DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant's response filed 6/18/2026 has been fully considered. The following rejections
and/or objections are either reiterated or newly applied.
Status of Claims
Claims 1-20 are pending and examined on the merits.
Priority
The instant application filed on 8/22/2022 claims the benefit of priority to U.S. Provisional Patent Application No. 63/245,639 filed on 9/17/2021. Thus, the effective filing date of the claims is 9/17/2021.
The applicant is reminded that amendments to the claims and specification must comply with 35 U.S.C. § 120 and 37 C.F.R. § 1.121 to maintain priority to an earlier-filed application. Claim amendments may impact the effective filing date if new subject matter is introduced that lacks support in the originally filed disclosure. If an amendment adds limitations that were not adequately described in the parent application, the claim may no longer be entitled to the priority date of the earlier filing.
Withdrawn Rejections
35 USC § 112(a)
The rejection of claim 19 under 35 USC 112(a) withdrawn in view of Applicant's claim amendments and remarks (page 5) filed on 6/18/2026.
35 USC § 112(b)
The rejection of claims 1, 11-12, 17, and 19 under 35 USC 112(b) withdrawn in view of Applicant's claim amendments and remarks (pages 4-5) filed on 6/18/2026. However, the newly recited rejection of claims 1-20 under 35 USC 112(b) is necessitated by claim amendments.
35 USC § 112(d)
The rejection of claim 2 under 35 USC 112(d) withdrawn in view of Applicant's claim amendments and remarks (page 6) filed on 6/18/2026.
35 USC § 101
The rejection of claims 1-10 and 12-20 under 35 USC 101 withdrawn in view of Applicant's claim amendments and arguments, "because the claimed technology improves the operation and reagent-consuming efficiency of a sequencing machine as part of physical sequencing pipeline" (Remarks 6/18/2026 pages 1-3). Specifically, these improvements are embodied in the amended additional element of a step which terminates a sequencing cycle of the one or more sample sequencing runs on the particular sequencing machine based on the determined failure source (Step 2A, Prong 2: the judicial exception is integrated into a practical application).
35 USC § 103
The rejections of claims 1, 3-10, 12-18, and 20 under 35 USC 103 withdrawn in view of Applicant's claim amendments filed on 6/18/2026.
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 1-20 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.
Claims 1, 12, and 17 recite "based on the determined failure source, terminate a sequencing cycle of the one or more sample sequencing runs on the particular sequencing machine". The claims do not previously require that the sample sequencing runs were performed on "the particular sequencing machine", and the failure source could be from "a nucleotide-sample slide" rendering "the particular sequencing machine" an alternative embodiment that is not required. Therefore, "the particular sequencing machine" lacks antecedent basis. Examiner notes the claims should be amended to recite that the one or more sample sequencing runs require a particular sequencing machine.
Claims 1 and 12 recite "based on the determined failure source, terminate a sequencing cycle of the one or more sample sequencing runs on the particular sequencing machine". It is not clear whether this step involves a processor transmitting instructions to terminate a sequencing cycle (which would be considered data output with the intended use to terminate a sequencing cycle outside the metes and bounds of the claimed system (claim 1) or computer-readable medium (claim 12)), or if the sequencer is part of the system, such that the processor is controlling the sequencer to terminate the sequencing (i.e. it is not clear if this step is just transmitting data, or if the system/computing device is required to include a sequencer). To further prosecution, claim 1 is interpreted as the system includes a sequencer in communication with the processor to terminate the sequencing (or similar amendment), and claim 12 is interpreted as the instructions cause a computing device in communication with a sequencer to terminate the sequencing (or similar amendment).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The rejection under 35 USC 103 of claims 1, 3-10, 12-18, and 20 contains newly recited portions and claims 2, 11, and 19 newly recited in whole, all necessitated by claim amendments.
Claims 1-7, 9-15, and 17-18 rejected under 35 U.S.C. 103 as being unpatentable over Blachly et al. (WO-2021126896) in view of Loose et al. (Nature methods 13.9 (2016): 751-754).
