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 .
Claims Status
Claims 1-15 are pending.
Claims 1-15 are examined.
Priority
The instant application is a national stage application of PCT/EP2020/081032, filed 11/05/2020, which claims priority to US provisional application No. 62/934120, filed 11/12/2019. Therefore, the Effective Filing Date (EFD) assigned to each of the claims 1-15 is the provisional filing date of application No. 62/934120, filed 11/12/2019.
Information Disclosure Statement
The Information Disclosure Statements filed 05/12/2022 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.
It is noted that certain references lack appropriate page numbers and correct author names as is required under 37 CFR 1.97. The Examiner has annotated the references herein. Applicant is kindly reminded to provide proper citations in compliance with 37 CFR 1.97 in all future submission to the office.
Drawings
The drawings filed 05/11/2022 are accepted.
Specification
The disclosure is objected to because of the following informalities:
In paragraph [0003], “the major techniques use to profile” should read “the major techniques used to profile”
In paragraph [0094], “the RNA editing statuss may comprise” should read “the RNA editing status
Appropriate correction is required.
Claim Objections
Claims 6, 9, and 15 are objected to because of the following informalities:
In claims 6, 9, and 15, “high-confidence RNA editing” should read “high-confidence RNA-editing”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 10 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The claim recites the limitation of “characterizing, using the expression data, an RNA editing and/or expression status for each of at least a plurality of variants within the set of variants”. The claim is indefinite because it is unclear on which set of variants the characterizing step should be performed. The previous step in the claim recites the step of merging the set of DNA variants and the set of RNA variants into a single set of variants, or validating the sequencing data. Thus, if the merging step is performed, it is unclear which variant set should be characterized as the step refers to “for each of at least a plurality of variants within the set of variants”, and the merged set of variants if referred to as “a single set of variants”.
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 1-15 are rejected under 35 U.S.C. 101 because the claimed inventions are directed to an abstract idea of mental steps, mathematic concepts, or a natural law without significantly more.
The MPEP at MPEP 2106.03 sets forth steps for identifying eligible subject matter:
(1) Are the claims directed to a process, machine, manufacture or composition of
matter?
(2A)(1) Are the claims directed to a judicially recognized exception, i.e. a law of nature,
a natural phenomenon, or an abstract idea?
(2A)(2) If the claims are directed to a judicial exception under Prong One, then is the
judicial exception integrated into a practical application?
(2B) If the claims are directed to a judicial exception and do not integrate the judicial
exception, do the claims provide an inventive concept?
With respect to step (1): Yes, the claims are directed to methods and a system.
With respect to step (2A)(1): The claims are directed to an abstract idea of mental processes.
“Claims directed to nothing more than abstract ideas (such as a mathematical formula or equation), natural phenomena, and laws of nature are not eligible for patent protection” (MPEP 2106.04). Abstract ideas include mathematical concepts (mathematical formulas or equations, mathematical relationships and mathematical calculations), certain methods of organizing human activity, and mental processes (procedures for observing, evaluating, analyzing/judging and organizing information (MPEP 2106.04(a)(2)). Laws of nature or natural phenomena include naturally occurring principles/relations that are naturally occurring or that do not have markedly different characteristics compared to what occurs in nature (MPEP 2106(b)).
