DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1-20 are pending and examined herein.
No claims are canceled.
Priority
As detailed on the 01 December 2023 filing receipt, the application claims priority as early as 29 June 2021. At this point in examination, all claims have been interpreted as being accorded this priority date as the effective filing date.
Information Disclosure Statement
Information disclosure statements (IDS) were filed on 21 July 2022, 10 November 2022, 08 August 2024, 26 September 2024, 14 November 2024, and 13 November 2025. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the references are being considered by the examiner except for the foreign patent document WO 2023/186819 in the 14 November 2024 document, which is struck through as it was not found in the application contents, and US 2017/0003405 in the 13 November 2025 document, which is struck through as it was duplicated.
Claim Rejections - 35 USC § 112(a)
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 1-14 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.
Claim 1 recites a system comprising at least one processor and a non-transitory computer readable medium which detects a signal from labeled nucleotide bases within a section of a nucleotide-sample slide. Claim 11 recites a non-transitory computer-readable medium which performs a similar step. Regarding the system, the base calling occurs in a sequencing device which is not recited in the claims. If the system is interpreted as a computer system, there does not appear to be hardware for detecting information from a slide (e.g., Figure 12). The computer-readable medium in claim 11 recites detecting a signal from a slide using a computing device, and similarly there does not appear to be sufficient written description for a computing device, considered to have the components disclosed in Figure 12, to perform this step. Dependent claims 2-10 and 12-14 are similarly rejected.
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 1-20 are rejected under 35 USC § 101 because the claimed inventions are directed to an abstract idea without significantly more. "Claims directed to nothing more than abstract ideas (such as a mathematical formula or equation), natural phenomena, and laws of nature are not eligible for patent protection" (MPEP 2106.04 § I). Abstract ideas include mathematical concepts, and procedures for evaluating, analyzing or organizing information, which are a type of mental process (MPEP 2106.04(a)(2)). The claims as a whole, considering all claim elements individually and in combination, are directed to a judicial exception at Step 2A, Prong 2, and the additional elements of the claims, considered individually and in combination, do not provide significantly more at Step 2B than the abstract idea of determining base calls and base call quality.
MPEP 2106 organizes JE analysis into Steps 1, 2A (Prong One & Prong Two), and 2B as analyzed below.
Step 1: Are the claims directed to a process, machine, manufacture, or composition of matter (MPEP 2106.03)?
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e., a law of
nature, a natural phenomenon, or an abstract idea (MPEP 2106.04(a-c))?
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application by an additional element (MPEP 2106.04(d))?
Step 2B: Do the claims recite a non-conventional arrangement of elements in addition to any identified judicial exception(s) (MPEP 2106.05)?
Step 1: Are the claims directed to a 101 process, machine, manufacture, or composition of matter (MPEP 2106.03)?
The claims are directed to a computer system (claims 1-10), a non-transitory computer-readable medium (claims 11-14), and method (claims 15-20), each of which falls within one of the categories of statutory subject matter. [Step 1: Yes]
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e., a law of nature, a natural phenomenon, or an abstract idea (MPEP 2106.04(a-c))?
With respect to Step 2A, Prong One, the claims recite judicial exceptions in the form of abstract ideas. MPEP § 2106.04(a)(2) further explains that abstract ideas are defined as:
• mathematical concepts (mathematical formulas or equations, mathematical relationships
and mathematical calculations) (MPEP 2106.04(a)(2)(I));
• certain methods of organizing human activity (fundamental economic principles or practices, managing personal behavior or relationships or interactions between people) (MPEP 2106.04(a)(2)(II)); and/or
• mental processes (concepts practically performed in the human mind, including observations, evaluations, judgments, and opinions) (MPEP 2106.04(a)(2)(III)).
The claims recite to “determine… a scaling factor and a noise level” (claims 1 and 11), where a scaling factor is disclosed as coefficient (pg. 16, paragraph [41]) determined by a least squares algorithm (pg. 10, paragraph [28]) and a noise level is a value based on signal variation (pg. 16, paragraph [41]) which forms part of a ratio and is thus a mathematical concept.
The claims recite to “generate a signal-to-noise-ratio metric” (claims 1 and 11), where generating a ratio and/or metric is interpreted as a verbal description of a mathematical concept.
