DETAILED ACTION
This application is a continuation of 16/421,653, now abandoned.
The Applicant’s response, received 02 January 2026, has been fully considered. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 21-40 are pending.
Claims 21-40 are rejected.
Priority
This application is a CON of 16/421,653, filed 24 May 2019,
which is a CON of 15/001,389, filed 20 January 2016 (abandoned)
which is a CON of 13/177,267, filed 06 July 2011 (Patent 9,268,903)
which claims benefit of 61/361,879, filed 06 July 2010.
Claim Objections
The objection to claim 24 in the Office action mailed 02 October 2025 is withdrawn in view of the amendment received 02 January 2026.
Claim Rejections - 35 USC § 112
The amendment received 02 January 2026 has been fully considered, however after further consideration, new grounds of rejection are raised under 35 U.S.C. 112(a) in view of the amendment.
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 21-40 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.
Claims 21, 27, and 32 recite the limitation “calculating…a paired quality value…based on a negative log odds of…,” and while the Specification does provide literal support for the term “negative log odds” at paragraphs [0063] & [0081], the Specification describes the pairing quality value (PQV) as “…generally associated with a phred-scaled quantitative measure of the confidence of aligning a read to the correct location in the reference genome…” and that the “…PQV may further be represented as the negative log odds of misaligning a read (-10log10[prob of error])” (para. [0063]), however one skilled in the relevant art would equate the expression (-10log10[prob of error]) with the standard formula for determining a Phred score (Q): (Q) = (-10log10[P]), where P is the estimated probability that the base is called incorrectly. Therefore, the Specification does not convey the difference between “the negative log odds of misaligning a read” and a phred score in such a way as to reasonably convey the difference to one skilled in the relevant art.
Claims 22-26, 28-31, and 33-40 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, for depending from either of claims 21, 27, or 32 and for failing to remedy the failure of either of claims 21, 27, or 32 to comply with the written description requirement.
The amendment received 02 January 2026 has been fully considered, however after further consideration, new grounds of rejection are raised under 35 U.S.C. 112(b) in view of the amendment.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 21-40 are 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 21, 27, and 32 are indefinite for reciting “calculating…a paired quality value…based on a negative log odds of…,” because it is not clear as to whether the “calculating…a paired quality value…” step is using a negative odds value or coefficient generated from a negative log odds equation (i.e., based on a negative log odds) as part of the “calculating” or if the end result of the step of “calculating…a paired quality value…” (i.e., the paired quality value) actually is the negative odds value or coefficient that is generated from a negative log odds equation. This limitation is interpreted to mean that the paired quality value generated by the calculating step is a negative odds value or coefficient that is generated from a negative log odds equation (e.g., a Phred quality score is a form of negative log odds).
Claims 22-26, 28-31, and 33-40 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, for depending from either of claims 21, 27, or 32 and for failing to remedy the indefiniteness of either of claims 21, 27, or 32.
Claim Rejections - 35 USC § 101
The amendment received 02 January 2026 has been fully considered, however after further consideration, the rejection of claim 21-38 under 35 U.S.C. 101 in the Office action mailed 02 October 2025 is maintained with modification in view of the amendment.
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 21-40 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claims recite both: (a) mathematical concepts, (e.g., mathematical relationships, formulas or equations, mathematical calculations); and (b) mental processes, i.e., concepts performed in the human mind, (e.g., observation, evaluation, judgement, opinion).
Subject matter eligibility evaluation in accordance with MPEP 2106.
Eligibility Step 1: Step 1 of the eligibility analysis asks: Is the claim to a process, machine, manufacture or composition of matter?
Claims 21-26 and 40 are directed to a method (i.e., a process) for classifying alignments of paired nucleic acid sequence reads; claims 27-31 are directed to a system (i.e., a machine or manufacture) for sequence alignment quality assessment; and claims 32-39 are directed to a method (i.e., a process) for sequence alignment quality assessment.
