DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claim Status
Claims 1-20 are pending.
Claim 19 is objected to.
Claims 1-20 are rejected.
Priority
The instant Application claims domestic benefit to US provisional applications 63/338,703 and 63/338,810, filed May 5 2022. Accordingly, each of claims 1-20 are afforded the effective filing date of the May 5 2022.
Information Disclosure Statement
The information disclosure statement (IDS) filed on Dec 12 2023 is in compliance with the provisions of 37 CFR 1.97 and has therefore been considered. A signed copy of the IDS document is included with this Office Action.
Drawings
The Drawings submitted May 5 2023 are accepted.
Nucleotide and/or Amino Acid Sequence Disclosures
The sequence listing submitted May 5 2023 has been accepted.
Claim Objections
The claims are objected to for the following informalities:
Claim 19 recites “INDELs”, which should be amended to write out the entire phrase rather than the abbreviation.
Claim Rejections - 35 USC § 112
35 U.S.C. 112(b)
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.
Claims 1-20 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 1 recites “more than one acceptable variants”. The term “acceptable” is a relative term which renders the claim indefinite. The term “acceptable” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Therefore, the metes and bounds of the more than one variants are not clear. Claims 2-20 are rejected based on their dependency from claim 1.
Claim 19 recites “the one or more variants”. There is insufficient antecedent basis for this limitation in the claim as there is no previous recitation of a one or more variants. Claim 1 previously recites “a position within the sequence that has more than one acceptable variants” and “determining which variant of the more than one acceptable variants”. It is not clear whether claim 19 intends to refer to the more than one acceptable variants, to the position within the sequence that has more than one acceptable variants, or to the determined variant. The rejection may be overcome by clarifying the antecedent basis of the limitation.
Claim 20 recites “wherein the flow measurement is measured by a sequencer based on the flow order”. It is unclear whether the wherein clause is intended to require measuring by a sequencer within the metes and bounds of the claimed invention, or if it is only further limiting the type of flow measurement used in the invention such that measuring by a sequencer is not required within the metes and bounds of the invention. As set forth in MPEP 2111.04.I, “wherein” clauses raise the question as to the limiting effect of the language in a claim. As the claims do not recite an active performance of the measuring by a sequencer, the metes and bounds of the claims are unclear. For compact examination, it is assumed that the measuring by a sequencer is not required to be performed. The rejection may be overcome by clarifying what steps are required to be performed.
35 U.S.C. 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 16 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 16 recites “wherein the average residual is a mean residual”. The term “mean” encompasses several types of means, including an arithmetic mean, which is equivalent to an average. Therefore, the claim recites an embodiment where the arithmetic mean does not further limit the average residual recited in claim 15, and an embodiment where the mean could be different from the average and therefore does not include all of the limitations recited in the claim from which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to one or more judicial exceptions without significantly more.
MPEP 2106 organizes judicial exception analysis into Steps 1, 2A (Prongs One and Two) and 2B as follows below. MPEP 2106 and the following USPTO website provide further explanation and case law citations: uspto.gov/patent/laws-and-regulations/examination-policy/examination-guidance-and-training-materials.
Framework with which to Evaluate Subject Matter Eligibility:
Step 1: Are the claims directed to a process, machine, manufacture, or composition of matter;
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e. a law of nature, a natural phenomenon, or an abstract idea;
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application (Prong Two); and
Step 2B: If the claims do not integrate the judicial exception, do the claims provide an inventive concept.
Framework Analysis as Pertains to the Instant Claims:
Step 1
With respect to Step 1: yes, the claims are directed to a method, i.e., a process, machine, or manufacture within the above 101 categories [Step 1: YES; See MPEP § 2106.03].
Step 2A, Prong One
With respect to Step 2A, Prong One, the claims recite judicial exceptions in the form of abstract ideas. The MPEP at 2106.04(a)(2) further explains that abstract ideas are defined as:
mathematical concepts (mathematical formulas or equations, mathematical relationships and mathematical calculations);
certain methods of organizing human activity (fundamental economic practices or principles, managing personal behavior or relationships or interactions between people); and/or
mental processes (procedures for observing, evaluating, analyzing/ judging and organizing information).
With respect to the instant claims, under the Step 2A, Prong One evaluation, the claims are found to recite abstract ideas that fall into the grouping of mental processes (in particular procedures for observing, analyzing and organizing information) and mathematical concepts (in particular mathematical relationships and formulas) as well as a law of nature or a natural phenomenon are as follows:
Independent claim 1: matching a sequence selected from a plurality of sequences with the sequence read, the sequence having a position within the sequence that has more than one acceptable variants;
determining which variant of the more than one acceptable variants matches the sequence;
generating a predicted flow measurement based on the matched sequence, the variant, and a flow order; and
labeling the sequence read and associated flow measurement with the predicted flow measurement.
Dependent claim 2: defining a plurality of sequences wherein sequences of the plurality of sequences have a position having more than one acceptable variant.
Dependent claim 3: determining the sequence read based on the associated flow measurement.
Dependent claim 4: aligning the labeled sequence read with other labeled sequence reads.
