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 .
Claim Status
Original claims 1-20 drawn to a method and sequencing system to implement a method of generating phasing corrected intensity values for sequencing reaction, a system and medium are currently under examination.
Priority
This application filed 6/15/2021 is a continuation of application 16/899716 filed 6/12/2020 (allowance mailed 6/25/2026) is a continuation of 15/153953, filed 5/13/2016 now US Patent 10689696 which was a 371 National stage filing of PCT/US14/68409 filed 12/3/204 which claims benefit to US provisional applications 61/915426 filed 12/12/2013, 61/915455 filed 12/12/2013 and 61/911319 filed 12/302013; and is the parent of 17/348212 filed 6/15/2021.
Information Disclosure Statement
The seven information disclosure statements (IDS) submitted between 6/17/2021 to 11/20/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
It is noted that several PCT written opinions for PCTs and applications filed in foreign countries have been cited (see IDS file 7/6/17/2021 for example) without providing the application or claims that were under review or that are relevant to the applications, or any indication of their importance to the present claims and it is unclear if the references cited in these reviews been provided. These citations have been acknowledged and considered for what is written but not in the context of the full prosecution they may represent.
Additionally, it is noted that the listing of references in the specification is not a proper information disclosure statement. See for example pages 14 and 17. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
Claims 1, 5, 14, 16, 18 are objected to because of the following informalities: in claim 1 lines 7 and 9 for example, the term ‘star5’ is recited which is not a word or particular term defined in the specification, which appears to be a typographical error.
Appropriate correction is required.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 10,689696 (application 15/153953). Although the claims at issue are not identical, they are not patentably distinct from each other because ‘696 sets forth a system and method which provides for broader claim limitations for each of the steps for evaluating sequence data generated from a platform where over-lapping signals representing nucleotide incorporation are assessed to determine the most likely base incorporation at each cycle. Both methods and a system to implement the methodology are present in the claim set of ‘696. Claim 1 of ‘696 for the method is provided as evidence for the method which is implemented.
A method comprising:
(a) performing a plurality of cycles of a sequencing by synthesis reaction such that, at each cycle, a signal is generated that is indicative of incorporation of a same nucleotide into a plurality of identical polynucleotides, whereby a portion of the signal is noise associated with phasing or pre-phasing;
(b) detecting the signal at each cycle in at least one channel, wherein the signal at each cycle includes an intensity value for each channel; and
(c) performing cycle-by-cycle phasing corrections by applying a new first order phasing correction at each cycle to the intensity value for each channel;
wherein the new first order phasing correction is calculated for each channel of each cycle, wherein the new first order phasing correction includes subtracting an intensity value of an immediately previous cycle from
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 16/899716 (parent of instant application, allowance mailed not issued yet). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims set forth a system and method which provides for broader claim limitations for each of the steps of ‘716 for evaluating sequence data generated from a platform where over-lapping signals representing nucleotide incorporation are assessed to determine the most likely base incorporation at each cycle. Claim 1 of ‘716 for the system is provided as evidence for the system and the method which is implemented.
A system comprising:
at least one processor; and
a non-transitory computer readable medium comprising instructions that, when executed by the at least one processor, cause the system to:
determine a base call for a nucleotide base of a polynucleotide;
generate an online-overlap metric, a purity metric, a phasing metric, and a start5 metric for the base call;
determine a quality score for the base call based on the online-overlap metric, the purity metric, the phasing metric, and the start5 metric; and
generate output-base-calling data comprising the base call for the nucleotide base and the quality score.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. It is noted that notice of allowance has been mailed, however the application has not yet gone to issuance.
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 1-20 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.