Regarding claims 1, 3-5, 7, 9-10, 12-15, and 17-18, Blachly teaches: determine base-call-error rates at which nucleotide-base calls generated by a sequencing pipeline for a sequenced reference genome differ from reference bases in a corresponding reference genome, and detect one or more base-call-error patterns from the base-call-error rates grouped according to base-call-error types identifying specific incorrect nucleotide-base calls made in place of correct nucleotide-base calls (which incorporates the limitations of claims 3-5, 7, 9-10, 13-15, and 18) (Para.0066 "The error profiles are determined through systematic experimentation, by determining how often a given NGS instrument (type or model) and combination of conditions correctly detected alleles, and the frequencies of correct and incorrect base calls and the related Q score distributions of these correct and incorrect calls at different genomic loci and in different genomic contexts for different combinations of kits/basecallers, etc", para.0095 "It was annotated whether the expected sequence was wildtype (matching the reference), had a mismatch (nucleotide substitution), or an insertion or deletion of nucleotides"; and para.0098 "To further improve accuracy, the process can be repeated separately for mismatches, insertions, and deletions, to identify an optimal scaling for each type of error. Furthermore, mismatches can also be further broken down to represent each potential 3- nucleotide codon that may be incorrectly called, to account for non-random patterns in the error profile").
Blachly also teaches based on the one or more base-call-error patterns, identify one or more sample base-call-error patterns for one or more sample sequencing runs that utilize one or more sequencing pipelines corresponding to the sequencing pipeline (Para.0098 "To further improve accuracy, the process can be repeated separately for mismatches, insertions, and deletions, to identify an optimal scaling for each type of error. Furthermore, mismatches can also be further broken down to represent each potential 3- nucleotide codon that may be incorrectly called, to account for non-random patterns in the error profile", the claimed “sample base-call-error pattern” being those identified as part of the “optimal scaling for each type of error” and the non-random patterns in the error profile correspond to the sequencing pipeline used).
Blachly also teaches based on a correlation between the one or more base-call-error patterns and the one or more sample base-call-error patterns, determine, for a base-call-error type corresponding to the sequencing pipeline, a failure source from a sequencing-pipeline material for a particular sequencing machine or a nucleotide-sample slide (Para.0014 "Alternatively or additionally, in some implementations, the step of receiving the locus-specific error profile for the base further includes reading the locus-specific error profile for the base from a lookup table (LUT). The LUT stores a plurality of sets of locus specific error profiles for the base. Additionally, each set of locus-specific error profiles for the base is associated with a different combination of a sequencing device model, a basecaller algorithm, a kit type, and/or a flowcell or chemistry type", i.e. Blachly is using a look-up table comprising pre-characterized error profiles that have been shown to be associated with known instrument setups suggests determining a failure source based on a correlation between one or more base-call-error patterns and one or more sample base-call-error patterns, because that is the purpose of this look-up table).
Blachly does not explicitly teach based on the determined failure source, terminate a sequencing cycle of the one or more sample sequencing runs on the particular sequencing machine.
However, Loose teaches rejecting reads from being further sequencing by a sequencing platform based on analysis real-time data (Page 1 col 1 paragraph 2 "Because MinION streams data from all channels simultaneously, can address channels independently and is able to reverse the voltage across the pore, in principle it can reject individual DNA molecules to enable selective sequencing. Reads that are rejected before being sequenced to completion are unlikely to be sequenced again [. . .]. We now describe a computational tool, which we also named Read Until, for controlling which sampled molecules are rejected for sequencing based on the identity of an initial set of sequenced bases").
Therefore, it would have been obvious to one of ordinary skill in the art as of the effective filing date of the claimed invention to modify the methods of Blachly as taught by Loose in order to selectively sequence reads from a sequencing library preparation resulting in less unnecessary sequencing (page 1 col 1 paragraph 1 "An ideal targeted sequencing approach would allow the selection of any subset of DNA from a pool of molecules with minimal specialized library preparation. Current methods are sophisticated but not perfect, and can result in unnecessary sequencing of regions that are not of interest. Similarly, it is difficult to balance multiple sources of input DNA for a single sequencing library, such as are found in amplicon-based sequencing, and ratios cannot subsequently be modified after library preparation is complete. These problems cannot be detected until the sequencing run is complete and data are available for analysis"). One skilled in the art would have a reasonable expectation of success because both methods are concerned with retaining higher quality sequence reads for further downstream analysis.