Therefore, the claims are encompassed by the categories of statutory subject matter, and thus, satisfy the subject matter eligibility requirements under step 1.
[Step 1: YES]
Eligibility Step 2A: First it is determined in Prong One whether a claim recites a judicial exception, and if so, then it is determined in Prong Two whether the recited judicial exception is integrated into a practical application of that exception.
Eligibility Step 2A Prong One: In determining whether a claim is directed to a judicial exception, examination is performed that analyzes whether the claim recites a judicial exception, i.e., whether a law of nature, natural phenomenon, or abstract idea is set forth or described in the claim.
Independent claim 21 recites the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas: i
mapping the first and second reads of each paired nucleic acid sequence read to a reference genome to form potential alignments, wherein one or more potential alignments are produced for each paired nucleic acid sequence read (i.e., mental processes);
each potential alignment satisfies a minimum threshold mismatch constraint (i.e., mental processes and mathematical concepts);
identifying potential paired alignments of the first and second reads of each paired nucleic acid sequence read (i.e., mental processes);
a distance between the first and second reads of each potential paired alignment is within an estimated insert size range (i.e., mental processes and mathematical concepts);
calculating an alignment score for each potential paired alignment (i.e., mental processes and mathematical concepts) based on:
a distance between the first and second reads (i.e., mental processes and mathematical concepts), and
a total number of mismatches for the first and second reads (i.e., mental processes and mathematical concepts);
selecting the potential paired alignment having a highest alignment score as a primary alignment for each paired nucleic acid sequence read (i.e., mental processes); and
calculating a paired quality value for the selected paired nucleic acid sequence reads based on a negative log odds of misaligning the paired nucleic acid reads (i.e., mental processes and mathematical concepts).
Independent claim 27 recites the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas:
map the read sequences to a reference genome to produce potential alignments, wherein one or more potential alignments are produced for a given read sequence (i.e., mental processes);
each potential alignment satisfies a minimum threshold mismatch constraint (i.e., mental processes and mathematical concepts);
calculate a quality value for each potential alignment (i.e., mental processes and mathematical concepts);
select the potential alignment having a highest quality value as a primary alignment for the given read sequence (i.e., mental processes), and
calculate a paired quality value for a selected pair of read sequences having respective highest quality values based on a negative log odds of misaligning the selected pair of read sequences (i.e., mental processes and mathematical concepts).
Independent claim 32 recites the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas:
mapping the read sequences to a reference genome to produce potential alignments, wherein one or more potential alignments are produced for a given read sequence (i.e., mental processes);
each potential alignment satisfies a minimum threshold mismatch constraint (i.e., mental processes and mathematical concepts);
calculating a quality value for each potential alignment (i.e., mental processes and mathematical concepts);
selecting the potential alignment having a highest quality value as a primary alignment (i.e., mental processes), and
calculating a paired quality value for a selected pair of read sequences having respective highest quality values based on a negative log odds of misaligning the selected pair of read sequences (i.e., mental processes and mathematical concepts).
Dependent claims 24-26, 28-31, and 33-38 recite the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas, as noted below.
Dependent claim 24 further recites:
the estimated insert size range is based on a standard deviation value derived from a distribution of estimated sizes of insert regions for the plurality of paired nucleic acid sequence reads (i.e., mental processes and mathematical concepts).
Dependent claim 25 further recites:
the calculated alignment score is a function of read alignment length (i.e., mental processes and mathematical concepts).
Dependent claim 26 further recites:
the calculated alignment score is a function of a total number of possible alignments for each read (i.e., mental processes and mathematical concepts).
Dependent claim 28 further recites:
the quality value is calculated for the potential alignment of the read sequence corresponding to a single fragment library type (i.e., mental processes and mathematical concepts).
Dependent claim 29 further recites:
the quality value is calculated for the potential alignment of the read sequence corresponding to a paired read library type (i.e., mental processes and mathematical concepts).