Dependent claim 12: determining a residual measurement based on a difference between the flow measurement and the predicted flow measurement.
Dependent claim 14: grouping the labeled sequence read and associated flow measurements with other sequence reads and associated flow measurements that have the same matching sequence and variant.
Dependent claim 15: determining an average residual at each position in a series of the flow measurement.
Dependent claim 16: wherein the average residual is a mean residual.
Dependent claim 17: determining a variance of the residual at each position in a series of the flow measurement.
Dependent claims 5-11, 13, and 18-20 recite further steps that limit the judicial exceptions in independent claim 1 and, as such, also are directed to those abstract ideas. For example, claims 5-6 further limit matching the sequence with the sequence read to including determining an amplicon associated with the sequence read and the associated primer length; claims 7-11 and 13 further limit what information the sequence read and associated flow measurement are labelled with; claim 18 further limits the sequence to being a nucleic acid sequence or a protein sequence; claim 19 further limits the variants to being a single nucleotide polymorphism, a multi-nucleotide polymorphism, or INDELs; and claim 20 further limits the flow measurement to being measured by a sequencer based on the flow order.
The abstract ideas recited in the claims are evaluated under the Broadest Reasonable Interpretation (BRI) and determined to each cover performance either in the mind and/or by mathematical operation because the method only requires a user to manually label a sequence read and associated flow measurement with a predicted flow measurement.
Without further detail as to the methodology involved in “matching”, “determining”, “generating”, “labeling”, and “grouping”, under the BRI, one may simply, for example, use pen and paper to determine a sequence read based on an associated flow measurement, match a sequence with the sequence read, determine a variant from a list of acceptable variants at a position of the sequence, generate a predicted flow measurement, determine an average/mean residual measurement and variance based on the difference between the flow measurement and the predicted flow measurement, label the sequence read and associated flow measurement with the predicted flow measurement, repeat the process for a plurality of sequences, and align or group the labeled sequence read with other labeled sequence reads. Such actions encompass observations, evaluations, judgments, which are concepts able to be performed in the human mind.
Those steps directed to “determining an average residual at each position in a series of the flow measurement” in claims 15-16 and “determining a variance of the residual at each position in a series of the flow measurement” in claim 17 require mathematical techniques as the only supported embodiments, as they express mathematical relationships in words.
Therefore, claim 1 and those claims dependent therefrom recite an abstract idea [Step 2A, Prong 1: YES; See MPEP § 2106.04].
Step 2A, Prong Two
Because the claims do recite judicial exceptions, direction under Step 2A, Prong Two, provides that the claims must be examined further to determine whether they integrate the judicial exceptions into a practical application (MPEP 2106.04(d)). A claim can be said to integrate a judicial exception into a practical application when it applies, relies on, or uses the judicial exception in a manner that imposes a meaningful limit on the judicial exception. This is performed by analyzing the additional elements of the claim to determine if the judicial exceptions are integrated into a practical application (MPEP 2106.04(d).I.; MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the judicial exceptions, the claim is said to fail to integrate the judicial exceptions into a practical application (MPEP 2106.04(d).III).
Additional elements, Step 2A, Prong Two
With respect to the instant recitations, the claims recite the following additional elements:
Independent claim 1: retrieving a sequence read having an associated flow measurement and an associated flow order.
Dependent claim 3: receiving the associated flow measurement.
Considerations under Step 2A, Prong Two
With respect to Step 2A, Prong Two, the additional elements of the claims do not integrate the judicial exceptions into a practical application for the following reasons. Those steps directed to data gathering, such as “retrieving” a sequence read and “receiving” the associated flow measurement, perform functions of collecting the data needed to carry out the judicial exceptions. Data gathering and outputting do not impose any meaningful limitation on the judicial exceptions, or on how the judicial exceptions are performed. Data gathering and outputting steps are not sufficient to integrate judicial exceptions into a practical application (MPEP 2106.05(g)).
The specification as published discloses that this “ application generally relates to methods, systems, and computer-readable media for applying a deep learning artificial neural network for correction of signal data obtained by next-generation sequencing systems, and, more specifically, to correct the signal data for improving the accuracy of base calling” at [0003], but does not provide a clear explanation for how the additional elements provide these improvements. Therefore, the additional elements do not clearly improve the functioning of a computer, or comprise an improvement to any other technical field. Further, the additional elements do not clearly affect a particular treatment; they do not clearly require or set forth a particular machine; they do not clearly effect a transformation of matter; nor do they clearly provide a nonconventional or unconventional step (MPEP2106.04(d)).
Thus, none of the claims recite additional elements which would integrate a judicial exception into a practical application, and the claims are directed to one or more judicial exceptions [Step 2A, Prong 2: NO; See MPEP § 2106.04(d)].
Step 2B (MPEP 2106.05.A i-vi)
According to analysis so far, the additional elements described above do not provide significantly more than the judicial exception. A determination of whether additional elements provide significantly more also rests on whether the additional elements or a combination of elements represents other than what is well-understood, routine, and conventional. Conventionality is a question of fact and may be evidenced as: a citation to an express statement in the specification or to a statement made by an applicant during prosecution that demonstrates a well-understood, routine or conventional nature of the additional element(s); a citation to one or more of the court decisions as discussed in MPEP 2106(d)(II) as noting the well-understood, routine, conventional nature of the additional element(s); a citation to a publication that demonstrates the well-understood, routine, conventional nature of the additional element(s); and/or a statement that the examiner is taking official notice with respect to the well-understood, routine, conventional nature of the additional element(s).