Additionally, Blachly et al. explicitly motivates employ combinations and sub-combinations of these complementary embodiments at least in para.0066, 0075, and 0104 including "Through experimentation and statistical analysis, locus-specific error profiles can be determined for the given allele and combination of Q score threshold/library kit/input nucleic acid type/flowcell/basecaller, etc" and otherwise motivating experimentation and optimization. Doing so merely combines prior art elements according to known methods to yield predictable results.
Regarding claim 2, Blachly and Loose teach the methods of Claim 1 on which this claim depends/these claims depend, respectively. Blachly also teaches determine base-call-error rates by determining normalized error rates expressed as a proportion of incorrect nucleotide-base calls relative to correct nucleotide-base calls for each nucleotide base type (Para.0095 "The percentage of reads matching each category at or above each minimum quality score cutoff was calculated to determine the expected overall error rate and error rate of each of the three types (mismatch, insertion, or deletion) of sequencing errors").
Regarding claim 6, Blachly and Loose teach the methods of Claim 1 on which this claim depends/these claims depend, respectively. Blachly also teaches providing, for display on a computing device associated with the sequencing pipeline, a notification indicating the failure source (Para.0072 "The report may be displayed on the display device 102 and/or printed on the printer 103").
Regarding claim 11, Blachly and Loose teach the methods of Claim 1 on which this claim depends/these claims depend, respectively. It would have been obvious to one of ordinary skill in the art to perform the claimed generation of a truncated manufacturing identification code and grouping sequencing runs by said code, as such a modification represents a predictable variation of known techniques in the art for applying identifying variables to experimental samples MPEP 2144.07, Art Recognized Suitability for an Intended Purpose). As evidenced by Blachly, the lookup table contains various pieces of device and reagent identifiers that would be suitable for the intended purpose of grouping sequencing runs by a set of manufacturing identification data.
Claim 8 rejected under 35 U.S.C. 103 as being unpatentable over Blachly et al. (WO-2021126896) and Loose et al. (Nature methods 13.9 (2016): 751-754) as applied to claims 1-7, 9-15, and 17-18 above, and further in view of Laehnemann et al. (Briefings in bioinformatics 17.1 (2016): 154-179).
Blachly et al. and Loose et al. are applied to claims 1, 3-7, 9-15, and 17-18.
Regarding claim 8, Blachly and Loose teach the method of Claim 1 on which this claim depends/these claims depend.
Blachly does not explicitly teach determine the base-call-error rates by utilizing a confusion matrix.
However, Laehnemann teaches determine the base-call-error rates by utilizing a confusion matrix (Page 19 col 2 second to last paragraph "Therefore, an approach used by several tools (Supplementary Note S5) is to employ an empirically determined base confusion matrix that gives the probability of every possible base substitution separately instead of assuming a uniform substitution probability (i.e. a matrix with 4 by 4 substitution probabilities)").
Therefore, it would have been obvious to one of ordinary skill in the art as of the effective filing date of the claimed invention to modify the methods of Blachly and Loose as taught by Laehnemann in order to characterize base calling errors common to high-throughput sequencing platforms (page 1 abstract "Characterizing the errors generated by common high-throughput sequencing platforms and telling true genetic variation from technical artefacts are two interdependent steps, essential to many analyses such as single nucleotide variant calling, haplotype inference, sequence assembly and evolutionary studies"). One skilled in the art would have a reasonable expectation of success because both methods are concerned with determining base call errors.
Claims 16 and 19 rejected under 35 U.S.C. 103 as being unpatentable over Blachly et al. (WO-2021126896) and Loose et al. (Nature methods 13.9 (2016): 751-754) as applied to claims 1-7, 9-15, and 17-18 above, and further in view of Laehnemann et al. (Briefings in bioinformatics 17.1 (2016): 154-179) and Landgrebe et al. (IEEE transactions on pattern analysis and machine intelligence 30.5 (2008): 810-822).