Dependent claim 30 further recites:
wherein for the paired read library type, the mapping produces aligned paired reads, wherein the aligned paired reads must have insert region sizes that fall within an estimated insert size range for the aligned paired reads, wherein the aligned paired reads are separated by an insert region, wherein the selected pair of read sequences corresponds to the aligned paired reads (i.e., mental processes and mathematical concepts).
Dependent claim 31 further recites:
the estimated insert size range is based on a standard deviation value derived from a distribution of estimated insert region sizes of the aligned paired reads (i.e., mental processes and mathematical concepts).
Dependent claim 33 further recites:
the quality value is calculated for the potential alignment of the read sequence corresponding to a single fragment library type (i.e., mental processes and mathematical concepts).
Dependent claim 34 further recites:
the quality value is calculated for the potential alignment of the read sequence corresponding to a paired read library type (i.e., mental processes and mathematical concepts).
Dependent claim 35 further recites:
the calculated quality value for each potential alignment is a function of read alignment length (i.e., mental processes and mathematical concepts).
Dependent claim 36 further recites:
the calculated quality value for each potential alignment is a function of number of read mismatches (i.e., mental processes and mathematical concepts).
Dependent claim 37 further recites:
wherein for the paired read library type, the mapping produces aligned paired reads, wherein the aligned paired reads must have insert region sizes that fall within an estimated insert size range for the aligned paired reads, wherein the aligned paired reads are separated by an insert region, wherein the selected pair of read sequences corresponds to the aligned paired reads (i.e., mental processes and mathematical concepts).
Dependent claim 38 further recites:
the estimated insert size range is based on a standard deviation value derived from a distribution of estimated insert region sizes of the aligned paired reads (i.e., mental processes and mathematical concepts).
The abstract ideas recited in the claims are evaluated under the broadest reasonable interpretation (BRI) of the claim limitations when read in light of and consistent with the specification. As noted in the foregoing section, the claims are determined to contain limitations that can practically be performed in the human mind with the aid of a pen and paper (e.g., mapping reads to a reference sequence, i.e., genome, requires performing one-to-one comparisons between two sequences; identifying potential paired alignments requires evaluating whether an alignment is within an estimated insert size range; and selecting a potential paired alignment having a highest score requires comparing values to make a selection), and therefore recite judicial exceptions from the mental process grouping of abstract ideas. Additionally, the recited limitations that are identified as judicial exceptions from the mathematical concepts grouping of abstract ideas (e.g., calculating an alignment score for each potential paired alignment involves calculating a distance between two reads, and also calculating the total number of mismatches for the two reads (e.g., in the specification: see equations 6 and 9 (paras. [0078] & [0081], respectively)) are abstract ideas irrespective of whether or not the limitations are practical to perform in the human mind.
Therefore, claims 21-40 recite an abstract idea.
[Step 2A Prong One: YES]
Eligibility Step 2A Prong Two: In determining whether a claim is directed to a judicial exception, further examination is performed that analyzes if the claim recites additional elements that when examined as a whole integrates the judicial exception(s) into a practical application (MPEP 2106.04(d)). A claim that integrates a judicial exception into a practical application will apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception. The claimed additional elements are analyzed to determine if the abstract idea is integrated into a practical application (MPEP 2106.04(d)(I); MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the abstract idea, the claim fails to integrate the abstract idea into a practical application (MPEP 2106.04(d)(III)).
The judicial exceptions identified in Eligibility Step 2A Prong One are not integrated into a practical application because of the reasons noted below.
Dependent claims 24-26, 28-31, and 33-38 do not recite any elements in addition to the judicial exception, and thus are part of the judicial exception.