With respect to the instant claims, the courts have found that receiving and outputting data are well-understood, routine, and conventional functions when claimed in a merely generic manner or as insignificant extra-solution activity (see Symantec, 838 F.3d at 1321, 120 USPQ2d at 1362 (utilizing an intermediary computer to forward information), buySAFE, Inc. v. Google, Inc., 765 F.3d 1350, 1355, 112 USPQ2d 1093, 1096 (Fed. Cir. 2014) (computer receives and sends information over a network), Versata Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1334, 115 USPQ2d 1681, 1701 (Fed. Cir. 2015), and OIP Techs., 788 F.3d at 1363, 115 USPQ2d at 1092-93, as discussed in MPEP 2106.05(d)(II)(i)). As such, the claims simply append well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception (MPEP2106.05(d)). The data gathering steps as recited in the instant claims constitute a general link to a technological environment which is insufficient to constitute an inventive concept which would render the claims significantly more than the judicial exception (MPEP2106.05(g)&(h)).
Taken alone, the additional elements do not amount to significantly more than the above-identified judicial exception(s). Even when viewed as a combination, the additional elements fail to transform the exception into a patent-eligible application of that exception. Thus, the claims as a whole do not amount to significantly more than the exception itself [Step 2B: NO; See MPEP § 2106.05].
Therefore, the instant claims are not drawn to eligible subject matter as they are directed to one or more judicial exceptions without significantly more. For additional guidance, applicant is directed generally to the MPEP § 2106.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
A. Claims 1-3, 5-7, 9-11, and 18-20 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Wise et al. (US 2019/0318806; newly cited; corresponds to CA-3065784 cited on the Dec 12 2023 IDS).
Claim 1 discloses a method for labeling sequence reads, the method comprising:
Wise discloses a variant classifier that uses trained deep neural networks to predict whether a given variant is somatic or germline, where one of the inputs into the networks includes a DNA sequence with a variant and a set of metadata features correlated with the variant (abstract).
retrieving a sequence read having an associated flow measurement and an associated flow order;
Wise teaches sequencing nucleic acids (i.e., a sequence read) to identify sequence variations using sequencing by synthesis, where a plurality of fluorescently-labeled nucleotides are used to sequence a plurality of clusters of amplified DNA present on the surface of an optical substrate (e.g., a surface that at least partially defines a channel in a flow cell), where a single type of nucleotide with a fluorophore (i.e., an associated flow measurement) is added per cycle (i.e., an associated flow order) [0087-0090]. Wise teaches receiving the sequencing data for subsequent analysis [0095]. Wise teaches that the DNA sequence is an image with multiple channels that numerically encode the four types of nucleotide bases, A, C, G, and T (i.e., an associated flow measurement and an associated flow order) ([0049]; FIG. 2-3).
matching a sequence selected from a plurality of sequences with the sequence read, the sequence having a position within the sequence that has more than one acceptable variants;
Wise teaches that the sample reads are directed toward predetermined genetic loci, such as those genetic loci having suspected STRs or suspected SNPs (i.e., the sequence having a position within the sequence that has more than one acceptable variants) [0095]. Wise teaches analyzing sequencing data to identify potential variant calls, where sample reads are assigned to corresponding genetic loci (i.e., matching a sequence selected from a plurality of sequences) based on the sequence of the nucleotides of the sample read or, in other words, the order of nucleotides within the sample read (e.g., A, C, G, T) [0119].
determining which variant of the more than one acceptable variants matches the sequence;
Wise teaches that the sample read may be designated as including a possible variant/allele of a particular genetic locus [0119]. Wise teaches that if a genetic locus is known for including SNPs, then the assigned reads that have been called for the genetic locus may undergo analysis to identify the SNPs of the assigned reads [0123] Wise teaches analyzing raw fragments to determine whether supporting variants exist at corresponding positions within the raw fragments [0124].
generating a predicted flow measurement based on the matched sequence, the variant, and a flow order; and
Wise teaches that the variant caller then outputs an indication of whether the raw fragment has a supporting variant at a particular position (i.e., a predicted flow measurement) [0124]. As Wise is considered to fairly teach the matched sequence, the variant, and a flow order while determining whether a raw fragment has a supporting variant as discussed above, it is considered that the predicted flow measurement taught by Wise is based on these features as well.
labeling the sequence read and associated flow measurement with the predicted flow measurement.
Wise teaches that the process analyzes one or more raw fragments associated with a sample read and outputs a corresponding variant call associated (i.e., labeling) with the raw fragments [0126].
Regarding claim 2, Wise teaches claim 1 as described above. Claim 2 further adds defining a plurality of sequences wherein sequences of the plurality of sequences have a position having more than one acceptable variant.