Mental processes recited in claim 1:
merging the aligned RNA sequencing data and aligned DNA sequencing data into a single merged alignment, wherein each read comprises a source identifier
identifying, in the single merged alignment, a plurality of variants relative to the reference genome, the plurality of variants comprising a plurality of different variant types, to generate a set of variants
characterizing, using the expression data, an RNA editing and/or expression status for each of at least a plurality of variants within the set of variants, wherein the expression status comprises one of a plurality of allele-specific expression categorizations comprising expression information for an alternative allele of the variant and expression information for a reference allele of the variant if there is one
generating a report comprising the characterized RNA editing and/or expression status for the plurality of variants within the set of variants
Mental processes recited in claim 7:
merge the aligned RNA sequencing data and aligned DNA sequencing data into a single merged alignment
identify, in the single merged alignment, a plurality of variants relative to the reference genome, the plurality of variants comprising a plurality of different variant types, to generate a set of variants
characterize, using the expression data, an RNA editing and/or expression status for each of at least a plurality of variants within the set of variants, wherein the expression status comprises one of a plurality of allele-specific expression categorizations comprising expression information for an alternative allele of the variant and expression information for a reference allele of the variant if there is one
generate a report comprising the characterized expression status for the plurality of variants within the set of variants
Mental processes recited in claim 10:
identifying a plurality of variants in the DNA sequencing data and a plurality of variants in the RNA sequencing data, each of the plurality of variants in the RNA sequencing data, each of the plurality of variants comprising a plurality of different variant types, to generate a set of DNA variants and a set of RNA variants
merging the set of DNA variants and the set of RNA variants into a single set of variants, or validating the plurality of variants in the DNA sequencing data or the plurality of variants in the RNA sequencing data with the variants in the other sequencing data type, to generate a single set of variants
characterizing, using the expression data, an RNA editing and/or expression status for each of at least a plurality of variants within the set of variants, wherein the expression status comprises one of a plurality of allele-specific expression categorizations comprising expression information for an alternative allele of the variants and express information for a reference allele of the variant if there is one
generating a report comprising the characterized expression status for the plurality of variants within the set of variants
Dependent claims 2, 3, 5, 6, 8, 9, 11, 12, 14, and 15 recite additional steps that either are directed to abstract ideas or further limit the judicial exceptions in independent claims 1, 7, and 10, and as such, are further directed to abstract ideas. Hence, the claims explicitly recite numerous elements that individually and in combination constitute abstract ideas. The relevant recitations are:
Claim 2: “wherein the plurality of variants are identified using an RNA sequencing data variant calling protocol”
Claim 3: “wherein the plurality of different variant types comprises at least single nucleotide variants, insertions, deletions, copy number variants, and gene fusions”
Claim 5: “wherein each of the plurality of allele-specific expression categorizations comprise an identifier describing the expression information for the alternative allele of the variant relative to the expression information for the reference allele of the variant, and wherein there are a plurality of different identifier”
Claim 6: “wherein the plurality of different identifiers comprise one or more of unexpressed site, unexpressed variant, expressed variant homozygous, expressed variant up regulated, expressed variant down regulated, expressed variant neutral, expressed variant with inconsistency, unexpressed variant with inconsistency, high-confidence RNA editing, and low-confidence RNA-editing”
Claim 8: “wherein each of the plurality of allele-specific expression categorizations comprise an identifier describing the expression information for the alternative allele of the variant relative to the expression information for the reference allele of the variant, and wherein there are a plurality of different identifier”
Claim 9: “wherein the plurality of different identifiers comprise one or more of unexpressed site, unexpressed variant, expressed variant homozygous, expressed variant up regulated, expressed variant down regulated, expressed variant neutral, expressed variant with inconsistency, unexpressed variant with inconsistency, high-confidence RNA editing, and low-confidence RNA-editing”
Claim 11: “wherein the plurality of variants are identified using an RNA sequencing data variant calling protocol”
Claim 12: “wherein the plurality of different variant types comprises at least single nucleotide variants, insertions, deletions, copy number variants, and gene fusions”
Claim 14: “wherein each of the plurality of allele-specific expression categorizations comprise an identifier describing the expression information for the alternative allele of the variant relative to the expression information for the reference allele of the variant, and wherein there are a plurality of different identifier”
Claim 15: “wherein the plurality of different identifiers comprise one or more of unexpressed site, unexpressed variant, expressed variant homozygous, expressed variant up regulated, expressed variant down regulated, expressed variant neutral, expressed variant with inconsistency, unexpressed variant with inconsistency, high-confidence RNA editing, and low-confidence RNA-editing”
The abstract ideas in the claims are evaluated under Broadest Reasonable Interpretation (BRI) and determined herein to each cover mental processes because the claims recite no more than performing mental process to analyze sequencing data and identify variants, and further using this analysis to characterize the data.
With respect to step (2A)(2): The claims must therefore be examined further to determine whether they integrate that abstract idea into a practical application (MPEP 2106.04(d)). The claimed additional elements are analyzed alone or in combination to determine if the judicial exception is integrated into a practical application (MPEP 2106.04(d).I.; MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the judicial exception, the claim fails to integrate the abstract idea into a practical application (MPEP 2106.04(d).III).