Claim analysis
Claim 1 is generally directed to a system which implements a method of detecting incorporation of nucleotides during PCR through the use of data obtained from two channels. More specifically, the claims are directed to a computer implemented method where the intensity is corrected using phasing to the values to reduce the noise of interfering nucleotides previously incorporated. More specifically, the method comprises a first step where a plurality of sequencing cycles are performed and ‘intensity values’ are obtained. No specific platform is required of the method or set forth in the system, however in view of the specification and art of record sequencing methods that produce values associated with nucleotide base incorporation are well known. Once the intensity values are obtained, the method sets forth in a wherein clause further processing of four distributions associated with each of the nucleotide bases, where the processing evaluating and assessing the highest likelihood value of the nucleotide base that was incorporated during a given cycle.
For step 1 of the 101 analysis, the claims are found to be directed to a statutory category of a method stored on a non-transitory medium.
For step 2A of the 101 analysis, the judicial exception of the claims are the steps of analyzing light intensity data by applying first order phasing correction to the values. The judicial exception is a set of instructions for analysis of sequence data, which is a mathematical concept to the extent that the claims encompass analysis of intensity data over time representing the incorporation of nucleotide bases of the sequence data generated on a given platform, and also Mental Processes, that is concepts performed in the human mind (including an observation, evaluation, judgment, opinion) because of the broad generic nature of the claims required for ‘determine’ and ‘generate’ which appear to encompass observation of intensity values or representation of multiple values on a graph after the data was obtained from the sequencing platform. The claim construction for claim 1 appears to provide that the method is separated into two parts, receiving data during the sequencing process and then further comprising processing the data once it is received, separating the judicial exception into a process of data analysis.
Recent guidance from the office requires that the judicial exception be evaluated under a second prong to determine whether the judicial exception is practically applied. In this case, the method requires performing a plurality of cycles of a sequencing reaction and obtaining ‘intensity values’ which is subsequently analyzed in the judicial exception. The two parts of the claim appear separate and are not integrated where one might affects the other in any meaningful way beyond simply obtaining data for further analysis.
The breadth of ‘determine’ and ‘generate’ encompasses non-transformative visual assessment of sequence data, coupled in part with prior knowledge of the correlation of what each intensity represents or correlates to for proper interpretation of the sequencing intensity value data that is first generated. This breadth does not impose a meaningful limit on the claim scope, such that all others are not precluded from using observation or mathematical assessment of values. The limitations required of the claim do not appear to integrate a judicial exception into a practical application; for example, merely including instructions to implement an abstract idea on a computer, or merely using a computer as a tool to perform an abstract idea, as discussed in MPEP § 2106.05(f). Computing, constructing datasets and using statistical models was well understood, conventional, and routinely performed in the art at the time the application was filed. Furthermore, the limitation of ‘selecting’ in the analysis nor the process of obtaining the data and does not change the steps to be performed. See MPEP § 2106.05(g) for a discussion on adding insignificant extra-solution (both pre-solution and post-solution) activity to the judicial exception. See also MPEP § 2106.05(h) for a discussion on generally linking the use of a judicial exception to a particular technological environment or field of use, here possible the field of sequence analysis. The claims appear to fall into the category of Mathematical Concepts, as it applies the use of statistics and mathematical relationships in analyzing probabilities, and also into the category of mental processes, as concepts performed in the human mind (including an observation, evaluation, judgment, opinion) because there is no apparent complexity to or amount of data that is collected and analyzed as presently claimed.
For step 2B of the 101 analysis, each of the independent claims recites additional elements and are found to be the steps of obtaining sequence data which was well known. As such, the claims do not provide for any additional element to consider under step 2B beyond steps to obtain data which is subsequently and separately analyzed. While system claims require a processor and computer medium (note the method claims themselves do not require such limitations), it is noted that in explaining the Alice framework, the Court wrote that "[i]n cases involving software innovations, [the step one] inquiry often turns on whether the claims focus on the specific asserted improvement in computer capabilities or, instead, on a process that qualifies as an abstract idea for which computers are invoked merely as a tool." The Court further noted that "[s]ince Alice, we have found software inventions to be patent-eligible where they have made non-abstract improvements to existing technological processes and computer technology." Moreover, these improvements must be specific -- "[a]n improved result, without more stated in the claim, is not enough to confer eligibility to an otherwise abstract idea . . . [t]o be patent-eligible, the claims must recite a specific means or method that solves a problem in an existing technological process." As indicated in the summary of the judicial exception above and in view of the teachings of the specification, the steps are drawn to analysis of sequence data. While the instruction are stored on a medium and could be implemented on a computer, together the steps do not appear to result in significantly more than a means to compare sequences. The judicial exception of the method as claimed can be performed by hand and in light of the previous claims to a computer medium and in light of the teaching of the specification on a computer. In review of the instant specification the methods do not appear to require a special type of processor and can be performed on a general purpose computer. Dependent claims set forth additional steps which are more specifically define the considerations and steps of calculating, and comparing, and do not add additional elements which result in significantly more to the claimed method for the analysis.