Wise teaches that the sample reads are directed toward predetermined genetic loci (i.e., a plurality of sequences, such as those genetic loci having suspected STRs or suspected SNPs (i.e., the sequence having a position within the sequence that has more than one acceptable variants) [0095].
Regarding claim 3, Wise teaches claim 1 as described above. Claim 3 further adds receiving the associated flow measurement; and determining the sequence read based on the associated flow measurement.
Wise teaches that the DNA sequence is an image with multiple channels that numerically encode the four types of nucleotide bases, A, C, G, and T [0049] that is produced from sequencing-by-synthesis over a flow cell [0088-0090], which reads on determining the sequence of the read from the associated flow measurement as instantly claimed.
Regarding claim 5, Wise teaches claim 1 as described above. Claim 5 further limits matching the sequence with the sequence read to including determining an amplicon associated with the sequence read, the amplicon selected from a plurality of amplicons.
Wise teaches that the term “sequence” includes or represents a strand of nucleotides coupled to each other, where the sequence may be an amplicon [0061; 0066]. Wise teaches that providing a reference sequence comprises identifying a locus-of-interest based upon the primer sequence of the PCR amplicon (i.e., determining an amplicon) [0066].
Regarding claim 6, Wise teaches claims 1 and 5 as described above. Claim 6 further adds determining a primer length of the sequence read, the primer length associated with the amplicon.
Wise teaches that the nucleic acid sequence may include a primer sub-sequence [0061; 0096]. Wise teaches analyzing the sequence reads to locate one or more identifying sequences (e.g., primer sequences) of nucleotides [0119]. Wise teaches that the analyzing the series of n nucleotides of the identifying sequence to determine if the series of n nucleotides of the identifying sequence effectively matches with one or more of the select sequences, where the number n may be a predetermined number, selected by an individual, or equal to the shortest primer sequence within a database (i.e., determining a primer length of the sequence read) [0120].
Regarding claim 7, Wise teaches claim 1 as described above. Claim 7 limits labeling to further include labeling the sequence read and associated flow measurement with the matching sequence and the variant.
Wise teaches that the process analyzes one or more raw fragments associated with a sample read and outputs a corresponding variant call associated (i.e., labeling) with the raw fragments [0126]. Wise teaches that when a potential variant call is identified, the process outputs an indication of the potential variant call, the variant sequence, the variant position and a reference sequence associated therewith (i.e., the matching sequence) [0126].
Regarding claim 9, Wise teaches claim 1 as described above. Claim 9 limits labeling to further include labeling the sequence read and associated flow measurement with an amplicon identifier.
Wise teaches that the process analyzes one or more raw fragments associated with a sample read and outputs a corresponding variant call associated (i.e., labeling) with the raw fragments [0126]. Wise teaches that when a potential variant call is identified, the process outputs an indication of the potential variant call, the variant sequence, the variant position and a reference sequence associated therewith [0126].Wise teaches that the term “sequence” includes or represents a strand of nucleotides coupled to each other, where the sequence may be an amplicon [0061; 0066]. Wise teaches that providing a reference sequence comprises identifying a locus-of-interest based upon the primer sequence of the PCR amplicon (i.e., determining an amplicon) [0066]. Wise teaches that the process analyzes one or more raw fragments associated with a sample read and outputs a corresponding variant call associated (i.e., labeling) with the raw fragments [0126]. Therefore, as is considered to fairly teach labeling the sequence read with an associated reference sequence, and Wise teaches that the reference sequences are associated with specific amplicons, it is considered that Wise also fairly teaches labeling the sequence reads with an associated amplicon.
Regarding claim 10, Wise teaches claim 1 as described above. Claim 10 limits labeling to further include labeling the sequence read and associated flow measurement with a model parameter.
Wise teaches that the process analyzes one or more raw fragments associated with a sample read and outputs a corresponding variant call associated (i.e., labeling) with the raw fragments [0126]. Wise teaches that when a potential variant call is identified, the process outputs an indication of the potential variant call, the variant sequence, the variant position and a reference sequence associated therewith [0126]. Wise also teaches a metadata correlator that that correlates each unclassified variant in the database with respective values of mutation characteristics, read mapping statistics, and occurrence frequency (each of which read on a model parameter), by associating/linking/appending (i.e., labeling) the found attributes with or to the variant [0130]. Wise teaches a model that has two deep neural networks: a convolutional neural network (CNN) and a fully-connected neural network (FCNN), and two inputs: a DNA sequence with a variant and a set of metadata features correlated with the variant, where a feature sequence (i.e., labeling the sequence read and associated flow measurement) is derived by concatenating the metadata features with the intermediate convolved feature that is produced by the CNN when it process the DNA sequence (abstract).
Regarding claim 11, Wise teaches claim 1 as described above. Claim 11 limits labeling to further include labeling the sequence read and associated flow measurement with a flow order.
