DETAILED ACTION
Applicant’s response, filed 23 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 .
Claim Status
Claims 1, 2, 4-19, and 30-32 are pending and examined herein.
Claims 1, 2, 4-19, and 30-32 are rejected.
Priority
Claims 1, 2, 4-19, and 30-32 are granted the claim to the benefit of priority to foreign application GB1914064.9 filed 30 September 2019. Thus, the effective filling date of claims 1, 2, 4-19, and 30-32 is 30 September 2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
b) In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete (on page 1 of the disclosure the size of the text file is provided in KB but the size of the text file should be provided in bytes). See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Drawings
The replacement drawings received 23 January 2026 are accepted.
Specification
The objection to the specification for reciting disclosing a sequence longer than 10 nucleotides with no SEQ ID on page 12 in Office action mailed 26 September 2025 is withdrawn in view of the amendment to the specification which adds a SEQ ID received 23 January 2026.
Claim Rejections - 35 USC § 112
The rejection on the ground of 112/b of claims 1-19 and 30-32 for reciting “the measure correlated to the probability” in claim 1 in Office action mailed 26 September 2025 is withdrawn in view of the amendment of “a measure correlated to a probability” received 23 January 2026.
The rejection on the ground of 112/b of claim 4 for reciting “relatively” in Office action mailed 26 September 2025 is withdrawn in view of the amendment which removes this limitation received 23 January 2026.
The rejection on the ground of 112/b of claims 10 and 13 for reciting “preferably greater than 10” (in claim 10) and “preferably greater than 99%” (in claim 13) in Office action mailed 26 September 2025 is withdrawn in view of the amendment which removes these limitations from their respective claims received 23 January 2026.
The rejection on the ground of 112/b of claim 32 for reciting “the probability” in Office action mailed 26 September 2025 is withdrawn in view of the amendment of “a probability” received 23 January 2026.
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.
The rejection below has been modified necessitated by amendment.
Claims 1, 2, 4-19, and 30-32 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
(Step 1)
Claims 1, 2, 4-19, 30, and 31 fall under that statutory category of a process and claim 32 falls under the statutory category of a machine.
(Step 2A prong 1)
Under the BRI, the instant claims recite judicial exceptions that are an abstract idea of the type that is in the grouping of a “mental process”, such as procedures for evaluating, analyzing or organizing information, and forming judgement or an opinion. The instant claims further recite judicial exceptions that are an abstract idea of the type that is in the grouping of a “mathematical concept”, such as mathematical relationships and mathematical equations.
Independent claims 1 and 32 recite mental processes of “applying a common minimizers function to each mutated sequence read… wherein the one or more respective minimizers are one or more representative k-mers that is or are listed first in an ordered list of possible k-mers”, “determining positions of the one or more minimizers…”, “determining positions of one or more mutations…”, “for at least two mutated sequence reads with a common minimizer, counting the number of mutations…”, “assembling the at least two mutated sequence reads based on the measure”, and “determining a sequence of at least a portion of the at least one target template nucleic acid based on the assembly”.
Dependent claim 9 recites a mental process of “generating the ordered list of possible k-mers …”. Dependent claim 11 recites a mental process of “binning the mutated sequence reads in one or more minimizer bins…”. Dependent claim 12 recites mental processes of “obtaining a set of non-mutated seed-masked k-mers by applying each one of one or more seed patterns…”, “for each mutated sequence read, applying the one or more seed patterns…”, and “determining the positions of the one or more mutations by identifying…”. Dependent claim 15 recites mental processes of “obtaining a respective set of non-mutated seed-masked…”, “creating a set of non-muted sample bit vectors…”, and “identifying the one or more positions in the mutated sequence…”. Dependent claim 16 recites mental processes of “for one or more of the mutated sequence reads, aligning the respective mutated sequence…” and “determining the positions of the one or more mutations in the respective mutated sequence read by identifying positions…”. Dependent claim 17 recites mental processes of “if a position in the respective mutated sequence read is aligned to the reference assembly, determining the position in the respective mutated sequence read…” and “if a position in the respective mutated sequence read is not aligned to the reference assembly, determining the position in the respective mutated sequence read…”. Dependent claim 18 recites a mental process of “determining the measure correlated to the probability that the at least two mutated sequence reads…”. Dependent claim 30 recites a mental process of “grouping the mutated sequence reads into groups…”. Dependent claim 31 recites a mental process of “reconstructing at least a portion of the target template nucleic acid sequence…”.