The claims recite to “generate, utilizing a base-call-quality model, a quality metric” (claim 1), where the step is interpreted as a mathematical concept in view of the specification, which discloses the model uses the ratio as an input into a Phred algorithm to generate a Q-score of accuracy (pg. 45, paragraph [111]).
The claims recite to determine a noise level by “determining… corrected intensity values” and “determining the noise level… based on the corrected intensity values” (claim 2). This claim is interpreted as modifying a value using another value based on the mathematical concepts discussed related to the independent claims and thus also a mathematical concept.
The claims recite to “determine… the corrected intensity values… the scaling factor… and correction offset factors” (claims 3), which are all interpreted as determining numerical values and thus mathematical concepts.
The claims recite to “determine the noise level” by “determining centroid intensity values” and “determining distances between the centroid intensity values and the corrected intensity values” (claim 4); determining a centroid and measuring distances between that value and intensity vales are mathematical concepts.
The claims recite to “determine… an average noise level” and “determine… the noise level corresponding to the signal” (claim 5), which are mathematical concepts related to determining and comparing an average.
The claims recite “determining a relationship” between values, “determining an error function,” and “determining the scaling factor by generating a partial derivative” (claim 6), all of which are verbal descriptions of mathematical concepts.
The claims recite to “generate the signal-to-noise-ratio metric” for different sections of the slide (claim 7), where determining the metric is already determined to be a mathematical concept.
The claims recite to “generate the quality metric estimating the error… by generating a Phred quality score” (claim 8), where generate a metric based on Phred is a mathematical concept.
The claims recite to “determine a chastity value” based on centroid differences and to “generate, utilizing the base-call-quality model, the quality metric” based on the values (claim 9), which are verbal descriptions of mathematical concepts.
The claims recite further aspects of determining noise levels, weighting noise levels, and using the weighted noise levels (claim 10), which are verbal descriptions of mathematical concepts.
The claims recite to “include or exclude a… call” (claim 11), which is a data evaluation or selection step practically performed by the human mind and thus a mental process.
The claims recite to “exclude… calls… based on determining that the signal-to-noise-ratio metric is lower than” the threshold (claim 12), which is a mental step of data selection and comparison.
The claims recite to “generate the signal-to-noise-ratio metric by equating the scaling factor to the signal to determine a ratio” (claim 13), which is a verbal description of mathematical steps.
The claims recite to “generate the signal-to-noise-ratio” for a given position (claim 14), which is a mathematical concept for the reasons explained above.
The claims recite “generating signal-to-noise-ratio metrics” based on the signals and determining ranges from the metrics (claim 15),
The claims recite “generating… intensity-value boundaries… according to one or more base-call models” (claim 15), where the step can be interpreted as a mental step of observing differences in data distributions.
The claims recite generating different boundaries corresponding to different nucleotide bases (claim 16), which is a mental step for the same reasons as its parent claim.
The claims recite generating calls for signals based on their occurrence inside nucleotide-specific ranges (claims 17-19), which is a mental step of data evaluation.
The claims recite generating boundaries according to Gaussian distributions models (claim 20), which is application of a mathematical concept.
Hence, the claims explicitly recite numerous elements that, individually and in combination,
constitute abstract ideas. The claims must therefore be examined further to determine whether they
integrate that abstract idea into a practical application (MPEP 2106.04(d)). [Step 2A: Yes]
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application by an additional element (MPEP 2106.04(d))?
The claims recite elements in addition to the abstract ideas: a system comprising at least one processor and non-transitory computer readable medium (claims 1 and 11) and detecting a signal from labeled nucleotide bases (claims 1, 11, 14-15, and 17-19).
The computer system is generically recited and amounts to instructions to apply the abstract idea using a computer, and therefore the claim does not integrate that abstract idea into a practical application. See MPEP 2106.04(d) § I; and MPEP 2106.05(f).
The detecting of signals from labeled nucleotide bases is a data gathering step necessary to perform the abstract quality control step. Data gathering is interpreted as insignificant extra solution activity and therefore the claim does not integrate that abstract idea into a practical application. See MPEP 2106.05(g).