Blachly et al. and Loose et al. are applied to claims 1, 3-7, 9-15, and 17-18.
Regarding claim 16, Blachly and Loose teach the method of Claim 1 on which this claim depends/these claims depend.
Blachly does not explicitly teach determining the base-call-error rates by utilizing a confusion matrix and normalizing a confusion matrix comprising base-call-error data based on a total of correct nucleotide-base calls for a specific type of nucleotide-base call.
However, Laehnemann teaches determining the base-call-error rates by utilizing a confusion matrix (Page 19 col 2 second to last paragraph "Therefore, an approach used by several tools (Supplementary Note S5) is to employ an empirically determined base confusion matrix that gives the probability of every possible base substitution separately instead of assuming a uniform substitution probability (i.e. a matrix with 4 by 4 substitution probabilities)").
However, Landgrebe teaches normalizing a confusion matrix (Page 12 Figure 4 "Normalised confusion matrix for the Digits dataset example, with unit weighting on the left, and a perturbation of φ7 on the right" demonstrates normalization of a multiclass confusion matrix, and it would have been obvious to normalize the error rates of the confusion matrix of Laehnemann with the normalization method on Landgrebe in order to make a proper comparison between failure sources because converting raw counts into proportions or percentages makes it easier to interpret imbalanced datasets).
Therefore, it would have been obvious to one of ordinary skill in the art as of the effective filing date of the claimed invention to modify the methods of Blachly and Loose as taught by Laehnemann in order to characterize base calling errors common to high-throughput sequencing platforms (page 1 abstract "Characterizing the errors generated by common high-throughput sequencing platforms and telling true genetic variation from technical artefacts are two interdependent steps, essential to many analyses such as single nucleotide variant calling, haplotype inference, sequence assembly and evolutionary studies"). One skilled in the art would have a reasonable expectation of success because both methods are concerned with determining base call errors.
Therefore, it would have been obvious to one of ordinary skill in the art as of the effective filing date of the claimed invention to modify the methods of Blachly and Loose as taught by Landgrebe in order to confer ROC analysis to the present pattern recognition problem (page 2 last paragraph "Extension to the multiclass case is attractive since it would confer the benefits of ROC analysis to many more problems in pattern recognition"). One skilled in the art would have a reasonable expectation of success because both methods are concerned with evaluating a confusion matrix of classifications.
Regarding claim 19, Blachly and Loose teach the method of Claim 17 on which this claim depends/these claims depend. Landgrebe teaches normalizing a confusion matrix (as indicated above for claim 16), and normalized error rates so that they “are comparable across sequencing runs” is inherent in normalizing data.
Claim 20 rejected under 35 U.S.C. 103 as being unpatentable over Blachly et al. (WO-2021126896) and Loose et al. (Nature methods 13.9 (2016): 751-754) as applied to claims 1-7, 9-15, and 17-18 above, and further in view of Tourlousse et al. (Microbiome 9.1 (Apr. 2021): 95).
Blachly et al. and Loose et al. are applied to claims 1, 3-7, 9-15, and 17-18.
Regarding claim 20, Blachly and Loose teaches the method of Claim 1 on which this claim depends/these claims depend.
Blachly does not explicitly teach determining the correlation between the one or more base-call-error patterns and the one or more sample base-call-error patterns by utilizing a variance components model to determine percentages of assignable cause variations for sequencing-pipeline materials contributing to base-call errors of the base-call-error type.
However, Tourlousse teaches determining the correlation between the one or more base-call-error patterns and the one or more sample base-call-error patterns by utilizing a variance components model to determine percentages of assignable cause variations for sequencing-pipeline materials contributing to base-call errors of the base-call-error type (Page 8 col 2 last paragraph "We next performed decomposition of variance components by analysis of variance (ANOVA) based on Aitchison distances and summarized variability in terms of qmCV values estimated from resulting metric variance components (see Supplementary Methods). With respect to sequencing library construction, both intermediate precision and interlaboratory reproducibility were high").