The claims recite steps of analyzing/evaluating data, organizing data, and making judgments/observations about data as “applying a common minimizers function…”, determining positions of the one or more minimizers, determining positions of one or more mutations, counting the number of mutations, assembling the at least two mutated sequence reads based on the measure, and based on the assembly, determining a sequence, identifying k-mers in an ordered set or predetermined set, binning reads based on a minimizer, applying seed patterns to sequences for determining mutation positions, aligning reads and determining mutation positions. The human mind is capable of analyzing data, organizing data, and making judgments/observations. Dependent claims 4-8, 10, 13, 14, 19 further limit the mental process recited in the independent claim but do not change their nature as a mental process. Therefore, claims 1-19 and 30-32 recite abstract ideas.
(Step 2A Prong 2)
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). Integration into a practical application is evaluated by identifying whether there are any additional elements recited in the claim and evaluating those additional elements to determine whether they integrate the exception into a practical application.
The additional element in claims 1 and 32 of using a generic computer to perform judicial exceptions does not integrate the judicial exceptions into a practical application because this is simply applying the judicial exceptions to a generic computer without an improvement to computer technology.
The additional element in claims 1, 2, and 32 of receiving data does not integrate the judicial exceptions into a practical application because this is adding insignificant extra solution activity of data gathering. This step is insignificant extra solution activity because the additional element of receiving data only interacts with the judicial exception by provide data to be processed by the judicial exceptions. It is noted that the informational content of the data received does not change the step of receiving data into a computer environment.
Thus, the additional elements do not integrate the judicial exceptions into a practical application and claims 1-19 and 30-32 are directed to the abstract idea.
(Step 2B)
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because:
The additional element in claims 1 and 32 of using a generic computer to perform judicial exceptions is conventional see MPEP 2106.05(b) and 2106.05(d)(II).
The additional element in claims 1 and 32 of receiving data is conventional see MPEP 2106.05(b) and 2106.05(d)(II).
Thus, the additional elements are not sufficient to amount to significantly more than the judicial exception because they are conventional.
Response to Arguments
Applicant's arguments filed 23 January 2026 have been fully considered but they are not persuasive.
Argument 1
Applicant argues claim 1 includes a technical solution to a technical problem of how to sequence nucleic acids from similar sequences. The technical problem is sequencing nucleic acids from sequence reads taken from a target nucleic acid having mutations, and the solution is to look at a common minimizer (k-mer) and one or more mutations to determine the sequence of a target nucleic acid (Reply p. 13).
This argument has been fully considered but found to be not persuasive. The MPEP states at 2106.05(a) “It is important to note, the judicial exception alone cannot provide the improvement. The improvement can be provided by one or more additional elements… In addition, the improvement can be provided by the additional element(s) in combination with the recited judicial exception”. Applicant argues the improvement (i.e., solution to the technical problem) is provided by the judicial exception of looking at a common minimizer (k-mer) and one or more mutations to determine the sequence of a target nucleic acid. It is noted that the judicial exception alone cannot provide the improvement. Thus, the argued improvement is realized in and provided by the judicial exceptions of analyzing sequencing data which is an improvement in the abstract idea itself (i.e., not an improvement to technology). Therefore, the claims do not provide an improvement to a technology or technical field.
Argument 2
Applicant argues that the claim as a whole or the practical application of sequencing target nucleic acids from sequence reads having mutations were not considered (Reply p. 14).
This argument has been fully considered but found to be not persuasive. It is noted that the claim as a whole was considered under Step 2A, Prong 2 of the analysis above. The additional element of a computer only interacts with the judicial exceptions in a manner that the generic computer is used as a tool to perform abstract ideas without an improvement to the functioning of the computer itself. The additional element of receiving data in a computer environment only interacts with the judicial exceptions by providing data to the judicial exceptions to process which is insignificant extra solution activity of data gathering. Further, a step of sequencing target nucleic acids from sequence reads having mutations is not recited in the claims and the receiving steps encompasses receiving data from a previously performed sequencing experiment. Therefore, the claims do not provide an additional element of performing sequencing in this manner and is not included in the analysis.