The additional elements in independent claims 21, 27, and 32 include:
a computing device comprising a processor and memory (claims 21 and 32);
a processor in communication with the next generation sequencing instrument (claim 27);
a next generation sequencing instrument configured to interrogate a sample to produce a plurality of read sequences from the sample (claim 27);
interrogating a sample, by a next generation sequencing instrument, to produce a plurality of read sequences from the sample (claim 32);
receiving a plurality of paired nucleic acid sequence reads, wherein each paired nucleic acid sequence read comprises a first read of a first tag derived from a first region of a polynucleotide and a second read of a second tag derived from a second region of the polynucleotide, the first and second reads produced by next generation sequencing, wherein the first tag and the second tag are separated by an insert region; (claim 21);
obtain the read sequences from the next generation sequencing instrument (claim 27);
obtaining the plurality of read sequences from the next generation sequencing instrument (claim 32);
output the potential alignments and associated quality values (claim 27); and
outputting the potential alignments and associated quality values (claim 32).
The additional elements in dependent claims 22, 23, 39, and 40 include:
wherein the paired nucleic acid sequence read is a mate-pair read (claim 22, further limiting the received data);
wherein the paired nucleic acid sequence read is a paired-end read (claim 23, further limiting the received data);
providing (i.e., outputting data) the paired quality value for use in detecting a variant in the selected pair of read sequences (claim 39); and
providing (i.e., outputting data) the paired quality value for use in detecting a variant in the selected paired nucleic acid sequence reads (claim 40).
The additional elements of a computing device comprising a processor and memory (claims 21 and 32); and a processor in communication with the next generation sequencing instrument (claim 27); invoke a computer and/or computer components merely as a tool for use in the claimed process, i.e., receiving data, and executing the abstract ideas, and therefore are not improvements to computer functionality itself, or an improvement to any other technology or technical field, and thus, do not integrate the judicial exceptions into a practical application (see MPEP 2106.04(d)(1)).
The additional elements of receiving data (claims 21, 22, and 23); obtaining data (claims 27 and 32); and outputting data (claims 27 and 32); are pre-solution and/or post-solution activities used in the claimed process – nominal additions to the claims that do not meaningfully limit the claims, and therefore do not add more than insignificant extra-solution activity to the judicial exceptions (MPEP 2106.05(g)).
The additional elements of a next generation sequencing instrument configured to interrogate a sample to produce a plurality of read sequences from the sample (claim 27); and interrogating a sample, by a next generation sequencing instrument, to produce a plurality of read sequences from the sample (claim 32); are steps in the process of gathering data for use in the claimed process, and therefore are insignificant extra-solution activities (MPEP 2106.05(g)).
The additional elements of providing the paired quality value for use in detecting a variant in the selected pair of read sequences(i.e., outputting data, e.g., results) (claim 39); and providing the paired quality value for use in detecting a variant in the selected paired nucleic acid sequence reads (i.e., outputting data, e.g., results) (claim 40); are merely post-solution activities of outputting data generated by the claimed process – a nominal or tangential addition to the claims that does not meaningfully limit the claims, and therefore does not add more than insignificant extra-solution activity to the judicial exceptions (MPEP 2106.05(g)).
Thus, the additionally recited elements merely invoke a computer as a tool, and/or amount to insignificant extra-solution activity, and as such, when all limitations in claims 21-40 have been considered as a whole (i.e., the analysis takes into consideration all the claim limitations and how those limitations interact and impact each other when evaluating whether the exception is integrated into a practical application), the claims are deemed to not recite any additional elements that would integrate a judicial exception into a practical application, and therefore claims 21-40 are directed to an abstract idea (MPEP 2106.04(d)).
[Step 2A Prong Two: NO]
Eligibility Step 2B: Because the claims recite an abstract idea, and do not integrate that abstract idea into a practical application, the claims are probed for a specific inventive concept. The judicial exception alone cannot provide that inventive concept or practical application (MPEP 2106.05). Identifying whether the additional elements beyond the abstract idea amount to such an inventive concept requires considering the additional elements individually and in combination to determine if they amount to significantly more than the judicial exception (MPEP 2106.05A i-vi).