Wise teaches sequencing nucleic acids (i.e., a sequence read) to identify sequence variations using sequencing by synthesis, where a plurality of fluorescently-labeled nucleotides are used to sequence a plurality of clusters of amplified DNA present on the surface of an optical substrate (e.g., a surface that at least partially defines a channel in a flow cell), where a single type of nucleotide with a fluorophore (i.e., an associated flow measurement) is added per cycle (i.e., an associated flow order) [0087-0090]. Wise teaches receiving the sequencing data for subsequent analysis [0095]. Wise teaches that the DNA sequence is an image with multiple channels that numerically encode the four types of nucleotide bases, A, C, G, and T (i.e., an associated flow measurement and an associated flow order) ([0049]; FIG. 2-3). It is therefore considered that the sequence read taught by Wise is inherently labeled with the associated flow order because the sequence read comprises sequences in an order.
Regarding claim 18, Wise teaches claim 1 as described above. Claim 18 further limits the sequence to a nucleic acid sequence or a protein sequence.
Wise teaches a variant classifier that acts on DNA sequences (i.e., nucleic acid sequences) (abstract; entire document is relevant).
Regarding claim 19, Wise teaches claims 1 and 18 as described above. Claim 19 further limits the one or more variants to a single nucleotide polymorphism, a multi-nucleotide polymorphism, or INDELs.
Wise teaches examining variants which may be single nucleotide polymorphisms (SNPs) short tandem repeats (STRs), which reads on a multi-nucleotide polymorphism, or insertions or deletions [0088; 0095; 0123; 0127; 0131].
Regarding claim 20, Wise teaches claim 1 as described above. Claim 20 further limits the flow measurement to being measured by a sequencer based on the flow order.
Wise teaches sequencing nucleic acids (i.e., a sequence read) to identify sequence variations using sequencing by synthesis, where a plurality of fluorescently-labeled nucleotides are used to sequence a plurality of clusters of amplified DNA present on the surface of an optical substrate (e.g., a surface that at least partially defines a channel in a flow cell), where a single type of nucleotide with a fluorophore is added per cycle (i.e., a flow order) [0087-0090]. Wise teaches that sequencing by synthesis technology is used by Illumina, and using Illumina sequencers [0065].
B. Claims 8 is rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Wise, as applied to claim 1 above, and as evidenced by Guo et al. (BMC Genomics, 2012 13(1), p.666; newly cited).
Regarding claim 8, Wise teaches claim 1 as described above. Claim 8 limits labeling to further include labeling the sequence read and associated flow measurement with a sequence direction.
Wise teaches that the process analyzes one or more raw fragments associated with a sample read and outputs a corresponding variant call associated (i.e., labeling) with the raw fragments [0126]. Wise also teaches a metadata correlator that that correlates each unclassified variant in the database with respective values of mutation characteristics, read mapping statistics, and occurrence frequency, by associating/linking/appending (i.e., labeling) the found attributes with or to the variant [0130]. Wise teaches a model that has two deep neural networks: a convolutional neural network (CNN) and a fully-connected neural network (FCNN), and two inputs: a DNA sequence with a variant and a set of metadata features correlated with the variant, where a feature sequence (i.e., labeling the sequence read and associated flow measurement) is derived by concatenating the metadata features with the intermediate convolved feature that is produced by the CNN when it process the DNA sequence (abstract). Wise teaches that the database of variant features can include Fisher strand bias [0132]. As evidenced by Guo, the Fisher Score computes a strand bias score (p. 2, col. 1, par. 1; p. 3, col. 1, par. 1-2) to account for positive and negative strand bias in Illumina short-read sequencing data (abstract).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
A. Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Wise, as applied to claim 1 in the above 35 USC 102 rejection, and in view of the features of Wise.
Regarding claim 4, Wise teaches claim 1 as described above. Claim 4 further adds aligning the labeled sequence read with other labeled sequence reads.
Wise teaches that sample reads designated (i.e., labeled) as including a possible variant/allele of a particular genetic locus may be collected, aggregated, or binned with other sample reads that have been designated as including possible variants/alleles of the genetic locus [0119]. Wise teaches that the terms “mapping”, “aligned,” “alignment,” or “aligning” refer to the process of comparing a read or tag to a reference sequence [0068]. Wise teaches that a sample read can be a consensus (e.g., averaged or weighted) sequence derived from multiple sample reads [0066]. Wise does not explicitly teach aligning the labeled sequence read with other labeled sequence reads as instantly claimed.
However, 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 modify, in the course of routine experimentation and with a reasonable expectation of success, the features of Wise to align the labeled sequence read with other labeled sequence reads as instantly claimed because Wise teaches collecting groups of reads designated to as including possible variants/alleles of the genetic locus and performing alignments as described above. Therefore, it would have been obvious to one of ordinary skill in the art to align those grouped sequence reads against each other rather than a reference genome. The motivation would have been to create a consensus sequence derived from multiple sample reads, as taught by Wise [0066].
B. Claims 12-17 are rejected under 35 U.S.C. 103 as being unpatentable over Wise, as applied to claims 1 in the above 35 USC 102 rejection, and in view of Hubbell et al. (US 2014/0296080; newly cited).
Regarding claim 12, Wise teaches claim 1 as described above. Claim 12 further adds determining a residual measurement based on a difference between the flow measurement and the predicted flow measurement, which Wise does not teach.