Claim 1 recites the following additional elements that are not abstract ideas:
obtaining DNA sequencing data for the genomic sample, the DNA sequencing data comprising a plurality of different variant types and aligned to a reference genome to generate aligned DNA sequencing data
obtaining RNA sequencing data for the genomic sample, the RNA sequencing data comprising a plurality of different variant types and aligned to the reference genome to generate aligned RNA sequencing data, and wherein the obtained RNA sequencing data further comprises expression data for each variant
Claim 7 recites the following additional elements that are not abstract ideas:
a reference genome
DNA sequencing data for the genomic sample, the DNA sequencing data comprising a plurality of different variant types and aligned to a reference genome to generate aligned DNA sequencing data
RNA sequencing data for the genomic sample, the RNA sequencing data comprising a plurality of different variant types and aligned to the reference genome to generate aligned RNA sequencing data, and wherein the obtained RNA sequencing data further comprises expression data for each variant
a processor
a user interface configured to provide the generated report
Claim 10 recites the following additional elements that are not abstract ideas:
obtaining DNA sequencing data for the genomic sample, the DNA sequencing data comprising a plurality of different variant types and aligned to a reference genome to generate aligned DNA sequencing data
obtaining RNA sequencing data for the genomic sample, the RNA sequencing data comprising a plurality of different variant types and aligned to the reference genome to generated aligned RNA sequencing data, and wherein the obtained RNA sequencing data further comprises expression data for each variant
The steps of obtaining sequence data and the element of a reference genome are directed to data gathering elements, as they gather the data on which the judicial exceptions are performed. Data gathering does not impose any meaningful limitation on the abstract idea, or how the abstract idea is performed. Data gathering steps are not sufficient to integrate an abstract idea into a practical application (MPEP 2106.05(g)). The elements of the processor and user interface are directed to generic computer elements. Hence, these are interpreted as mere instructions to apply the abstract idea using a computer, and therefore the claim does not integrate that abstract idea into a practical application. The courts have weighed in and consistently maintained that when, for example, a memory, display, processor, machine, etc. ... are recited so generically (i.e., no details are provided) that they represent no more than mere instructions to apply the judicial exception on a computer, and these limitations may be viewed as nothing more than generally linking the use of the judicial exception to the technological environment of a computer (see MPEP 2106.05(f)).
Dependent claims 4 and 13 relate to further limitations of data gathering as they limit the type of data obtained.
None of these dependent claims recite additional elements, alone or in combination, which would integrate a judicial exception into a practical application.
Lastly, the claims have been evaluated with respect to step (2B): Because the claims recite an abstract idea, and do not integrate that abstract idea into a practical application, the claims lack a specific inventive concept. Under said analysis, Applicant is reminded that the judicial exception alone cannot provide that inventive concept or practical application (MPEP 2106.05). Identifying whether the additional elements beyond the abstract idea amount to such an inventive concept requires considering the additional elements individually and in combination to determine if they provide significantly more than the judicial exception (MPEP 2106.05.A i-vi).
With respect to the instant claims, the additional elements described above do not rise to the level of significantly more than the judicial exception. As set forth in the MPEP at 2106.05(d)(I), determinations of whether or not additional elements (or a combination of additional elements) may provide significantly more and/or an inventive concept rests in whether or not the additional elements (or combination of elements) represents well-understood, routine, conventional activity. Said assessment is made by a factual determination stemming from a conclusion that an element (or combination of elements) is widely prevalent or in common use in the relevant industry, which is determined by either 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 claim 1: The additional elements of obtaining DNA sequencing data for the genomic sample, the DNA sequencing data comprising a plurality of different variant types and aligned to a reference genome to generate aligned DNA sequencing data and obtaining RNA sequencing data for the genomic sample, the RNA sequencing data comprising a plurality of different variant types and aligned to the reference genome to generate aligned RNA sequencing data, and wherein the obtained RNA sequencing data further comprises expression data for each variant do not rise to the level of significantly more than the judicial exception. As recited in the Specification at paragraphs [0002] and [0003], DNA and RNA sequencing are the major techniques used to profile the genome and transcriptome, and the Specification discloses that it is becoming more common to generate multiple types of -omic data with the existence of several commercial assays. As such, it is recognized that these additional limitations are routine, well understood, and conventional in the art. These limitations do not improve the functioning of a computer, or comprise an improvement to any other technical field, they do not require or set forth a particular machine, they do not affect a transformation of matter, nor do they provide a non-conventional or unconventional step. As such, these limitations fail to rise to the level of significantly more.