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception(s) because of the reasons noted below.
Dependent claims 24-26, 28-31, and 33-38 do not recite any elements in addition to the judicial exception(s).
The additional elements recited in independent claims 21, 27, and 32 and dependent claims 22, 23, 39, and 40 are identified above, and carried over from Step 2A: Prong Two along with their conclusions for analysis at Step 2B. Any additional element or combination of elements that was considered to be insignificant extra-solution activity at Step 2A: Prong Two was re-evaluated at Step 2B, because if such re-evaluation finds that the element is unconventional or otherwise more than what is well-understood, routine, conventional activity in the field, this finding may indicate that the additional element is no longer considered to be insignificant; and all additional elements and combination of elements were evaluated to determine whether any additional elements or combination of elements are other than what is well-understood, routine, conventional activity in the field, or simply append well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, per MPEP 2106.05(d).
The additional elements of a computing device comprising a processor and memory (claims 21 and 32); a processor in communication with the next generation sequencing instrument (claim 27); receiving data (claims 21, 22, and 23); obtaining data (claims 27 and 32); and outputting data (claims 27, 32, 39, and 40); are conventional computer components and/or functions (see MPEP at 2106.05(b) and 2106.05(d)(II) regarding conventionality of computer components and computer processes).
The additional element of a next generation sequencing instrument (claims 27 and 32); is conventional. Evidence for the conventionality is shown by Shendure et al. (Nature Biotechnology, 2008, Vol. 26, No. 10, pp. 1135-1145, as cited in the Information Disclosure Statement received 11 September 2023). Shendure et al. reviews next-generation sequencing (Title; and Abstract) and shows that massively parallel DNA sequencing platforms have become widely available, reducing the cost of DNA sequencing by over two orders of magnitude, and democratizing the field by putting the sequencing capacity of a major genome center in the hands of Individual investigators (Abstract). Shendure et al. further shows applications of next-generation sequencing such as discovery of inherited and acquired structural variation using paired end sequencing (Table 2) and using mate-paired reads, useful in de novo assembly and for mapping structural variants, for example, and that are available with all of the next-generation platforms (page 1141, col. 2, para. 1).
Therefore, when taken alone, all additional elements in claims 21-40 do not amount to significantly more than the above-identified judicial exception(s). Even when evaluated as a combination, the additional elements fail to transform the exception(s) into a patent-eligible application of that exception. Thus, claims 21-40 are deemed to not contribute an inventive concept, i.e., amount to significantly more than the judicial exception(s) (MPEP 2106.05(II)).
[Step 2B: NO]
Response to Arguments
The Applicant’s arguments/remarks received 02 January 2026 have been fully considered, but are not persuasive.
The Applicant refers to the Memorandum entitled “Advance notice of change to the MPEP in light of Ex Parte Desjardins,” December 5, 2025 (“Memorandum” herein) on pages 7-8 of the Remarks, and states on page 8 (para. 2) that in Enfish, the data structure claims to a self-referential table for a computer database were directed to an improvement in computer capabilities and not directed to an abstract idea, and further states that the presently claimed subject matter is fully consistent with patentable subject matter as defined by the Federal Circuit’s decision in Enfish. The Applicant further states that as was the case in Enfish, the present claims are directed to a non-abstract improvement in computer technology and nucleic acid sequencing technology, and that the use of potential alignments, associated quality values, and paired quality values as data structures in the present claims is consistent with the finding of subject matter eligibility in Enfish. The Applicant further states (para. 3) that the Applicant’s specification at paragraph [0062] emphasizes the improvement to efficiency by the presently claimed method and system, and further states (para. 4) that the Applicant’s specification at paragraph [0065] emphasizes the improvement to accuracy by the presently claimed method and system. Finally, the Applicant states on page (para. 1) that the potential alignments, associated quality values, paired quality value for the selected paired nucleic acid in the presently claimed systems and methods are superior to previous systems and methods for computer technology and nucleic acid sequencing technology, and improve accuracy and efficiency.