Argument 3
Applicant argues the method of claim 1 which involves a method of determining a target nucleic acid sequence by determining whether at least two mutated sequence reads derive from the same sequence comprising mutations provides an improvement to the field of diagnostic testing and therefore are patent eligible (Reply p. 14)
This argument has been fully considered but found to be not persuasive. The MPEP states at 2106.05(a) “It is important to note, the judicial exception alone cannot provide the improvement. The improvement can be provided by one or more additional elements… In addition, the improvement can be provided by the additional element(s) in combination with the recited judicial exception”. The determination of an improvement to technology has two steps, the identification of additional elements (which define the technology) and the evaluation of the additional elements to determine if the improvement is provided by and realized in the additional elements either by the additional elements themselves or the additional element in combination with the judicial exception (i.e. the interaction between the judicial exceptions and the additional elements).
In the instant claims, the additional elements are using a generic computer as a tool to perform judicial exceptions and receiving data in a computer environment (the content of the data falls under the abstract idea itself because the content does not change the active step of receiving data in a computer environment). Argued improvement in the technical field of diagnostic testing is not provided by or realized in the recited additional elements. This argued improvement falls under the judicial exceptions themselves of how the sequencing data is analyzed which is not an improvement to a technology/technical field because the judicial exceptions alone cannot provide the improvement. Therefore, the claims do not recite an improvement to technology because the improvement is not provided by the additional elements.
Argument 4
Applicant argues that aspects of the claims improve computational efficiency through binning mutated sequences (Reply p. 14).
This argument has been fully considered but found to be not persuasive. The MPEP states at 2106.05(a) “It is important to note, the judicial exception alone cannot provide the improvement. The improvement can be provided by one or more additional elements… In addition, the improvement can be provided by the additional element(s) in combination with the recited judicial exception”. The determination of an improvement to technology has two steps, the identification of additional elements (which define the technology) and the evaluation of the additional elements to determine if the improvement is provided by and realized in the additional elements either by the additional elements themselves or the additional element in combination with the judicial exception (i.e. the interaction between the judicial exceptions and the additional elements).
In the instant claims, the additional element of the computer is used as a tool to perform judicial exceptions (i.e., the abstract ideas). The MPEP states “In computer-related technologies, the examiner should determine whether the claim purports to improve computer capabilities or, instead, invokes computers merely as a tool. Enfish, LLC v. Microsoft Corp., 822 F.3d 1327, 1336, 118 USPQ2d 1684, 1689 (Fed. Cir. 2016)” (see MPEP 2106.05(a)(I)). Although the abstract idea itself may be more computationally efficient, the abstract idea of binning mutated sequences does not interact with the generic computer in manner where the computer itself is functioning in a different/ improved manner. The abstract idea of binning groups organizes data into groups containing similar sequences which aids in the abstract idea of counting the number of mutations with matching and mismatching positions. This provides an efficient manner to perform counting which falls under the abstract idea itself. Using the computer to perform this efficient abstract idea of counting does not improve the functioning of the computer because the computational efficiency comes solely from the abstract idea while the computer is still only applied as a tool to perform this particular abstract idea. Thus, the claims do not provide an improvement to computer functionality.
Argument 5
Applicant argues that when claim 1 is viewed as a whole it is not conventional (Reply p. 15).
This argument has been fully considered but found to be not persuasive. The MPEP states at 2106.05(d) “Another consideration when determining whether a claim recites significantly more than a judicial exception is whether the additional element(s) are well-understood, routine, conventional activities previously known to the industry” which shows that the analysis of conventionality is reserved for additional elements (either an additional element alone or an additional element in combination with other additional elements).
In the instant claims, the additional elements are using a generic computer as a tool to perform judicial exceptions and receiving data in a computer environment (the content of the data falls under the abstract idea itself because the content does not change the active step of receiving data in a computer environment). It is noted that an active step of sequencing nucleic acid sequences is not recited in the claims and the receiving steps encompasses receiving data from a previously performed sequencing experiment. Therefore, the additional elements, alone and in combination with each other, are conventional as shown by MPEP 2106.05(b) and MPEP 2106.05(d)(II).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The rejection below has been modified necessitated by amendment.
Claims 1, 10, 11, 18, 19, and 30-32 are rejected under 35 U.S.C. 103 as being unpatentable over Levy et al. (Proceedings of the National Academy of Sciences 111.43 (2014): E4632-E4637; previously cited) in view of Liu et al. (Bioinformatics, Volume 35, Issue 12, June 2019, Pages 2066–2074; previously cited).