With respect to claim 4: The additional element of the obtained RNA sequencing data comprises gene expression data, transcript expression data, exon expression data, splicing data, and/or allele-specific expression data does not rise to the level of significantly more than the judicial exception. As recited in the Specification at paragraphs [0002] and [0003], RNA sequencing is a major technique used to profile the transcriptome, and that RNA sequencing is primarily used to measure gene and transcript expression levels. As such, it is recognized that these additional limitations are routine, well understood, and conventional in the art. These limitations do not improve the functioning of a computer, or comprise an improvement to any other technical field, they do not require or set forth a particular machine, they do not affect a transformation of matter, nor do they provide a non-conventional or unconventional step. As such, these limitations fail to rise to the level of significantly more.
With respect to claim 7: The additional elements of a reference genome, obtaining DNA sequencing data for the genomic sample, the DNA sequencing data comprising a plurality of different variant types and aligned to a reference genome to generate aligned DNA sequencing data, obtaining RNA sequencing data for the genomic sample, the RNA sequencing data comprising a plurality of different variant types and aligned to the reference genome to generate aligned RNA sequencing data, and wherein the obtained RNA sequencing data further comprises expression data for each variant, a processor, and a user interface do not rise to the level of significantly more than the judicial exception. As recited in the Specification at paragraphs [0002] and [0003], DNA and RNA sequencing are the major techniques used to profile the genome and transcriptome, and the Specification discloses that it is becoming more common to generate multiple types of -omic data with the existence of several commercial assays. Furthermore, as exemplified in the MPEP at 2106.05(f) with reference to Alice Corp. 573 US at 223, 110 USPQ2d at 1983 “claims that amount to nothing more than an instruction to apply the abstract idea using a generic computer do not render an abstract idea eligible”. Therefore, the device constitutes no more than a general link to a technological environment, which is insufficient to constitute an inventive concept that would render the claims significantly more than the abstract idea (see MPEP 2105(b)I-III). As such, it is recognized that these additional limitations are routine, well understood, and conventional in the art. These limitations do not improve the functioning of a computer, or comprise an improvement to any other technical field, they do not require or set forth a particular machine, they do not affect a transformation of matter, nor do they provide a non-conventional or unconventional step. As such, these limitations fail to rise to the level of significantly more.
With respect to claim 10: The additional elements of obtaining DNA sequencing data for the genomic sample, the DNA sequencing data comprising a plurality of different variant types and aligned to a reference genome to generate aligned DNA sequencing data and obtaining RNA sequencing data for the genomic sample, the RNA sequencing data comprising a plurality of different variant types and aligned to the reference genome to generate aligned RNA sequencing data, and wherein the obtained RNA sequencing data further comprises expression data for each variant do not rise to the level of significantly more than the judicial exception. As recited in the Specification at paragraphs [0002] and [0003], DNA and RNA sequencing are the major techniques used to profile the genome and transcriptome, and the Specification discloses that it is becoming more common to generate multiple types of -omic data with the existence of several commercial assays. As such, it is recognized that these additional limitations are routine, well understood, and conventional in the art. These limitations do not improve the functioning of a computer, or comprise an improvement to any other technical field, they do not require or set forth a particular machine, they do not affect a transformation of matter, nor do they provide a non-conventional or unconventional step. As such, these limitations fail to rise to the level of significantly more.
With respect to claim 13: The additional element of the obtained RNA sequencing data comprises gene expression data, transcript expression data, exon expression data, splicing data, and/or allele-specific expression data does not rise to the level of significantly more than the judicial exception. As recited in the Specification at paragraphs [0002] and [0003], RNA sequencing is a major technique used to profile the transcriptome, and that RNA sequencing is primarily used to measure gene and transcript expression levels. As such, it is recognized that these additional limitations are routine, well understood, and conventional in the art. These limitations do not improve the functioning of a computer, or comprise an improvement to any other technical field, they do not require or set forth a particular machine, they do not affect a transformation of matter, nor do they provide a non-conventional or unconventional step. As such, these limitations fail to rise to the level of significantly more
In combination, the collection or generation of the data, acted upon by the judicial exception, fail to rise to the level of significantly more. The data gathering steps provide the data for the judicial exception. No non-routine step or element has clearly been identified.