Hence, the claims recite additional elements that do not integrate the abstract ideas into a practical application. The claims must therefore be examined further to determine conventionality of the additional elements alone or in combination (MPEP 2105). [Step 2A Prong Two: No]
Step 2B: Do the claims recite a non-conventional arrangement of elements in addition to any identified judicial exception(s) (MPEP 2106.05)?
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 of 101 analysis determines whether the claims contain additional elements that amount to an inventive concept, and an inventive concept cannot be furnished by an abstract idea itself (MPEP 2106.05).
The claims recite the following elements in addition to the abstract ideas: a system comprising at least one processor and non-transitory computer readable medium (claims 1 and 11) and detecting a signal from labeled nucleotide bases (claims 1, 11, 14-15, and 17-19).
The claims recite a computer for receiving information and performing calculations, which are conventional computer functions (see Symantec, 838 F.3d at 1321, 120 USPQ2d at 1362 (utilizing an intermediary computer to forward information), buySAFE, Inc. v. Google, Inc., 765 F.3d 1350, 1355, 112 USPQ2d 1093, 1096 (Fed. Cir. 2014) (computer receives and sends information over a network), Versata Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1334, 115 USPQ2d 1681, 1701 (Fed. Cir. 2015), and OIP Techs., 788 F.3d at 1363, 115 USPQ2d at 1092-93; Flook, 437 U.S. at 594, 198 USPQ2d at 199 (recomputing or readjusting alarm limit values); Bancorp Services v. Sun Life, 687 F.3d 1266, 1278, 103 USPQ2d 1425, 1433 (Fed. Cir. 2012). MPEP 2106.05(d)(II)(i)) pertains.
The step of detecting signals from labeled nucleotide bases, interpreted in light of the specification as using a camera in a sequencing-by-synthesis system to capture images of irradiated fluorophore tags (pg. 1, paragraph [2]) is conventional at the effective filing date of the instant application, and taught in a review by Gupta (Trends in Biotechnology 26(11): 602-611, 2008; newly cited) as using camera imaging to obtain images of fluorescent dye tagged to nucleotides upon incorporation (pg. 604, col. 2, second and third paragraphs; Fig. 1).
Therefore, the recited additional elements, alone or in combination with the judicial exceptions, do not appear to provide an inventive concept. [Step 2B: No]
Conclusion: Claims are Directed to Non-statutory Subject Matter
For these reasons, the claims, when the limitations are considered individually and as a whole,
are directed to an abstract idea and lack an inventive concept. Hence, the claimed invention does not
constitute significantly more than the abstract idea, so the claims are rejected under 35 USC § 101 as
being directed to non-statutory subject matter.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 8, and 11-14 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Tomaney (US 20110256631 A1; previously cited on the 13 November 2025 IDS form).
Claim 1 recites a system comprising at least one processor and a non-transitory computer readable medium comprising instructions. It is remarked that automating a manual activity is not sufficient to distinguish over the prior art. MPEP 2144.04(iii) pertains.
Tomaney teaches a computer readable medium and a computer with a processor (paragraph [66]).
Claim 1 recites to detect a signal from labeled nucleotide bases within a section of a nucleotide-sample slide.
Tomaney teaches “analyzing fluorescent signals from sequence by incorporation systems” (paragraph [10]).
Claim 1 recites to determine, for the section of the nucleotide-sample slide, a scaling factor and a
noise level corresponding to the signal based on intensity values for the signal.
Tomaney teaches a scaling factor as normalizing pulse brightness (paragraph [135]); the specification discloses the scaling factor accounts for amplitude/brightness variation (pg. 16, paragraph [41]) and pulse may be normalized (paragraph [135]) and thus scaled. Tomaney teaches background noise levels (paragraph [135]).
Claim 1 recites to generate a signal-to-noise-ratio metric for the section of the nucleotide-sample slide based on the scaling factor and the noise level.
Tomaney teaches a ratio of the signal in a signal event compared to background noise as a signal to noise ratio (paragraph [83]).
Claim 1 recites to generate, utilizing a base-call-quality model, a quality metric estimating an error of a nucleotide-base call corresponding to the signal based on the signal-to-noise-ratio metric.
