims do not recite additional elements (i.e., such as wet lab steps) that provide the feature of using calibration sequences. Therefore, this feature is not considered for conventionality because it is not an additional element. Claim 1 does not require a physical step of sequencing and is interpreted as receiving already generated sequencing data and the further limiting of the sample (as set out in claim 10) is interpreted as limiting the content of the already generated sequencing data being received. Further, the additional element of obtaining data in a computer environment is a step of insignificant extra solution activity of data gathering because this additional element only interacts with the judicial exceptions by providing data to be processed by the judicial exception. It is noted that the content of the data obtained is part of the abstract idea and it does not change the active step of obtaining data in a computer environment.
Conclusion
No claims are allowed.
This Office action is a Non-Final action. A shortened statutory period for reply to this action is set to expire THREE MONTHS from the mailing date of this action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JONATHAN EDWARD HAYES whose telephone number is (571)272-6165. The examiner can normally be reached M-F 9am-5pm.
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, Olivia Wise can be reached at 571-272-2249. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/J.E.H./Examiner, Art Unit 1685
/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685