The claims have all been examined to identify the presence of one or more judicial exceptions. Each additional limitation in the claims has been addressed, alone and in combination, to determine whether the additional limitations integrate the judicial exception into a practical application. Each additional limitation in the claims has been addressed, alone and in combination, to determine whether those additional limitations provide an inventive concept which provides significantly more than those exceptions. Individually, the limitations of the claims and the claims as a whole have been found lacking.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-5 are rejected under 35 U.S.C. 103 as being unpatentable over. Reuter et al. (US 2018/0080021 A1, IDS reference) in view of Grant et al. (“Comparative analysis of RNA-Seq alignment algorithms and the RNA-seq unified mapper (RUM), bioinformatics, published 2011).
Regarding claim 1, Reuter et al. teaches a method of characterizing variant RNA editing and/or expression status for a plurality of variants identified from a genomic sample using a variant analysis system (paragraph [0019]), comprising:
obtaining DNA sequencing data for the genomic sample, the DNA sequencing data comprising a plurality of different variant types (paragraph [0008]) and aligned to a reference genome to generate aligned DNA sequencing data (paragraph [0096]);
obtaining RNA sequencing data for the genomic sample, the RNA sequencing data comprising a plurality of different variant types (paragraph [0008]) and aligned to the reference genome to generate aligned RNA sequencing data (paragraph [0096]), and wherein the obtained RNA sequencing data further comprises expression data for each variant ([0142]);
identifying a plurality of variants relative to the reference genome, the plurality of variants comprising a plurality of different variant types, to generate a set of variants (paragraphs [0100]; [0141]; [0154]; claim 22; etc.);
characterizing, using the expression data, an RNA editing and/or expression status for each of at least a plurality of variants within the set of variants, wherein the expression status comprises one of a plurality of allele-specific expression categorizations comprising expression information for an alternative allele of the variant and expression information for a reference allele of the variant if there is one (paragraphs [0144]; [0155]; [0157]; [0159]; etc.); and
generating a report comprising the characterized expression status for the plurality of variants within the set of variants (paragraph [0155]).
Reuter et al. does not teach the claim element of merging the aligned RNA sequencing data and aligned DNA sequencing data into a single merged alignment, wherein each read comprises a source identifier.
However, Grant et al. teaches a comparative analysis of RNA-seq alignment algorithms and the RNA-seq unified mapper. Grant et al. teaches merging genome and transcriptome alignments into a single merged alignment and that doing so achieves better disambiguation, in particular for reads that extend into introns (page 2518, column 2, paragraph 2; Figure 3).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have incorporated the merging of the aligned reads of Grant et al. to the method of Reuter et al. because Reuter et al. is directed to a method of combined DNA and RNA sequencing for comprehensive profiling (Abstract), and Grant et al. is directed to a method of validating RNA-seq alignment algorithms for detecting novel transcript features such as novel exons and alternative splicing. Thus, one would have a reasonable expectation of success of combining the prior art references to identify variants from DNA and RNA sequences and one would be motivated to do so in order to achieve better disambiguation with variant calling.
Regarding claim 2, the claim is directed to the plurality of variants being identified using an RNA sequencing data variant calling protocol. Reuter et al. teaches the method of claim 1 in view of Grant et al. Reuter et al. also teaches identifying variants through an RNA sequencing data variant calling protocol (claim 22).
Regarding claim 3, the claim is directed to the plurality of different variant types comprising at least single nucleotide variants, insertions, deletions, copy number variants, and gene fusions. Reuter et al. teaches the method of claim 1 in view of Grant et al. Reuter et al. also teaches the different variant types comprising an insertion, deletion, substitution, or fusion (paragraph [0016]).
Regarding claim 4, the claim is directed to the obtained RNA sequencing data comprising gene expression data, transcript expression data, exon expression data, splicing data, and/or allele-specific expression data. Reuter et al. teaches the method of claim 1 in view of Grant et al. Reuter et al. also teaches the RNA sequencing data comprising gene expression data (paragraph [0142], [0159]).
Regarding claim 5, the claim is directed to each of the plurality of allele-specific expression categorizations comprising an identifier describing the expression information for the alternative allele of the variant relative to the expression information for the reference allele of the variant, and wherein there is a plurality of different identifiers. Reuter et al. teaches the method of claim 1 in view of Grant et al. Reuter et al. teaches identifiers describing the allele-specific expression information relative to the reference comprising increased expression (paragraph [0065]), and loss of heterozygosity (paragraph [0120]).
Claims 7 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Reuter et al. in view of Grant et al., as applied to claims 1-5, and further in view of Chudova et al. (US 2020/0075123 A1, filed September 2019).