Tomaney teaches a base-call-quality algorithm as Phred, which is further taught as taking into account factors such as signal to noise ratio (paragraph [153]).
Claim 2 recites to determine, for the section of the nucleotide-sample slide, the noise level corresponding to the signal based on the intensity values for the signal by determining, for the section of the nucleotide-sample slide, corrected intensity values for the signal and determining the noise level corresponding to the signal based on the corrected intensity values for the signal.
Tomaney teaches correcting intensities contaminated by crosstalk, where crosstalk is a type of noise (paragraph [182]), and correcting for background noise (paragraph [168]).
Claim 3 recites to determine, for the section of the nucleotide-sample slide, the corrected intensity values for the signal by determining the corrected intensity values based on the intensity values for the signal, the scaling factor corresponding to the signal, and correction offset factors corresponding to the signal.
Tomaney teaches correcting intensity (paragraph [182]) including an offset for a given pulse (paragraph [195]).
Claim 8 recites to generate the quality metric estimating the error of the nucleotide-base call corresponding to the signal based on the signal-to-noise-ratio metric by generating a Phred quality score estimating an accuracy of the nucleotide-base call corresponding to the signal based on the signal-to-noise-ratio metric.
Tomaney teaches Phred for quality-based base-calling using the signal to noise metric (paragraph [153]).
Claim 11 recites a non-transitory computer-readable medium storing instructions thereon that,
when executed by at least one processor, to detect a signal from labeled nucleotide bases within a section of a nucleotide-sample slide, to determine, for the section of the nucleotide-sample slide, a scaling factor and a noise level corresponding to the signal based on intensity values for the signal, and to generate a signal-to-noise-ratio metric for the section of the nucleotide-sample slide based on the scaling factor and the noise level.
Tomaney teaches the limitations of the processor, detecting a signal, determining a scaling factor and noise level, and generating a signal-to-noise ratio as related to claim 1 above.
Claim 11 recites, based on comparing the signal-to-noise-ratio metric to a signal-to-noise-ratio threshold, to include or exclude a nucleotide-base call corresponding to the signal within or from nucleotide base- call data.
Tomaney further teaches thresholding to exclude signal data (paragraph [85]).
Claim 12 recites to exclude subsequent nucleotide-base calls corresponding to subsequent signals detected from subsequent labeled nucleotide bases added to a cluster of oligonucleotides within the section of the nucleotide-sample slide based on determining that the signal-to-noise-ratio metric is lower than the signal-to-noise-ratio threshold.
Tomaney teaches the signal must exceed signal threshold level (paragraph [83]), interpreted as exclusion when the level is lower.
Claim 13 recites to generate the signal-to-noise-ratio metric by equating the scaling factor to the signal to determine a ratio of the scaling factor to the noise level.
Tomaney teaches relating signal to noise to generate the signal to noise ratio (paragraph [83]), where the signal is brightness or intensity of a pulse which may be normalized (paragraph [135]) and thus scaled.
Claim 14 recites to detect the signal by detecting the signal from the labeled nucleotide bases incorporated into a growing oligonucleotide at a genomic position later determined in alignment with a reference genome and generate the signal-to-noise-ratio metric for the nucleotide-base call at the genomic
position corresponding to the signal.
Tomaney teaches a signal detection into a growing polynucleotide strand (paragraph [150]) and subsequent sequence alignments (paragraph [166]), and determining a consensus at a given position (paragraph [216]).
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 factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Tomaney as applied to claims 1-3, 8, and 11-14 in the rejection under 35 USC 102(a)(1) and (a)(2) above and further in view of Rothberg (US 20190237160 A1; previously cited on the 10 November 2022 IDS form).
Claim 4 recites to determine the noise level corresponding to the signal based on the corrected intensity values for the signal by determining centroid intensity values for the nucleotide-base call corresponding to the signal and determining distances between the centroid intensity values and the corrected intensity values for the signal.
Tomaney teaches calibration based on centroid determination (paragraph [168]) but not specifically determining noise based on distance between centroids.
Rothberg teaches a base caller in which distances to the centroids are determined and assigning the nucleotide incorporation even to the closest centroid (pg. 14, paragraph [144]).