In the instant case, the claims comprise steps of assessing sequence data and is considered the judicial exception. It is noted that while the claims set forth or imply information about the sequences being analyzed, this is only description of the data being analyzed and context and user defined. As such, the instant claims set forth an inventive concept that are drawn only to an abstract process that only manipulates data and, therefore, are not directed to statutory subject matter. No additional steps are recited in the instantly claimed invention that would amount to significantly more than the judicial exception than broad known means to obtain sequence data represented by ‘intensity values’. Furthermore, if a claim is directed essentially to a method of calculating, using a mathematical formula, even if the solution is for a specific purpose, the claimed method is non-statutory. In other words, patenting abstract idea (designing probes to a target sequence) cannot be circumvented by attempting to limit the use to a particular technological environment or purpose and desired result.
One way to overcome a rejection for non-patent-eligible subject matter is to persuasively argue that the claimed subject matter is not directed to a judicial exception. Another way for the applicants to overcome the rejection is to persuasively argue that the claims contain elements in addition to the judicial exception that either individually or as an ordered combination are not well understood, routine, or conventional. Another way for the applicants to overcome the rejection is to persuasively argue that the claims as a whole result in an improvement to a technology. Persuasive evidence for an improvement to a technology could be a comparison of results of the claimed subject matter with results of the prior art, or arguments based on scientific reasoning that the claimed subject matter inherently results an improvement over the prior art. The applicants should show why the claims require the improvement in all embodiments.
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 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.
Claims 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Whiteford et al. and Garcia et al. (both of record).
Sequencing system capable of recording light intensity in two and more channels were known and used to characterize sequencing reactions. For example, Whiteford teaches a method of generating a phasing-corrected intensity value (phase correction of a current cycle's intensity, [page 2196, 1st column, "2.2.2 Phasing correction”]) comprising: (a) performing a plurality of cycles of a sequencing (sequencing performed across N cycles, [page 2195, 2nd column, “2.1.3 Object identification and intensity extraction”]) by synthesis reaction such that, at each cycle, a signal is generated indicative of incorporation of the same nucleotide into a plurality of identical polynucleotides (A cycle of chemistry is performed which synthesizes a single fluorescently labelled complementary base to each DNA molecule, [page 2194, 2nd column, “2 METHODS”]), whereby a portion of the signal is noise associated with a nucleotide incorporated during a previous cycle (During each cycle, labelled nucleotides are incorporated into these molecules. However, this is driven by stochastic chemical processes, so some molecules may fail to incorporate a labelled nucleotide, or may fail to block and incorporate >1 nt. This manifests itself as a leakage in intensity between cycles. For example, if a G base is present in cycle 2, we will see a small amount of G intensity leaking into cycles 1 and 3, [page 2196,1st column, “2.2.2 Phasing correction”]; see also description of Fig. 4); (b) detecting the signal at each cycle, the signal having an intensity value (four intensities per cycle across N cycles, [page 2195, 2nd column, “2.1.3 Object identification and intensity extraction”]; intensities detected across each cycle, Fig. 4 description); and (c) correcting the intensity value for phasing by applying a first order phasing correction to the intensity value (phasing correction for each cycle, [page 2196, 1st column, “2.2.2 Phasing correction”]); wherein a new first order phasing correction is calculated for each cycle (correct each cycle and