Regarding claim 7, Reuter et al. teaches a system (paragraph [0019]) for characterizing expression status for a plurality of variants identified from a genomic sample comprising:
obtaining DNA sequencing data for the genomic sample, the DNA sequencing data comprising a plurality of different variant types (paragraph [0008]) and aligned to a reference genome to generate aligned DNA sequencing data (paragraph [0096]);
obtaining RNA sequencing data for the genomic sample, the RNA sequencing data comprising a plurality of different variant types (paragraph [0008]) and aligned to the reference genome to generate aligned RNA sequencing data (paragraph [0096]), and wherein the obtained RNA sequencing data further comprises expression data for each variant ([0142]);
identifying a plurality of variants relative to the reference genome, the plurality of variants comprising a plurality of different variant types, to generate a set of variants (paragraphs [0100]; [0141]; [0154]; claim 22; etc.);
characterizing, using the expression data, an RNA editing and/or expression status for each of at least a plurality of variants within the set of variants, wherein the expression status comprises one of a plurality of allele-specific expression categorizations comprising expression information for an alternative allele of the variant and expression information for a reference allele of the variant if there is one (paragraphs [0144]; [0155]; [0157]; [0159]; etc.); and
generating a report comprising the characterized expression status for the plurality of variants within the set of variants (paragraph [0155]).
Reuter et al. teaches a kit for the simultaneous generation of RNA and DNA libraries (paragraph [0019]), available computer programs to aid in the alignment of the analysis (paragraph [0047]), and computationally assembling sequencing libraries into contigs (paragraph [0096]).
Reuter et al. does not teach the claim element of a processor and user interface configured to provide the generated report, and merging the aligned RNA sequencing data and aligned DNA sequencing data into a single merged alignment, wherein each read comprises a source identifier.
However, Grant et al. teaches a comparative analysis of RNA-seq alignment algorithms and the RNA-seq unified mapper. Grant et al. teaches a computer-implemented analysis as evidenced by the used algorithms (Abstract) and thus inherently teaches a processor. Grant et al. teaches merging genome and transcriptome alignments into a single merged alignment and that doing so achieves better disambiguation, in particular for reads that extend into introns (page 2518, column 2, paragraph 2; Figure 3).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have incorporated the merging of the aligned reads of Grant et al. to the system of Reuter et al. because Reuter et al. is directed to a method and system of combined DNA and RNA sequencing for comprehensive profiling (Abstract), and Grant et al. is directed to a method of validating RNA-seq alignment algorithms for detecting novel transcript features such as novel exons and alternative splicing. Thus, one would have a reasonable expectation of success of combining the prior art references to identify variants from DNA and RNA sequences and one would be motivated to do so in order to achieve better disambiguation with variant calling.
Grant et al. does not teach the claim elements of a user interface configured to provide the generated report.
However, Chudova et al. teaches genetic variant detection based on merged and unmerged reads. Chudova et al. teaches a computer system that is programmed to implement the method, the system comprising a processor and a communication interface (paragraph [0150]). Furthermore, Chudova et al. teaches a user interface for providing a report (paragraph [0161]).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have incorporated the user interface of Chudova et al. to the system of Reuter et al. because Reuter et al. and Chudova et al. are both directed to identifying variants in sequencing data (see Abstracts of both). Chudova et al. discloses an interface for providing the reported variant characterizations (paragraph [0161]). Thus, one of ordinary skill in the art would have a reasonable expectation of success of incorporating a technologically implemented system with an interface that provides the reported variants, by combining the prior art references.
Regarding claim 8, the claim is directed to each of the plurality of allele-specific expression categorizations comprising an identifier describing the expression information for the alternative allele of the variant relative to the expression information for the reference allele of the variant, and wherein there is a plurality of different identifiers. Reuter et al. teaches the system of claim 7 in view of Grant et al. and further in view of Chudova et al. Reuter et al. teaches identifiers describing the allele-specific expression information relative to the reference comprising increased expression (paragraph [0065]), and loss of heterozygosity (paragraph [0120]).
Claims 10-14 are rejected under 35 U.S.C. 103 as being unpatentable over Reuter et al. in view of Wilkerson et al. (“Integrated RNA and DNA sequencing improves mutation detection in low purity tumors, published June 2014, IDS reference).