Independent claim 1 is directed to receiving a plurality of mutated sequence reads, each mutated sequence read corresponding to a subsequence of a sequence comprising mutations, wherein the sequence comprising mutations comprises mutations compared to a sequence not comprising mutations;
Levy et al. shows receiving a plurality of mutated sequence reads which are subsequences of a template sequence read that contains mutations compared to the original templates (Levy et al. page E4634).
determining positions of one or more mutations in each mutated sequence read;
Levy et al. shows that that the mutation positions are identified through the alignment of mutated sequence reads to the original template (Levy et al. page E4633 figure 1 and page 4634 figure 2).
for at least two mutated sequence reads with a common minimizer, counting the number of mutations with matching position or with mismatching position when the respective minimizers are aligned in order to determine the measure correlated to the probability that the at least two mutated sequence reads derive from the same sequence comprising mutations,
Levy et al. shows matching mutation patterns from overlapping reads which is based on the number of mutations with matching positions and is a measure that the mutated sequence reads derive from the same template (Levy et al. page 4634 figure 2). Levy et al. shows a scoring method that reflects how unlikely it is that the reads agree on their mutation patterns by chance which is used for mutational pattern matching (Levy et al. page E4637 right col.).
assembling the at least two mutated sequence reads based on the measure,
Levy et al. shows assembling the mutated DNA sequences by overlapping mutation patterns (Levy et al. page 4634 figure 2).
and determining a sequence of at least a portion of the at least one target template nucleic acid based on the assembly
Levy et al. shows each mutated template has a unique end tag and based on the assembly of mutated sequence reads by matching mutation patterns the original templates are recovered (Levy et al. page 4634 figure 2).
Levy et al. does not show applying a common minimizer function to each mutated sequence read, thereby determining one or more respective minimizers for each mutated sequence read, wherein the one or more respective minimizers are one or more respective k-mers that is or are listed first in an ordered list of possible k-mers, determining positions of the one or more respective minimizers in each mutated sequence read, wherein the one or more respective minimizers are one or more representative k-mers that is or are listed first in an ordered list of possible k-mers.
Like Levy et al., Liu et al. shows a sequence assembly algorithm for the generation of contigs. Liu et al. shows a minimizer of a string is its lexicographically smallest k-mer and shows that a list of minimizers from a string can be derived from the all-possible substrings shifting from the beginning of the string to the end (Liu et al. page 2068 left col.). Liu et al. further shows computing the first minimizers in this list (Liu et al. page 2068 left col.). Liu et al. shows determining the positions of the minimizer in multiple sequences (Liu et al. page 2070 Fig. 1).
Independent Claim 32 is directed to a computer comprising a processor configured to perform the same method set out in claim 1.
Levy et al. shows the use of an assembly algorithm which is software implemented on a generic computer (Levy et al. page E4636 left col.). It is noted that the limitations are the same as claim 1 and are addressed above.
Claim 10 is directed to wherein each minimizer is a k-mer of length greater than 5.
Levy et al. does not show wherein each minimizer is a k-mer of length greater than 5.
Liu et al. shows the use of a k-mer length 31 for the minimizer (Liu et al. page 2068 right col. and page 2070 figure 1).
Claim 11 is directed to binning the mutated sequence reads in one or more minimizer bins, such that each minimizer bin contains mutated sequence reads having a common minimizer and does not contain mutated sequence reads not having a common minimizer, and wherein the step of counting the number of mutations with matching position and/or with mismatching position is performed only on mutated sequence reads in the same minimizer bin.
Levy et al. does not show binning the mutated sequences reads in one or more minimizer bins.
Liu et al. shows hashing minimizers to a hash table where the key of the hash table is the minimizer and the value of the hash is a set of the read index, the position of the minimizer and the strand label. Since the minimizer is used as the key for the hash table then the sequences that are binned together all have the same minimizer (Liu et al. page 2068 right col.).
Claim 18 is directed to determining the measure correlated to the probability that the at least two mutated sequence reads derive from the same sequence comprising mutations based on the number of mutations with matching position and/or with mismatching position.
Levy et al. shows a scoring method that reflects how unlikely it is that the reads agree on their mutation patterns by chance which is used for mutational pattern matching (Levy et al. page E4637 right col.).