channel independently, [page 2196, 1st column, “2.2.2 Phasing correction”]). Further, Whiteford teaches the method of claim 1, wherein the first order phasing correction comprises subtracting an intensity value from the immediately previous cycle from the intensity value of the current cycle (From these we calculate the fraction of the intensity that has leaked between cycles and use this as our phasing estimate. This phasing estimation is then applied as a correction where this fraction of the current cycle’s intensity is subtracted from subsequent and previous cycles and added to the current cycle, [page 2196, 1st column, “2.2.2 Phasing correction”]).; and further comprising subtracting an intensity value from the immediately subsequent cycle from the intensity value of the current cycle (From these we calculate the fraction of the intensity that has leaked between cycles and use this as our phasing estimate. This phasing estimation is then applied as a correction where this fraction of the current cycle’s intensity is subtracted from subsequent and previous cycles and added to the current cycle, [page 2196, 1st column, “2.2.2 Phasing correction”]). Whiteford teaches the method of claim 1, wherein the sequencing run utilizes two-channel base calling (offset exists between channels...reference image for each channel is correlated against the other channels, [page 2195, 2nd column, “2.1.2 Image correlation”]; see also 2.2 Base calling). Whiteford teaches the method of claim 1, wherein the sequencing run utilizes one-channel base calling (a cluster would fluoresce in a single channel and the sequence of the template could be readily determined, [page 2194, 2nd column, “2 METHODS”]; see also 2.2 Base calling, [page 2195, 2nd column]). Whiteford teaches the method of claim 1, wherein the sequencing run utilizes four-channel base calling (four channels, [2.1. Image analysis]; see also 2.2 Base calling).
Similarly, Garcia teaches a method (methods and systems for analysis of image data generated at multiple reference points, and particularly to image and sequence data generated during DNA sequencing, [0003]) of generating a phasing-corrected intensity value (phase-correct intensities for a given cycle, [0187]) comprising: (a) performing a plurality of cycles of a sequencing (multiple cycles of a sequencing run, [0186]-[0187]) by synthesis reaction (sequencing-by-synthesis, [0090], [0169], [0007], [0088]) such that, at each cycle (cycle, [0189]-[0191]), a signal is generated (signal, [0192]-[0193]) indicative of incorporation of the same nucleotide into a plurality of identical polynucleotides (identifying a nucleotide base, [0189], each differently colored signal corresponds to a different nucleotide base, [0192]; Due to an interaction between the dye and the DNA base incorporated in the previous cycle, the intensities in certain color channels may be decreased (quenched) in cycles following those cycles where a G nucleotide was incorporated, [0202]), whereby a portion of the signal is noise associated with a nucleotide incorporated during a previous cycle ("signal overlap with background" (SOWB) refers to a measurement of the separation of the signal from the noise in previous and subsequent cycles, [0201]; "Shifted Purity G adjustment” refers to a measurement of the separation of the signal from the noise for the current base call only, while also accounting for G quenching effects. Due to an interaction between the dye and the DNA base incorporated in the previous cycle, the intensities in certain color channels may be decreased (quenched) in cycles following those cycles where a G nucleotide was incorporated, [0202]); (b) detecting the signal at each cycle, the signal having an intensity value (determining the intensity of each differently colored signal for the current cycle, [0191]-[0192]); and (c) correcting the intensity value for phasing by applying a first order phasing correction to the intensity value (to phase-correct intensities for a given cycle, the inverse of the phasing matrix is taken and the matrix row corresponding to the cycle is extracted. As a result, the vector of actual intensities for cycles 1 through N is the product of phasing matrix inverse and observed intensities for cycles 1 through N, [0187]); wherein