Therefore, it would have been obvious to one of ordinary skill in the art as of the effective filing date of the claimed invention to modify the methods of Blachly and Loose as taught by Tourlousse in order to summarize and compare variability of base call errors across protocols (page 5 col 1 paragraph 2 "Finally, base call error rates were largely comparable across protocols, although positional effects were observed in some cases"). One skilled in the art would have a reasonable expectation of success because both methods are concerned with comparing variability of base call error patterns.
Response to Arguments under 35 USC § 103
Applicant’s arguments filed 6/18/2026 are fully considered but they are not persuasive.
Applicant asserts that Blachly fails to teach or suggest the amended limitation of "detect[ing] one or more base-call-error patterns from the base-call-error rates grouped according to base-call-error types identifying specific incorrect nucleotide-base calls made in place of correct nucleotide-base calls" (Remarks 6/18/2026 pages 6-7). Examiner notes that Blachly does suggest identifying specific incorrect nucleotide-base calls because that is exactly what is needed in order to describe variant-allele error categories (comparing a sequence read to a reference to identify errors), which Applicant concedes is taught by Blachly (also see figures 8A and 8B for specific base-call-error rates).
Applicant asserts that Blachly "further fails to describe or suggest claim limitations for determining a failure source based on a correlation between one or more base-call-error patterns and one or more sample base-call-error patterns" because "Blachly associated pre-characterized error profiles with known instrument setups" (Remarks 6/18/2026 page 8). Examiner notes that the "sources" (i.e. instrument setups) are likewise known for the instant claim. The fact that Blachly is using a look-up table comprising pre-characterized error profiles that have been shown to be associated with known instrument setups further reinforces the assertion that Blachly does in fact teach or suggest determining a failure source based on a correlation between one or more base-call-error patterns and one or more sample base-call-error patterns, because that is the purpose of the look-up table.
Applicant also asserts that Blachly "further fails to describe or suggest claim limitations for terminating a sequence cycle based on a determined failure source" (Remarks 6/18/2028 pages 8-9). Examiner concedes Applicant's assertion, however, a new rejection under 35 USC 103 has been applied as it was necessitate by claim amendments. It is indicated above that Blachly in combination with Loose render obvious the amended limitation of terminating a sequencing cycle of the one or more sample sequencing runs on the particular sequencing machine based on a failure source because Loose teaches rejecting reads from being further sequencing by a sequencing platform based on analysis real-time data (Page 1 col 1 paragraph 2 "Because MinION streams data from all channels simultaneously, can address channels independently and is able to reverse the voltage across the pore, in principle it can reject individual DNA molecules to enable selective sequencing. Reads that are rejected before being sequenced to completion are unlikely to be sequenced again [. . .]. We now describe a computational tool, which we also named Read Until, for controlling which sampled molecules are rejected for sequencing based on the identity of an initial set of sequenced bases").
Therefore, it would have been obvious to one of ordinary skill in the art as of the effective filing date of the claimed invention to modify the methods of Blachly as taught by Loose in order to selectively sequence reads from a sequencing library preparation resulting in less unnecessary sequencing (page 1 col 1 paragraph 1 "An ideal targeted sequencing approach would allow the selection of any subset of DNA from a pool of molecules with minimal specialized library preparation. Current methods are sophisticated but not perfect, and can result in unnecessary sequencing of regions that are not of interest. Similarly, it is difficult to balance multiple sources of input DNA for a single sequencing library, such as are found in amplicon-based sequencing, and ratios cannot subsequently be modified after library preparation is complete. These problems cannot be detected until the sequencing run is complete and data are available for analysis"). One skilled in the art would have a reasonable expectation of success because both methods are concerned with retaining higher quality sequence reads for further downstream analysis.
Additionally, Blachly et al. explicitly motivates employ combinations and sub-combinations of these complementary embodiments at least in para.0066, 0075, and 0104 including "Through experimentation and statistical analysis, locus-specific error profiles can be determined for the given allele and combination of Q score threshold/library kit/input nucleic acid type/flowcell/basecaller, etc" and otherwise motivating experimentation and optimization. Doing so merely combines prior art elements according to known methods to yield predictable results.
Conclusion
No claims are 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 TH REE-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 finaI action.
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/R.A.P./Examiner, Art Unit 1686
/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685
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