Claim 19 is directed to wherein the measure correlated to the probability that the at least two mutated sequence reads derive from the same sequence comprising mutations is one of i) a probability density that the at least two mutated sequence reads derive from the same sequence comprising mutations, and ii) a score function that is correlated to the probability density that the at least two mutated sequence reads derive from the same sequence comprising mutations.
The BRI of the method only requires one these measures. Levy et al. shows a scoring method that reflects how unlikely it is that the reads agree on their mutation patterns by chance which is used for mutational pattern matching (Levy et al. page E4637 right col.). This score is correlated with the probability density that these mutated sequence reads derive from the same sequence comprising mutations.
Claim 30 is directed to wherein assembling the mutated sequence reads based on the measure comprises grouping the mutated sequence reads into groups to the sequence comprising mutations and assembling each group separately.
Levy et al. shows that the mutated sequences are grouped by mutation patterns and are assembled by overlapping mutation patterns thus the assemblies for each mutational pattern are performed individually (Levy et al. page E4634 figure 2).
Claim 31 is directed to determining a sequence comprises reconstructing at least a portion of the target template nucleic acid sequence by using error correction to infer a most likely sequence not comprising mutations based on the assembled sequence comprising mutations.
Levy et al. shows that the mutated sequence reads are aligned to the original template and the mutated sequence reads are grouped/assembled based on mutation patterns (Levy et al. page E4634 figure 2). Levy et al. shows that the mutational method is the process of converting cytidine to a uridine and upon amplification because a thymidine (Levy et al. page E4633 figure 1). It would have been obvious to one of ordinary skill in the art that since the position of the mutation relative to the reference is known and the mutational process is known (i.e. C to T) that the reconstruction of the original sequence can be achieved by changing the mutation positions from T back to C.
An invention would have been obvious to one or ordinary skill in the art if some motivation in the prior art would have led that person to modify reference teachings to arrive at the claimed invention. It would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified the method of assembling mutated template reads to determine the if the mutated reads derive from the same sequence of Levy et al. to incorporate the compression method of utilizing common minimizers for contig assembly of Liu et al. because utilizing common minimizers is a compression technique used in sequence assembly which reduces memory consumption and efficiently stores large amounts of sequencing data (Liu et al. page 2066 abstract). One would have a reasonable expectation of success because Levy et al. provides a method that processes mutated sequence reads for assembly and to determine if the mutated reads derive from the same sequence while Liu et al. shows a compression method that can intake the mutation sequence reads and group them by common minimizers before the assembly to efficiently store the sequencing data.
The rejection below has been modified necessitated by amendment.
Claims 2 and 4-9 are rejected under 35 U.S.C. 103 as being unpatentable over Levy et al. in view of Liu et al. as applied to claims 1 above, and further in view of Nordström et al. (Nat Biotechnol 31, 325–330 (2013); previously cited).
Levy et al. in view of Liu et al. as applied to claims 1 does not show receiving a plurality of non-mutated sequence reads.
Claim 2 is directed to receiving a plurality of non-mutated sequence reads, each non-mutated sequence read corresponding to a subsequence of the sequence not comprising mutations.
Like Levy et al. in view of Liu et al., Nordström et al. shows a process of sequence assembly. Nordström et al. shows receiving sequence reads from two related samples distinguished by mutagen-induced changes only (i.e. mutation reads and non-mutation reads) (Nordström et al. page 326 figure 1 and online methods “k-mer counting and selection” subsection).
Nordström et al. shows a process of extracting k-mers present in one sample, but not in the other to collect a group of sample-specific k-mers. Therefore, sample-specific k-mers for the mutation reads will be a collection of k-mers that are only present in the mutation reads and not the non-mutated reads (Nordström et al. online methods “k-mer counting and selection” subsection).
Claim 4 is directed to wherein the k-mers of the ordered list of possible k-mers are ordered based on the probability that the k-mers exist in the sequence comprising mutations and do not exist in the sequence not comprising mutations. Claim 5 is directed to wherein the ordered list of possible k-mers consists of k-mers that exist more often in the plurality of mutated sequence reads than in the plurality of non- mutated sequence reads.
Levy et al. in view of Liu et al. does not show the k-mers of the ordered list of possible k-mers are ordered based on the probability that the k-mers exist in the sequence comprising mutations and do not exist in the sequence not comprising mutations, the ordered list of possible k-mers consists of k-mers that exist more often in the plurality of mutated sequence reads than in the plurality of non- mutated sequence reads.