These arguments are not persuasive, because first, regarding the Applicant’s attempt at analogizing the instant claims to Enfish, the instant claims are not analogous to the claims in Enfish, because the instant claims broadly recite steps for identifying potential paired alignments of nucleic acid sequence read data, whereas in contrast, the improvement recited in Enfish is found in a data structure that corresponds to a storage and retrieval structure configured in a computer memory comprising a self-referential table that is designed to improve the way a computer stores and retrieves data in memory, and thus is an improvement to computer functionality itself. Stated a different way, the improvement was found in the structure of the table itself (e.g., relationships between rows and columns) as arranged (i.e., configured) in a physical memory device, irrespective of any particular data being stored or searched. Second, regarding the Applicant’s assertion of improved efficiency and accuracy, it is noted that a purported improvement to the efficiency and accuracy of a data analysis algorithm is not an improvement to computer functionality itself, and not an improvement to any other technology or technical area, at least because the claims do not recite any additional elements that apply, rely on, or use the judicial exception(s) in a manner that imposes a meaningful limit on the judicial exception(s), as noted and discussed in the above rejection.
Claim Rejections - 35 USC § 103
The amendment received 02 January 2026 has been fully considered, however after further consideration, the rejection of claims 21-38 under pre-AIA 35 U.S.C. 103(a) in the Office action mailed 02 October 2025 is maintained with modification in view of the amendment, as noted below.
New claims 39 and 40 are rejected under pre-AIA 35 U.S.C. 103(a).
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.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 21-40 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Zhang (US 2008/0189049, as cited in the Office action mailed 02 October 2025) in view of Li et al (Genome Research, 2008, Vol. 18, pp. 1851-1858, as cited in the Information Disclosure Statement (IDS) received 11 September 2023).
Regarding claims 21, 27, and 32, Zhang shows systems, methods, and analytical approaches for short read sequence assembly using a reference genome (Abstract); advantageously aligning pair-wise short read sequence information with a greater degree of confidence and accuracy as compared to conventional approaches (para. [0039]); methodologies for generating paired sequencing information (para. [0021]); mapping reads to a reference genome according to a mismatch number (para. [0027], & FIG. 3A); determining the positioning of paired reads with respect to the reference genome allowing for a selected number or range of mismatches between each mate pair sequence (para. [0027]); an approximate or expected distance between the mate pairs (paras. [0029], [0032], & [0052]); and using numbers of reads (matches and mismatches) to estimate alignments (para. [0064]).
Regarding claims 21, 27, and 32, Zhang does not show calculating an alignment score for each potential paired alignment based: a distance between the first and second reads, and a total number of mismatches for the first and second reads (claim 21); calculating a quality value for each potential alignment (claims 27 and 32); selecting the potential alignment having a highest quality value as a primary alignment (claims 21, 27, and 32); or calculating a paired quality value for the selected paired nucleic acid sequence reads based on a negative log odds of misaligning the paired nucleic acid reads.
Regarding claims 21, 27, and 32, Li et al. shows methods of mapping short DNA sequencing reads using mapping quality scores (Title) that are a measure of the confidence that a read actually comes from the position in the reference genome that is aligned to by the mapping algorithm (Abstract). Li et al. further shows the algorithm searches for sequences based on a mismatch score threshold, and to evaluate the reliability of alignments, MAQ assigns each individual alignment a phred-scaled quality score (capped at 99) (i.e., a negative log-odds score (or more precisely, a negative log-probability)), which measures the probability that the true alignment is not the one found by MAQ (page 1852, col. 1, para. 5), and further shows the algorithm tests a maximum allowed distance between mates of paired-end reads (page 1857, col. 1, para. 1) and assigning mapping quality scores based the proper distance between pair mappings (page 1857, col. 1, para. 4). Li et al further shows describing a potential read alignment position as a hit (page 1856, col. 1, para. 1), and then shows a process for selecting a mapping based on a quality score assigned to both reads (page 1857, col. 1, para. 4).