However, the prior art to Hubbell discloses a method for evaluating variant likelihood. Hubbell teaches obtaining measured values corresponding to an ensemble of sequencing reads for at least some of the template polynucleotide strands in at least one of the defined spaces; and evaluating a likelihood that a variant sequence is present given the measured values corresponding to the ensemble of sequencing reads, the evaluating comprising: determining a measurement confidence value for each read in the ensemble of sequencing reads and modifying at least some model-predicted values using a first bias for forward strands and a second bias for reverse strands (abstract). Hubbell teaches determining residuals representing differences between measured and predicted values of nucleotides ([0070; 0072; 0080]; FIG. 9B and D).
Regarding claim 13, Wise teaches claim 1, and in view of Hubbell, claim 12 as described above. Claim 11 limits labeling to further include labeling the sequence read and associated flow measurement with the residual measurement.
Wise teaches that the process analyzes one or more raw fragments associated with a sample read and outputs a corresponding variant call associated (i.e., labeling) with the raw fragments [0126]. However, neither Wise nor Hubbell teach labeling the sequence read and associated flow measurement with the residual measurement
However, 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 modify, in the course of routine experimentation and with a reasonable expectation of success, the method of Wise with the method of Hubbell to label the sequences, as taught by Wise, with the residuals taught by Hubbell, because such a modification represents a simple substitution of one of the pieces of information used to label the sequences as taught by Wise with a piece of information as taught by Hubbell. One of ordinary skill in the art would have been able to carry out such a substitution, and the results would be reasonably predictable.
Regarding claim 14, Wise teaches claim 1, and in view of Hubbell, claim 12 as described above. Claim 14 further adds grouping the labeled sequence read and associated flow measurements with other sequence reads and associated flow measurements that have the same matching sequence and variant.
Wise teaches that sample reads designated as including a possible variant/allele of a particular genetic locus may be collected, aggregated, or binned with other sample reads that have been designated as including possible variants/alleles of the genetic locus [0119].
Regarding claims 15-17, Wise teaches claim 1, and in view of Hubbell, claim 12 and 14 as described above. Claim 15 further adds determining an average residual at each position in a series of the flow measurement. Claim 16 recites that the average residual to a mean residual. Claim 17 further adds determining a variance of the residual at each position in a series of the flow measurement. Wise does not teach these limitations.
However, Hubbell teaches determining differences between measured and model-predicted values (i.e., residuals) at each nucleotide flow may be assumed to follow independent normal distributions each having a mean and a variance [0083].
Regarding claims 12-17, 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 combine, in the course of routine experimentation and with a reasonable expectation of success, Wise and Hubbell because both references disclose methods for detecting variants in nucleic acid sequencing data. The motivation to examine residuals, or differences between measured and model-predicted values, would have been to estimate measurement confidence values, as taught by Hubbell [0080].
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1-7, 9-11, and 18-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/700,683 in view of Wise et al. (US 2019/0318806; newly cited; corresponds to CA-3065784 cited on the Dec 12 2023 IDS). Claim 8 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/700,683 in view of Wise, as applied to claim 1, and as evidenced by Guo et al. (BMC Genomics, 2012 13(1), p.666; newly cited). Claims 12-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/700,683 in view of Wise, as applied to claim 1, and further in view of Hubbell et al. (US 2014/0296080; newly cited).
This is a provisional nonstatutory double patenting rejection.
Reference claim 1 discloses the limitations of instant claim 1 (“second genotyping call data representing a plurality of candidate gene sequences” is equivalent to “the sequence having a position within the sequence that has more than one acceptable variants”; “determining a match score” is equivalent to “matching a sequence”; “making a genotyping call” is equivalent to “generating a predicted flow measurement”) except for “retrieving a sequence read having an associated flow measurement and an associated flow order” and “labeling the sequence read and associated flow measurement with the predicted flow measurement”.
However, Wise discloses a variant classifier that uses trained deep neural networks to predict whether a given variant is somatic or germline, where one of the inputs into the networks includes a DNA sequence with a variant and a set of metadata features correlated with the variant (abstract). Wise teaches sequencing nucleic acids (i.e., a sequence read) to identify sequence variations using sequencing by synthesis, where a plurality of fluorescently-labeled nucleotides are used to sequence a plurality of clusters of amplified DNA present on the surface of an optical substrate (e.g., a surface that at least partially defines a channel in a flow cell), where a single type of nucleotide with a fluorophore (i.e., an associated flow measurement) is added per cycle (i.e., an associated flow order) [0087-0090]. Wise teaches receiving the sequencing data for subsequent analysis [0095]. Wise teaches that the DNA sequence is an image with multiple channels that numerically encode the four types of nucleotide bases, A, C, G, and T (i.e., an associated flow measurement and an associated flow order) ([0049]; FIG. 2-3). Wise teaches that the process analyzes one or more raw fragments associated with a sample read and outputs a corresponding variant call associated (i.e., labeling) with the raw fragments [0126].
Reference claim 1 discloses the limitations of instant claim 2 (“second genotyping call data representing a plurality of candidate gene sequences”).
Reference claim 1 discloses the limitations of claim 18 (“A method of genotyping a gene sequence”).