a new first order phasing correction is calculated for each cycle (The relevant intensity files for neighboring cycles (determined by the size of the phasing window) are loaded and color-corrected using the color matrix. Those values are then used to determine a phasing-corrected intensity vector for the current cycle, [0191]). Garcia teaches the method of claim 71, wherein the sequencing run utilizes two-channel base calling (intensity measurements from two channels, [0028], [0065]; base calling, [0189]-[0193]). Garcia teaches the method of claim 71, wherein the sequencing run utilizes one-channel base calling (A, C, G and T are detected in separate channels, [0136]) and wherein the sequencing run utilizes four-channel base calling (each cycle involves simultaneous delivery of four different nucleotide types to the array and each nucleotide type has a spectrally distinct label. Four images can then be obtained, each using a detection channel that is selective for one of the four different labels, [0096]; intensity values are obtained from four color channels, [0204]). Further, Garcia teaches a system (system for analysis of image data generated at multiple reference points, and particularly to image and sequence data generated during DNA sequencing, [0003]) for generating a phasing-corrected intensity value (phase-correct intensities for a given cycle, [0187]), the system comprising: a processor; a storage capacity; and a program (system can comprise: a processor; a storage capacity; and a program, [0032]), the program comprising instructions for: (a) performing a plurality of cycles of a sequencing (multiple cycles of a sequencing run, [0186]-[0187]) by synthesis reaction (sequencing-by-synthesis, [0090], [0169], [0007], [0088]) such that, at each cycle (cycle, [0189]-[0191]), a signal is generated (signal, [0192]-[0193]) indicative of incorporation of the same nucleotide into a plurality of identical polynucleotides (identifying a nucleotide base, [0189], each differently colored signal corresponds to a different nucleotide base, [0192]; Due to an interaction between the dye and the DNA base incorporated in the previous cycle, the intensities in certain color channels may be decreased (quenched) in cycles following those cycles where a G nucleotide was incorporated, [0202]), whereby a portion of the signal is noise associated with a nucleotide incorporated during a previous cycle ("signal overlap with background" (SOWB) refers to a measurement of the separation of the signal from the noise in previous and subsequent cycles, [0201]; "Shifted Purity G adjustment" refers to a measurement of the separation of the signal from the noise for the current base call only, while also accounting for G quenching effects. Due to an interaction between the dye and the DNA base incorporated in the previous cycle, the intensities in certain color channels may be decreased (quenched) in cycles following those cycles where a G nucleotide was incorporated, [0202]); (b) detecting the signal at each cycle, the signal having an intensity value (determining the intensity of each differently colored signal for the current cycle, [0191]-[0192]); and (c) correcting the intensity value for phasing by applying a first order phasing correction to the intensity value (to phase-correct intensities for a given cycle, the inverse of the phasing matrix is taken and the matrix row corresponding to the cycle is extracted. As a result, the vector of actual intensities for cycles 1 through N is the product of phasing matrix inverse and observed intensities for cycles 1 through N, [0187]); wherein a new first order phasing correction is calculated for each cycle (The relevant intensity files for neighboring cycles (determined by the size of the phasing window) are loaded and color-corrected using the color matrix. Those values are then used to determine a phasing-corrected intensity vector for the current cycle, [0191]). Additionally, Garcia d teaches the system of claim 10, wherein the sequencing run utilizes two-channel base calling (intensity measurements from two channels, [0028], [0065]; base calling, [0189]-[0193]); and a system of claim 10, wherein the sequencing run utilizes one-channel base calling (A, C, G and T are detected in separate channels, [0136]).