Regarding claim 22, Zhang further shows sequence reads as mate pair reads (paras. [0005] & [0018]; and FIGS. 1, 3A, & 3B).
Regarding claims 24, 31, and 38, Zhang further shows mate pair sequencing can be used to determine the existence and size of an insertion by calculating the average deviation from the average distance (i.e., between reads) (para. [0022]).
Regarding claims 30 and 37, Zhang further shows that mate pair tags or reads may be aligned allowing for a small number of mismatches and that for pairs of mate pair tags or reads in which only one mate pair tag is successfully mapped, an attempt may be made to align the non-matching second mate pair tag to allow a permissible gap in the read but still constrain the alignment to the relatively small region (para. [0034]); the size of the small region may be determined by the range of the insert size (para. [0052]); and the mate pair sequences comprise non-overlapping pairwise sequences separated by an intervening sequence length (para. [0005]).
Regarding claims 23, 25, 26, 28, 29, 33, 34, 35, 36, 39, and 40, Zhang does not show the paired nucleic acid sequence read is a paired-end read (claim 23); the calculated alignment score is a function of read alignment length (claims 25 and 35); the calculated alignment score is a function of a total number of possible alignments for each read (claim 26); the quality value is calculated for the potential alignment of the read sequence corresponding to a single fragment library type (claims 28 and 33); the quality value is calculated for the potential alignment of the read sequence corresponding to a paired read library type (claims 29 and 34); the calculated quality value for each potential alignment is a function of number of read mismatches (claim 36); or providing the paired quality value for use in detecting a variant in the selected pair of read sequences (claim 39); or providing the paired quality value for use in detecting a variant in the selected paired nucleic acid sequence reads (claim 40).
Regarding claims 23 and 34, Li et al. further shows using paired-end reads (page 1852, col. 1, para. 6).
Regarding claims 25 and 35, Li et al. further shows using read length in determining a quality score (page 1856, col. 1, para. 4).
Regarding claims 26 and 36, Li et al. further shows that in order to evaluate the reliability of alignments, each individual alignment is assigned a score as part of the process of reporting, and mapping quality scores and mapping all reads that match the genome (page 1852, col. 1, para. 5).
Regarding claims 28 and 33, Li et al. further shows assigning each individual alignment of single end reads a mapping quality score (page 1856, col. 1, paras. 7-8).
Regarding claims 29 and 34, Li et al. further shows a paired-end read alignment mode (page 1856, col. 2, paras. 8-9).
Regarding claims 39 and 40, Li et al. further shows that with the default MAQ options, simulated reads were aligned against the whole human reference genome excluding Y and unassembled contigs (page 1853, col. 1, para. 2, top), and also simulated reads without introducing any mutations, and for these data, the mapping quality could be more accurately estimated, which is sufficient for most mapping-based applications, including structural variant calling and SNP calling (page 1853, col. 1, para. 2, bottom).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method shown by Zhang by incorporating methods for determining quality scoring of read alignments, as discussed by Li et al. and discussed above. One of ordinary skill in the art would have been motivated to combined the methods of Zhang with the methods of Li et al. because Zheng shows a method that overcomes false alignments that can reduce overall quality and confidence (para. [0024]), but does not show assigning quality scores to potential alignments that could aid in selecting the best alignments, however Li et al. shows methods for mapping short DNA sequencing reads using mapping quality scores, which are a measure of the confidence that a read actually comes from the position it is aligned to by the mapping algorithm (Abstract). This modification would have had a reasonable expectation of success given that both Zhang and Li et al. disclose methods for the accurate mapping of sequence reads.