The reference application does not disclose the limitations of claims 3-17 and 19-20.
However, regarding claim 3, Wise teaches that the DNA sequence is an image with multiple channels that numerically encode the four types of nucleotide bases, A, C, G, and T [0049] that is produced from sequencing-by-synthesis over a flow cell [0088-0090], which reads on determining the sequence of the read from the associated flow measurement as instantly claimed.
However, regarding claim 4, Wise teaches that sample reads designated (i.e., labeled) as including a possible variant/allele of a particular genetic locus may be collected, aggregated, or binned with other sample reads that have been designated as including possible variants/alleles of the genetic locus [0119]. Wise teaches that the terms “mapping”, “aligned,” “alignment,” or “aligning” refer to the process of comparing a read or tag to a reference sequence [0068]. Wise teaches that a sample read can be a consensus (e.g., averaged or weighted) sequence derived from multiple sample reads [0066]. Wise does not explicitly teach aligning the labeled sequence read with other labeled sequence reads as instantly claimed.
However, 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 modify, in the course of routine experimentation and with a reasonable expectation of success, the features of Wise to align the labeled sequence read with other labeled sequence reads as instantly claimed because Wise teaches collecting groups of reads designated to as including possible variants/alleles of the genetic locus and performing alignments as described above. Therefore, it would have been obvious to one of ordinary skill in the art to align those grouped sequence reads against each other rather than a reference genome. The motivation would have been to create a consensus sequence derived from multiple sample reads, as taught by Wise [0066].
However, regarding claim 5, Wise teaches that the term “sequence” includes or represents a strand of nucleotides coupled to each other, where the sequence may be an amplicon [0061; 0066]. Wise teaches that providing a reference sequence comprises identifying a locus-of-interest based upon the primer sequence of the PCR amplicon (i.e., determining an amplicon) [0066].
However, regarding claim 6, Wise teaches that the nucleic acid sequence may include a primer sub-sequence [0061; 0096]. Wise teaches analyzing the sequence reads to locate one or more identifying sequences (e.g., primer sequences) of nucleotides [0119]. Wise teaches that the analyzing the series of n nucleotides of the identifying sequence to determine if the series of n nucleotides of the identifying sequence effectively matches with one or more of the select sequences, where the number n may be a predetermined number, selected by an individual, or equal to the shortest primer sequence within a database (i.e., determining a primer length of the sequence read) [0120].
However, regarding claim 7, Wise teaches that the process analyzes one or more raw fragments associated with a sample read and outputs a corresponding variant call associated (i.e., labeling) with the raw fragments [0126]. Wise teaches that when a potential variant call is identified, the process outputs an indication of the potential variant call, the variant sequence, the variant position and a reference sequence associated therewith (i.e., the matching sequence) [0126].
However, regarding claim 8, Wise teaches that the process analyzes one or more raw fragments associated with a sample read and outputs a corresponding variant call associated (i.e., labeling) with the raw fragments [0126]. Wise also teaches a metadata correlator that that correlates each unclassified variant in the database with respective values of mutation characteristics, read mapping statistics, and occurrence frequency, by associating/linking/appending (i.e., labeling) the found attributes with or to the variant [0130]. Wise teaches a model that has two deep neural networks: a convolutional neural network (CNN) and a fully-connected neural network (FCNN), and two inputs: a DNA sequence with a variant and a set of metadata features correlated with the variant, where a feature sequence (i.e., labeling the sequence read and associated flow measurement) is derived by concatenating the metadata features with the intermediate convolved feature that is produced by the CNN when it process the DNA sequence (abstract). Wise teaches that the database of variant features can include Fisher strand bias [0132]. As evidenced by Guo, the Fisher Score computes a strand bias score (p. 2, col. 1, par. 1; p. 3, col. 1, par. 1-2) to account for positive and negative strand bias in Illumina short-read sequencing data (abstract).
However, regarding claim 9, Wise teaches that the process analyzes one or more raw fragments associated with a sample read and outputs a corresponding variant call associated (i.e., labeling) with the raw fragments [0126]. Wise teaches that when a potential variant call is identified, the process outputs an indication of the potential variant call, the variant sequence, the variant position and a reference sequence associated therewith [0126].Wise teaches that the term “sequence” includes or represents a strand of nucleotides coupled to each other, where the sequence may be an amplicon [0061; 0066]. Wise teaches that providing a reference sequence comprises identifying a locus-of-interest based upon the primer sequence of the PCR amplicon (i.e., determining an amplicon) [0066]. Wise teaches that the process analyzes one or more raw fragments associated with a sample read and outputs a corresponding variant call associated (i.e., labeling) with the raw fragments [0126]. Therefore, as is considered to fairly teach labeling the sequence read with an associated reference sequence, and Wise teaches that the reference sequences are associated with specific amplicons, it is considered that Wise also fairly teaches labeling the sequence reads with an associated amplicon.