Combining Tomaney and Rothberg
An invention would have been obvious to one of ordinary skill in the art if some motivation in the prior art would have led that person to modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention. One would have been motivated to combine the centroid distance based measurement for base calling of Rothberg with the base calling method of Tomaney because Rothberg teaches determining a centroid per nucleotide and selecting nucleotide centroid with the shortest distance to the signal as the base call has advantages such as not requiring an algorithm (paragraph [142]) or with a number of different putative clusters (paragraph [139]). Tomaney and Rothberg are both directed to the shared field of endeavor of base calling and their combination would be prima facie obvious.
Claims 6-7 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Tomaney as applied to claims 1-3, 8, and 11-14 in the rejection under 35 USC 102(a)(1) and (a)(2) above and further in view of Langlois (US 20180260940 A1; previously cited on the 10 November 2022 IDS form).
Claim 6 recites to determine, for the section of the nucleotide-sample slide, the scaling factor corresponding to the signal based on the intensity values for the signal by determining a relationship between a measured intensity for the labeled nucleotide bases and variation correction coefficients comprising the scaling factor, determining an error function based on the relationship between the measured intensity and the variation correction coefficients, and determining the scaling factor by generating a partial derivative of the error function with respect to the scaling factor.
Langlois teaches correction coefficients related to partial derivatives of an error function (paragraphs [80-82]).
Claim 7 recites to generate the signal-to-noise-ratio metric for the section of the nucleotide-sample slide by generating the signal-to-noise-ratio metric for a well of a patterned flow cell or a subsection of a non-patterned flow cell.
Langlois teaches base calling applied to a patterned flow cell (paragraph [50]).
Claim 9 recites to determine a chastity value for the section of the nucleotide-sample slide based on distances between the intensity values for signal and intensity values of a nearest centroid and between the intensity values for the signal and intensity values for at least one additional centroid and generate, utilizing the base-call-quality model, the quality metric based on the signal-to-noise- ratio metric and the chastity value.
Langlois teaches chastity as a scoring metric that provides a measure of the overall quality of a spot location on a tile and may be determined both before and after applying distortion correction coefficients to a spot location (paragraph [39]). Langlois also teaches the distance to the nearest centroid divided by the distance to the second nearest centroid as a metric of quality (paragraph [93]).
Combining Tomaney and Langlois
An invention would have been obvious to one of ordinary skill in the art if some motivation in the prior art would have led that person to modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention. One would have been motivated to combine the correction coefficient as taught by Langlois with the base calling method of Tomaney because Langlois teaches such steps decrease imaging distortion and optimally correct an image (abstract), thus increasing the quality of the scoring for that image (paragraph [52]). Tomaney and Rothberg are both directed to the shared field of endeavor of base calling and their combination would be prima facie obvious.
Claims 15-20 are rejected under 35 U.S.C. 103 as being unpatentable over Tomaney as applied to claims 1-3, 8, and 11-14 in the rejection under 35 USC 102(a)(1) and (a)(2) above and further in view of Rothberg (US 20190237160 A1; previously cited on the 10 November 2022 IDS form).
Claim 15 recites detecting signals from labeled nucleotide bases within sections of at least one nucleotide sample slide.
Tomaney teaches “analyzing fluorescent signals from sequence by incorporation systems” (paragraph [10]).
Claim 15 recites generating signal-to-noise-ratio metrics for the sections of the at least one nucleotide sample slide based on the signals and noise levels corresponding to the signals.
Tomaney teaches a ratio of the signal in a signal event compared to background noise as a signal to noise ratio (paragraph [83]) and a base-call-quality algorithm, such as Phred, which takes into account factors such as signal to noise ratio (paragraph [153]).
Claim 15 recites determining signal-to-noise-ratio ranges for the signal-to-noise-ratio metrics.
Tomaney teaches at least standard deviations of ranges (paragraph [137]).
Claim 15 recites generating, for each signal-to-noise-ratio range of the signal-to-noise-ratio ranges, intensity-value boundaries for differentiating signals corresponding to different nucleotide bases
according to one or more base-call-distribution models.
Tomaney does not clearly teach intensity value boundaries for the different nucleobases.
Rothberg teaches an expected range of intensities for a nucleotide (paragraph [139]).