Regarding claim 10, Reuter et al. teaches a method for characterizing expression status for a plurality of variants identified from a genomic sample, using a variant analysis system (paragraph [0019]), comprising:
obtaining DNA sequencing data for the genomic sample, the DNA sequencing data comprising a plurality of different variant types (paragraph [0008]) and aligned to a reference genome to generate aligned DNA sequencing data (paragraph [0096]);
obtaining RNA sequencing data for the genomic sample, the RNA sequencing data comprising a plurality of different variant types (paragraph [0008]) and aligned to the reference genome to generate aligned RNA sequencing data (paragraph [0096]), and wherein the obtained RNA sequencing data further comprises expression data for each variant ([0142]);
identifying a plurality of variants relative to the reference genome, the plurality of variants comprising a plurality of different variant types, to generate a set of variants (paragraphs [0100]; [0141]; [0154]; claim 22; etc.);
characterizing, using the expression data, an RNA editing and/or expression status for each of at least a plurality of variants within the set of variants, wherein the expression status comprises one of a plurality of allele-specific expression categorizations comprising expression information for an alternative allele of the variant and expression information for a reference allele of the variant if there is one (paragraphs [0144]; [0155]; [0157]; [0159]; etc.); and
generating a report comprising the characterized expression status for the plurality of variants within the set of variants (paragraph [0155]).
Reuter et al. does not teach the claim element of merging the set of DNA variants and the set of RNA variants into a single set of variants, or validating the plurality of variants in the DNA sequencing data or the plurality of variants in the RNA sequencing data with the variants in the other sequencing data type, to generate a single set of variants.
However, Wilkerson et al. teaches integrated RNA and DNA sequencing improves mutation detection in low purity tumors. Wilkerson et al. teaches merging of allowed variant sites between DNA and RNA to be merged for the sites to have the same genomic positions prior to statistical testing, so that the evidence is combined despite slightly different representations in sequence alignment (page e107, column 2, paragraph 1).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have incorporated the step of merging the identified variants of Wilkerson et al. to the method of Reuter et al. because Reuter et al. and Wilkerson et al. are both directed to combined RNA and DNA sequencing (see Abstracts of both). Thus, one of ordinary skill in the art would have a reasonable expectation of combining RNA and DNA sequencing to identify variants and merging identified variants, and one would be motivated to do so in order for the variants to have the same genomic positions prior to the statistical analysis of the variants (Wilkerson et al. page e107, column 2, paragraph 1).
Regarding claim 11, the claim is directed to the plurality of variants being identified using an RNA sequencing data variant calling protocol. Reuter et al. teaches the method of claim 10 in view of Wilkerson et al. Reuter et al. also teaches identifying variants through an RNA sequencing data variant calling protocol (claim 22).
Regarding claim 12, the claim is directed to the plurality of different variant types comprising at least single nucleotide variants, insertions, deletions, copy number variants, and gene fusions. Reuter et al. teaches the method of claim 10 in view of Wilkerson et al. Reuter et al. also teaches the different variant types comprising an insertion, deletion, substitution, or fusion (paragraph [0016]).
Regarding claim 13, the claim is directed to the obtained RNA sequencing data comprising gene expression data, transcript expression data, exon expression data, splicing data, and/or allele-specific expression data. Reuter et al. teaches the method of claim 10 in view of Wilkerson et al. Reuter et al. also teaches the RNA sequencing data comprising gene expression data (paragraph [0142], [0159]).
Regarding claim 14, the claim is directed to each of the plurality of allele-specific expression categorizations comprising an identifier describing the expression information for the alternative allele of the variant relative to the expression information for the reference allele of the variant, and wherein there is a plurality of different identifiers. Reuter et al. teaches the method of claim 10 in view of Wilkerson et al. Reuter et al. teaches identifiers describing the allele-specific expression information relative to the reference comprising increased expression (paragraph [0065]), and loss of heterozygosity (paragraph [0120]).
Conclusion
No claims are allowed.
Claims 6, 9, and 15 appear to be free from the art as the prior art does not seem to teach or fairly suggest the limitations of “wherein the plurality of different identifiers comprise one or more of unexpressed site, unexpressed variant, expressed variant homozygous, expressed variant up regulated, expressed variant down regulated, expressed variant neutral, expressed variant with inconsistency, unexpressed variant with inconsistency, high-confidence RNA editing, and low-confidence RNA-editing”.
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/E.A.S./Examiner, Art Unit 1686
/LARRY D RIGGS II/Supervisory Patent Examiner, Art Unit 1686