Nordström et al. shows a process of extracting k-mers present in one sample, but not in the other to collect a group of sample-specific k-mers. Therefore, sample-specific k-mers for the mutation reads will be a collection of k-mers that are only present in the mutation reads and not the non-mutated reads (Nordström et al. online methods “k-mer counting and selection” subsection).
Claim 6 is directed to wherein the ordered list of possible k-mers consists of k-mers that exist n or more times in the plurality of mutated sequence reads and exist less than n times in the plurality of non-mutated sequence reads, where n is an integer greater or equal to 1. Claim 7 is directed to wherein the ordered list of possible k- mers consists of k-mers that do not exist in the plurality of non-mutated sequence reads. Claim 8 is directed to wherein n is 2.
Levy et al. in view of Liu et al. does not show wherein the ordered list of possible k-mers consists of k-mers that exist n or more times in the plurality of mutated sequence reads and exist less than n times in the plurality of non-mutated sequence reads, where n is an integer greater or equal to 1, wherein the ordered list of possible k- mers consists of k-mers that do not exist in the plurality of non-mutated sequence reads, or wherein n is 2.
Nordström et al. shows a process of extracting k-mers present in one sample, but not in the other to collect a group of sample-specific k-mers (Nordström et al. Online Methods “k-mer counting and selection”). Therefore, this predetermined set of mutation sample-specific k-mers appears less than 1 time (i.e. 0 times) in the non-mutated. Nordström et al. further shows that the process considers true k-mers to be k-mers that occur at least twice (Nordström et al. Online Methods “k-mer counting and selection”).
Claim 9 is directed to generating the ordered list of possible k-mers based on a comparison of the k-mers in the plurality of mutated sequence reads and the k-mers in the plurality of non-mutated sequence reads.
Levy et al. in view of Liu et al. does not show generating the ordered list of possible k-mers based on a comparison of the k-mers in the plurality of mutated sequence reads and the k-mers in the plurality of non-mutated sequence reads.
Nordström et al. shows a process of extracting k-mers present in one sample, but not in the other to collect a group of sample-specific k-mers (Nordström et al. Online Methods “k-mer counting and selection”).
An invention would have been obvious to one or ordinary skill in the art if some motivation in the prior art would have led that person to modify reference teachings to arrive at the claimed invention. It would have been obvious to one of ordinary skill in the art before the effective filling date to have modified the k-mer set in which the minimizer function is applied to in Levy et al. in view of Liu et al. with the predetermined sample-specific k-mers which only exist in one sample but not the other of Nordström et al. because this would allow for the minimizer to be sample-specific (i.e. only present in one sample but not the other or more probable in one sample but not the other) leading to storing sample specific reads which will aid in the assembly process based on sample specific mutational patterns (Nordström et al. Online Methods “k-mer counting and selection”). One would have a reasonable expectation of success because Levy et al. in view of Liu et al. shows applying a minimizer function to a set of k-mers while Nordström et al. shows generating a k-mer set that is specific to a sample.
The rejection below was previously recited.
Claims 12, 13, and 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Levy et al. in view of Liu et al. in view of Nordström et al. as applied to claim 2 above, and further in view of Girotto et al. (Theoretical Computer Science 698 (2017): 88-99; previously cited).
Claim 12 is directed to wherein the step of determining the positions of the one or more mutations in each mutated sequence read comprises: obtaining a set of non-mutated seed-masked k-mers by applying each one of one or more seed patterns to k-mers in the plurality of non-mutated sequence reads; for each mutated sequence read, applying the one or more seed patterns to k-mers in the respective mutated sequence read to obtain a plurality of mutated seed-masked k-mers, and determining the positions of the one or more mutations by identifying the one or more positions in the mutated sequence read that are masked by all of the seed patterns that correspond to the mutated seed-masked k-mers of the plurality of mutated seed-masked k-mers that exists in the set of non-mutated seed-masked k-mers.
Levy et al. in view of Liu et al. in view of Nordström et al. as applied to claims 2 and 4-9 does not show the use of seed-masked k-mers in the process of determining positions of mutations.