Claim 16 recites generating, for a first signal-to-noise-ratio range, a first set of intensity-value boundaries corresponding to the different nucleotide bases according to a first base-call-distribution model and generating, for a second signal-to-noise-ratio range, a second set of intensity-value boundaries corresponding to the different nucleotide bases according to a second base-call distribution model, the second set of intensity-value boundaries differing from the first set of intensity-value boundaries.
Rothberg teaches different ranges for base calls for more than one nucleotide (Fig. 13), where the areas around the clusters are interpreted as the intensity ranges.
Claim 17 recites detecting a first signal corresponding to a first signal-to-noise-ratio metric within the first signal-to-noise-ratio range and having a set of intensity values outside of the first set of intensity value boundaries and outside the second set of intensity-value boundaries, detecting a second signal corresponding to a second signal-to-noise-ratio metric within the second signal-to-noise-ratio range and having the set of intensity values, generating a first nucleotide-base call for the first signal based on the first set of intensity value boundaries for the first base-call-distribution model, and generating a second nucleotide-base call for the second signal based on the second set of intensity-value boundaries for the second base-call-distribution model.
This claim is interpreted as teaching base-calling based on a range of signal-to-noise and intensity. Tomaney teaches generating a signal-to-noise metric as discussed above, and Rothberg teaches calling a base if it falls within an expected intensity range for a nucleotide (paragraph [139]).
Claim 18 recites detecting a signal from a subset of labeled nucleotide bases from a cluster of
oligonucleotides within a section of a nucleotide-sample slide; generating a signal-to-noise-ratio metric, within a signal-to-noise-ratio range, for the section of the nucleotide-sample slide based on the signal; and
determining a nucleotide-base call corresponding to the signal based on a set of intensity value boundaries of the intensity-value boundaries corresponding to the signal-to-noise-ratio range.
Tomaney teaches generating a signal-to-noise metric as discussed above, and Rothberg teaches calling a base if it falls within an expected intensity range for a nucleotide (paragraph [139]).
Claim 19 recites detecting an additional signal from an additional subset of labeled nucleotide bases from an additional cluster of oligonucleotides within an additional section of the nucleotide-sample
slide; generating an additional signal-to-noise-ratio metric, within an additional signal-to-noise ratio range, for the additional section of the nucleotide-sample slide based on the additional signal, wherein the additional signal-to-noise-ratio range differs from the signal-to-noise-ratio range; and determining an additional nucleotide-base call corresponding to the additional signal based on an additional set of intensity-value boundaries of the intensity-value boundaries corresponding to the additional signal-to-noise-ratio range.
Rothberg teaches calling a base if it falls within an expected range for a nucleotide (paragraph [139]) for four nucleotides (Fig. 13).
Claim 20 recites generating the intensity-value boundaries according to on one or more Gaussian distribution models for each signal-to-noise-ratio range of the signal-to-noise-ratio ranges.
Rothberg teaches modeling the intensities of the different nucleotides in a normal distribution (Fig. 17A-D), where a Gaussian distribution is interpreted as reading on a normal distribution.
Combining Tomaney and Rothberg
An invention would have been obvious to one of ordinary skill in the art if some motivation in the prior art would have led that person to modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention. One would have been motivated to combine the centroid distance based measurement for base calling of Rothberg with the base calling method of Tomaney because Rothberg teaches determining a centroid per nucleotide and selecting nucleotide centroid with the shortest distance to the signal as the base call has advantages such as not requiring an algorithm (paragraph [142]) or with a number of different putative clusters (paragraph [139]). Tomaney and Rothberg are both directed to the shared field of endeavor of base calling and their combination would be prima facie obvious.
Claims Free of the Prior Art
Claims 5 and 10, which recite averaging noise levels for previous sequencing cycles and correcting or weighting an instant noise correction for an instant cycle is not taught by the above applied art – Tomaney, Rothberg, and Langlois – and thus these claims would be considered free of the prior art in the event the parent claim 1 is also free of the art or otherwise combined with parent claim 1.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Robert J Kallal whose telephone number is (571)272-6252. The examiner can normally be reached Monday through Friday 8 AM - 4 PM EST.
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/Robert J. Kallal/Examiner, Art Unit 1685