However, regarding claim 10, Wise teaches that the process analyzes one or more raw fragments associated with a sample read and outputs a corresponding variant call associated (i.e., labeling) with the raw fragments [0126]. Wise teaches that when a potential variant call is identified, the process outputs an indication of the potential variant call, the variant sequence, the variant position and a reference sequence associated therewith [0126]. Wise also teaches a metadata correlator that that correlates each unclassified variant in the database with respective values of mutation characteristics, read mapping statistics, and occurrence frequency (each of which read on a model parameter), by associating/linking/appending (i.e., labeling) the found attributes with or to the variant [0130]. Wise teaches a model that has two deep neural networks: a convolutional neural network (CNN) and a fully-connected neural network (FCNN), and two inputs: a DNA sequence with a variant and a set of metadata features correlated with the variant, where a feature sequence (i.e., labeling the sequence read and associated flow measurement) is derived by concatenating the metadata features with the intermediate convolved feature that is produced by the CNN when it process the DNA sequence (abstract).
However, regarding claim 11, Wise teaches sequencing nucleic acids (i.e., a sequence read) to identify sequence variations using sequencing by synthesis, where a plurality of fluorescently-labeled nucleotides are used to sequence a plurality of clusters of amplified DNA present on the surface of an optical substrate (e.g., a surface that at least partially defines a channel in a flow cell), where a single type of nucleotide with a fluorophore (i.e., an associated flow measurement) is added per cycle (i.e., an associated flow order) [0087-0090]. Wise teaches receiving the sequencing data for subsequent analysis [0095]. Wise teaches that the DNA sequence is an image with multiple channels that numerically encode the four types of nucleotide bases, A, C, G, and T (i.e., an associated flow measurement and an associated flow order) ([0049]; FIG. 2-3). It is therefore considered that the sequence read taught by Wise is inherently labeled with the associated flow order because the sequence read comprises sequences in an order.
However, regarding claim 12, the prior art to Hubbell discloses a method for evaluating variant likelihood. Hubbell teaches obtaining measured values corresponding to an ensemble of sequencing reads for at least some of the template polynucleotide strands in at least one of the defined spaces; and evaluating a likelihood that a variant sequence is present given the measured values corresponding to the ensemble of sequencing reads, the evaluating comprising: determining a measurement confidence value for each read in the ensemble of sequencing reads and modifying at least some model-predicted values using a first bias for forward strands and a second bias for reverse strands (abstract). Hubbell teaches determining residuals representing differences between measured and predicted values of nucleotides ([0070; 0072; 0080]; FIG. 9B and D).
However, regarding claim 13, Wise teaches that the process analyzes one or more raw fragments associated with a sample read and outputs a corresponding variant call associated (i.e., labeling) with the raw fragments [0126]. However, neither Wise nor Hubbell teach labeling the sequence read and associated flow measurement with the residual measurement
However, 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 modify, in the course of routine experimentation and with a reasonable expectation of success, the method of Wise with the method of Hubbell to label the sequences, as taught by Wise, with the residuals taught by Hubbell, because such a modification represents a simple substitution of one of the pieces of information used to label the sequences as taught by Wise with a piece of information as taught by Hubbell. One of ordinary skill in the art would have been able to carry out such a substitution, and the results would be reasonably predictable.
However, regarding claim 14, Wise teaches that sample reads designated as including a possible variant/allele of a particular genetic locus may be collected, aggregated, or binned with other sample reads that have been designated as including possible variants/alleles of the genetic locus [0119].
However, regarding claim 15-17, However, Hubbell teaches determining differences between measured and model-predicted values (i.e., residuals) at each nucleotide flow may be assumed to follow independent normal distributions each having a mean and a variance [0083].
However, regarding claim 19, Wise teaches examining variants which may be single nucleotide polymorphisms (SNPs) short tandem repeats (STRs), which reads on a multi-nucleotide polymorphism, or insertions or deletions [0088; 0095; 0123; 0127; 0131].
However, regarding claim 20, Wise teaches sequencing nucleic acids (i.e., a sequence read) to identify sequence variations using sequencing by synthesis, where a plurality of fluorescently-labeled nucleotides are used to sequence a plurality of clusters of amplified DNA present on the surface of an optical substrate (e.g., a surface that at least partially defines a channel in a flow cell), where a single type of nucleotide with a fluorophore is added per cycle (i.e., a flow order) [0087-0090]. Wise teaches that sequencing by synthesis technology is used by Illumina, and using Illumina sequencers [0065].
Regarding claims 1-11 and 18-20, 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 combine, in the course of routine experimentation and with a reasonable expectation of success, the reference application and Wise because both references disclose methods for detecting variants in nucleic acid sequencing data. The motivation would have been to use a method which prepares data for a deep neural network for variant classification, as taught by Wise [0020].
Regarding claims 12-17, 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 combine, in the course of routine experimentation and with a reasonable expectation of success, the reference application in view of Wise and Hubbell because both references disclose methods for detecting variants in nucleic acid sequencing data. The motivation to examine residuals, or differences between measured and model-predicted values, would have been to estimate measurement confidence values, as taught by Hubbell [0080].
Conclusion
No claims are allowed.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to JANNA NICOLE SCHULTZHAUS whose telephone number is (571)272-0812. The examiner can normally be reached on Monday - Friday 8-4.
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/JANNA NICOLE SCHULTZHAUS/Examiner, Art Unit 1685
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