Like Levy et al. in view of Liu et al. in view of Nordström et al., Girotto et al. shows matching k-mers based on similarities to determine positions of mutations between reads. Girotto et al. shows applying a seed pattern (such as 111*1) to sequences (such as TGAAG and TGACG) to obtain seed masked k-mers (Girotto et al. page 90 second full paragraph). Girotto et al. shows that the seed masked k-mers of TGAAG and TGACG using the seed pattern 111*1 allows for one mutation at the position labeled * (Girotto et al. page 90 second full paragraph).
Claim 13 is directed to wherein the one or more seed patterns are chosen such that the probability of obtaining identical seed-masked k-mers by applying at least one of the one or more seed patterns to any k-mer in the plurality of mutated sequence reads and to a corresponding k-mer in the plurality of non-mutated sequence reads is greater than 90%.
Levy et al. in view of Liu et al. in view of Nordström et al. as applied to claims 2 and 4-9 does not show the one or more seed patterns are chosen such that the probability of obtaining identical seed-masked k-mers by applying at least one of the one or more seed patterns to any k-mer in the plurality of mutated sequence reads and to a corresponding k-mer in the plurality of non-mutated sequence reads is greater than 90%.
Girotto et al. shows the structure of the spaced seeds is critical to the evaluation criteria (Girotto et al. page 9 fourth full paragraph). Girotto et al. shows spaced seeds are proposed for maximizing the hit probability (i.e. the probability of obtaining identical seed-masked sequences) (Girotto et al. page 9 fourth full paragraph).
Claim 15 is directed to wherein each of the plurality of mutated sequence reads corresponds to a subsequence of a sequences comprising mutations associated with one of a plurality of samples, and each of the plurality of non-mutated sequence reads corresponds to a subsequence of a sequence not comprising mutations associated with the one of the plurality of samples, wherein each sequence comprising mutations comprises mutations compared to a respective sequence not comprising mutations, wherein obtaining a set of non-mutated seed-masked k-mers comprises obtaining a respective set of non-mutated seed-masked k-mers for each sample, further comprising creating a set of non-mutated sample bitvectors, each non-mutated sample bitvector defining, for a respective k-mer in the set of non-mutated seed-masked k-mers, in which of the plurality of samples the respective k-mer exists, and wherein determining the positions of the one or more mutations comprises, for each mutated sequence read, and for each set and/or each combination of sets of non-mutated seed- masked k-mers, identifying the one or more positions in the mutated sequence read that are masked by all of the seed patterns that correspond to the mutated seed-masked k-mers of the plurality of mutated seed-masked k-mers that exists in the respective set or combination of sets of non-mutated seed-masked k-mers, and associating the identified one or more positions with the one or more samples associated with the respective set or combination of sets of non-mutated seed-masked k-mers.
Levy et al. in view of Liu et al. in view of Nordström et al. as applied to claims 2 and 4-9 does not show the use of seed-masked k-mers in the process of determining positions of mutations, creating bitvectors, and identifying masked positions.
Girotto et al. shows applying a seed pattern (such as 111*1) to sequences (such as TGAAG and TGACG) to obtain seed masked k-mers (Girotto et al. page 90 second full paragraph). Girotto et al. shows that the seed masked k-mers of TGAAG and TGACG using the seed pattern 111*1 allows for one mutation at the position labeled * (Girotto et al. page 90 second full paragraph).
Claim 16 is directed to wherein the step of determining the positions of the one or more mutations in each mutated sequence read comprises: for one or more of the mutated sequence reads, aligning the respective mutated sequence read to a reference assembly; and determining the positions of the one or more mutations in the respective mutated sequence read by identifying positions in the respective mutated sequence read of differences between the respective mutated sequence read and the reference assembly.
Levy et al. shows that that the mutation positions are identified through the alignment of mutated sequence reads to the original template (Levy et al. page E4633 figure 1 and page 4634 figure 2).
Claim 17 is directed to wherein the step of determining the positions of the one or more mutations in each mutated sequence read comprises for each mutated sequence read: if a position in the respective mutated sequence read is aligned to the reference assembly, determining the position in the respective mutated sequence read to be a position of a mutation in the respective mutated sequence read if the position in the respective mutated sequence read is a position at which the respective mutated sequence read differs from the reference assembly, and if a position in the respective mutated sequence read is not aligned to the reference assembly, determining the position in the respective mutated sequence read to be a position of a mutation in the respective mutated sequence read if the position in the respective mutated sequence read is a position that is masked by all of the seed patterns that correspond to the mutated seed-masked k-mers of the plurality of mutated seed-masked k-mers that exists in the set of non-mutated seed-masked k-mers.