Response to Arguments
The Applicant’s arguments/remarks received 02 January 2026 have been fully considered, but are not persuasive.
The Applicant states on page 9 (para. 4) of the Remarks that independent claims 21, 27, and 32 have been amended to include the limitation “calculating, by the computing device, a paired quality value for the selected paired nucleic acid sequence reads based on a negative log odds of misaligning the paired nucleic acid reads,” and further states (paras. 5 & 6) that Li does not teach or suggest this element.
This argument is not persuasive, because Li shows that in order to evaluate the reliability of alignments, MAQ assigns each individual alignment a phred-scaled quality score (capped at 99) (i.e., a negative log-odds score (or more precisely, a negative log-probability)), which measures the probability that the true alignment is not the one found by MAQ (page 1852, col. 1, para. 5). Stated simply, a phred-scaled quality score is a type of log-odds score.
The Applicant states on page 9 (para. 7) that likewise, Zhang does not describe calculation of a paired quality value, and further states on page 10 that Zhang in view of Li, along or in combination, do not teach or suggest “calculating, by the computing device, a paired quality value for the selected paired nucleic acid sequence reads based on a negative log odds of misaligning the paired nucleic acid reads.”
These arguments are not persuasive, because first, the Li reference is relied on to show estimating mapping quality using paired-end reads, as discussed in the above rejection, and second, the Li reference is relied on to show using a negative log odds score, also as discussed in the above rejection.
Double Patenting
The rejection of claims 21, 22, 23, 24, 25, 26, 27, 29, 30, 31, 32, 34, 35, 36, 37, and 38 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13 of U.S. Patent No. 9,268,903 in the Office action mailed 02 October 2025 is maintained in view of the amendment received 02 January 2026.
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 21, 22, 23, 24, 25, 26, 27, 29, 30, 31, 32, 34, 35, 36, 37, and 38 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13 of U.S. Patent No. 9,268,903. Although the claims at issue are not identical, the claims of U.S. Patent No. 9,268,903 are not patentably distinct from the instant claims, and therefore anticipate the instant claims.
Regarding instant claims 21 and 36, claim 1 of U.S. Patent No. 9,268,903 discloses the limitations of instant claims 21 and 36.
Regarding instant claim 27, claim 7 of U.S. Patent No. 9,268,903 discloses the limitations of instant claim 27.
Regarding instant claim 32, claim 10 of U.S. Patent No. 9,268,903 discloses the limitations of instant claim 32.
Regarding instant claim 22, claim 2 of U.S. Patent No. 9,268,903 discloses the limitations of instant claim 22.
Regarding instant claims 23, 29, and 34, claim 3 of U.S. Patent No. 9,268,903 discloses the limitations of instant claims 23, 29, and 34.
Regarding instant claim 24, claim 4 of U.S. Patent No. 9,268,903 discloses the limitations of instant claim 24.
Regarding instant claim 25, claim 5 of U.S. Patent No. 9,268,903 discloses the limitations of instant claim 25.
Regarding instant claim 26, claim 6 of U.S. Patent No. 9,268,903 discloses the limitations of instant claim 26.
Regarding instant claim 30, claim 8 of U.S. Patent No. 9,268,903 discloses the limitations of instant claim 30.
Regarding instant claim 31, claim 9 of U.S. Patent No. 9,268,903 discloses the limitations of instant claim 31.
Regarding instant claim 35, claim 11 of U.S. Patent No. 9,268,903 discloses the limitations of instant claim 35.
Regarding instant claim 37, claim 12 of U.S. Patent No. 9,268,903 discloses the limitations of instant claim 37.
Regarding instant claim 38, claim 13 of U.S. Patent No. 9,268,903 discloses the limitations of instant claim 38.
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 THREE-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 final action.
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/S.W.B./Examiner, Art Unit 1687
/Joseph Woitach/Primary Examiner, Art Unit 1687
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