While neither reference provides for the exact language of the claims, Whiteford teaches the method of claim 1, but is silent regarding wherein the phasing correction comprises: l(cycle)corrected = l(cycle) N - X'l(cycle) N-1 - Y*l(cycle) N+1. However, Whiteford teaches the phasing correction comprises subtracting a fraction of intensity values from subsequent or previous cycle’s intensity value (From these we calculate the fraction of the intensity that has leaked between cycles and use this as our phasing estimate. This phasing estimation is then applied as a correction where this fraction of the current cycle’s intensity is subtracted from subsequent and previous cycles and added to the current cycle, [page 2196, 1st column, see “2.2.2 Phasing correction"]). Garcia is directed to a method (methods and systems for analysis of image data generated at multiple reference points, and particularly to image and sequence data generated during DNA sequencing, [0003]) of generating a phasing-corrected intensity value (phase-correct intensities for a given cycle, [0187]) and teaches subtracting background noise from intensity values ([0167]-[0168]) and separation of signal from noise by multiplying intensity values with constants (“signal overlap with background” (SOWB) refers to a measurement of the separation of the signal from the noise in previous and subsequent cycles, [0201]; “Shifted Purity G adjustment” refers to a measurement of the separation of the signal from the noise for the current base call only, while also accounting for G quenching effects. Due to an interaction between the dye and the DNA base incorporated in the previous cycle, the intensities in certain color channels may be decreased (quenched) in cycles following those cycles where a G nucleotide was incorporated. In some embodiments, the measurement of the separation of signal from noise is adjusted for G quenching by multiplying T channel intensity for a cycle following a G incorporation by 1.3, and by multiplying A channel intensity for a cycle following a G incorporation by 1.05, [0202]). Furthermore, deriving the relationship between the corrected intensity and intensities of previous and subsequent cycles as recited in the claim is a matter of mere mathematical manipulation, a known practice in the art.
It would have been obvious to one of ordinary skill in the art at the time of the invention to have wherein the phasing correction comprises: I (cycle)corrected = l(cycle) N - X*l(cycle) N-1 - Y*l(cycle) N+1 in the method of Whiteford, based on the teachings of Garcia, since where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. The motivation for doing so would be to provide phasing correction taking into account signal leakage between previous and subsequent cycles (see Whiteford, [page 2196, 1st column, see “2.2.2 Phasing correction"] and Garcia, Phasing Estimation, [0186]-[0187]). Additionally, Whiteford as modified teaches the method of claim 4 but is silent regarding wherein the values of X and/or Y are chosen to optimize a chastity determination. However, Whiteford teaches chastity determination (2.2.3 Chastity filtering, page 2196). Garcia teaches choosing values to optimize chastity determination (Merging Signals Using Chastity Determination, [0159]-[0164]; chastity can be calculated using the following exemplary method. Let A designate the maximum channel signal for a cluster in a cycle, and B designate the second highest signal. In the event that B is negative, 1-B is added to both A and B, to force non-negative values. Chastity is defined as A/(A+B). Using this definition, chastity ranges from a minimum of 0.5 to a maximum of 1. Higher-chastity calls are more likely to be correct. Thus, in some embodiments, clusters which have two or more base calls with chastity value less than a threshold value, for example less than 0.6 in the first 25 cycles are filtered, [0161], [0183], [0197], [0200]). Furthermore, deriving the relationship between the corrected intensity and intensities of previous and subsequent cycles as recited in the claim is a matter of mere mathematical manipulation, a known practice in the art. It would have been obvious to one of ordinary skill in the art at the time of the invention to have wherein the values of X and/or Y are chosen to optimize a chastity determination in the method of Whiteford, based on the teachings of Garcia, since where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. The motivation for doing so would be to allow clusters to be merged using chastity and base call information combined or chastity alone (Garcia, [0164]). Furthermore, deriving the relationship between the corrected intensity and intensities of previous and subsequent cycles as recited in the claim is a matter of mere mathematical manipulation, a known practice in the art. It was also a well-known practice in the art at the time to use mean values for mathematical optimization. It would have been obvious to one of ordinary skill in the art at the time of the invention to have the chastity determination comprises mean chastity in the method of Whiteford, based on the teachings of Garcia, since where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. The motivation for doing so would be to allow clusters to be merged using chastity and base call information combined or chastity alone (Garcia, [0164]). Given the detailed guidance, there would have been a reasonable expectation of success given the examples provided in both references.
Conclusion
No claim is allowed.
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/Joseph Woitach/Primary Examiner, Art Unit 1687
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