Levy et al. shows that that the mutation positions are identified through the alignment of mutated sequence reads to the original template (Levy et al. page E4633 figure 1 and page 4634 figure 2). Levy et al. shows the mutation positions are identified through a mutated sequence read differing from the original template at a position (Levy et al. page E4633 figure 1 and page 4634 figure 2).
An invention would have been obvious to one or ordinary skill in the art if some motivation in the prior art would have led that person to modify reference teachings to arrive at the claimed invention. It would have been obvious to one of ordinary skill in the art before the effective filling date to have modified the process of determining positions of mutations between reads of Levy et al. in view of Liu et al. in view of Nordström et al. with the process of spaced seed masking for matching sequences of Girotto et al. because this would allow for mismatches in predetermined positions, which improves accuracy and decreases the memory requirements (Girotto et al. abstract). One would have a reasonable expectation of success because Levy et al. in view of Liu et al. in view of Nordström et al. shows matching sequences for determining positions of mutations while Girotto et al. shows a process of increasing the accuracy of matching sequence.
The rejection below was previously recited.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Levy et al. in view of Liu et al. in view of Nordström et al. in view of Girotto et al. as applied to claim 12 above, and further in view of Frith et al. (Nucleic Acids Research, Volume 42, Issue 7, 1 April 2014; previously cited)
Levy et al. in view of Liu et al. in view of Nordström et al. in view of Girotto et al. as applied to claim 12, 13, and 15-17 does not show wherein the one or more seed patterns consist of one or more transition seed patterns.
Claim 14 is directed to wherein the sequence comprising mutations comprises transition mutations compared to the sequence not comprising mutations; and wherein the one or more seed patterns consist of one or more transition seed patterns.
Like Levy et al. in view of Liu et al. in view of Nordström et al. in view of Girotto et al., Frith et al. shows the use of transition-constrained seeds for sequence pair matching (Frith et al. page 2 left col.).
An invention would have been obvious to one or ordinary skill in the art if some motivation in the prior art would have led that person to modify reference teachings to arrive at the claimed invention. It would have been obvious to one of ordinary skill in the art before the effective filling date to have modified the seed patterns used for sequence matching in Levy et al. in view of Liu et al. in view of Nordström et al. in view of Girotto et al. with the transition-constrained seeds for sequence pair matching because this would allow for positions to tolerate transitions (such as c to t) transitions but not transversions (Frith et al. page 2 left col.). One would be motivated to make this modification because the mutated sequence reads used in the analysis of Levy et al. in view of Liu et al. in view of Nordström et al. in view of Girotto et al. are mutations in which convert C to T and this toleration would allow for better sequence matching between mutated sequences and non-mutated sequences for identify matches that have undergone transitions. One would have a reasonable expectation of success because Levy et al. in view of Liu et al. in view of Nordström et al. in view of Girotto et al. shows the use of seed patterns for sequence matching while Frith et al. shows a specific seed structure to be used in sequence matching.
Response to Arguments
Applicant's arguments filed 23 January 2026 have been fully considered but they are not persuasive.
Applicant argues that Levy, Lui, and Nordstrom, alone or in combination, teach or reasonably suggest the claimed method in which a common minimizer function is applied to each mutated sequence read to determine a respective minimizer, in which the respective minimizer is listed first in an ordered list as recited in claim 1 (Reply p. 16). Applicant argues as recited in claims 4-7 the ordered list is based on the types of k-mers in a set of sequences from mutation sequences and non-mutation sequences (Reply p. 17).
This argument has been fully considered but found to be not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). As show above, Liu et al. further shows computing the first minimizers in an ordered list of possible k-mers for sequence reads (Liu et al. page 2068 left col.). Further, Nordstrom et al. provides the extraction of sample specific k-mers to be used for analysis. As stated above, when modified this list for computing minimizers in reads consist of k-mers which are in one sample and not in a different sample. Thus, claim 1 is obvious over Levy in view of Liu et al. as set out above. Further claims 4-7 are obvious over Levy in view of Liu et al. in view of Nordstrom et al. described above.
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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/J.E.H./Examiner, Art Unit 1685
/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685
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