Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1-39, 42, 49-51,53-57, 59-61, 64, 66, 68, 74-79 are cancelled.
Claims 40,41, 43-48,52,62-63,65,67,69-73,80 are currently pending and under exam herein.
Claims 40,41,43-48,52,62-63,65,67,69-73,80 are rejected.
Canceled claim 42 is out of order and appears after claim 45.
Priority
The application claims priority from a provisional application 63/209,608 filed on June 11, 2021. Therefore, the effective filing date of the application is June 11, 2021.
Drawings
The Drawings filed on 6/10/2022 were considered.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on October 4, 2022 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
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 40,41,43-48,52,62-63,65,67,69-73,80 are eligible under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea.
Subject matter eligibility evaluation in accordance with MPEP 2106:
Eligibility Step 1: Claims 40,41,43-48,52,62-63,65,67,69-73,80 are directed to a system that determines repeat expansion status of a gene of interest. Therefore, these claims are encompassed by the categories of statutory subject matter, and thus, satisfy the subject matter eligibility requirements under step 1.
[Step 1: YES]
Eligibility Step 2A: First it is determined in Prong One whether a claim recites a judicial exception, and if so, then it is determined in Prong Two whether the recited judicial exception is integrated into a practical application of that exception.
Eligibility Step 2A Prong One: In determining whether a claim is directed to a judicial exception, examination is performed that analyzes whether the claim recites a judicial exception, i.e., whether a law of nature, natural phenomenon, or abstract idea is set forth or described in the claim.
Independent claim 40 recites the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas:
aligning the plurality of sequence reads to a sequence graph to generate a plurality of aligned sequence reads, wherein the sequence graph represents a locus of a gene of interest and comprises a repeat sequence representation flanked by non-repeat sequences of the locus of the gene, and wherein the plurality of aligned sequence reads comprises the plurality of sequence reads and alignments of the plurality of sequence reads to the sequence graph (mathematical process, mental process);
determining a number of occurrences of a plurality of repeat sequences in aligned sequence reads of the plurality of aligned sequence reads using a first occurrence threshold and a first quality threshold (mathematical process, mental process);
determining a frequency indication of a number of occurrences of a pathogenic repeat sequence relative to a total number of occurrences of the plurality of repeat sequence(s) (mathematical process, mental process);
determining the subject has zero, one, or two alleles with a repeat expansion at the locus of the gene of interest using the plurality of aligned sequence reads; an (mathematical process, mental process);
determining a repeat expansion status at the locus of the gene of interest of the subject using the frequency indication of the number of occurrences of the pathogenic repeat sequence relative to the total number of occurrences of the plurality of repeat sequences (mathematical process, mental process).
Dependent claim 41 recites the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas:
wherein the gene of interest is replication factor C subunit 1 (RFC 1) (mathematical process, mental process).
Dependent claim 43 recites the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas:
wherein the repeat expansion is associated with or causes a disease, optionally wherein the disease is cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) (mathematical process, mental process).
Dependent claim 44 recites the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas:
wherein the repeat sequence representation is AARRG (mathematical process, mental process).
Dependent claim 45 recites the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas:
wherein the pathogenic repeat sequence is AAGGG or ACAGG (mathematical process, mental process).
Dependent claim 46 recites the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas:
determining the subject has zero, one, or two alleles with a repeat expansion at the locus of the gene of interest using the plurality of aligned sequence reads that are in-repeat reads or flanking reads (mental process).
Dependent claim 47 recites the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas:
wherein the subject has two alleles with repeat expansion at the locus of the gene of interest (mathematical process, mental process).
Dependent claim 48 recites the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas:
wherein determining the repeat expansion status at the locus of the gene of interest comprises: determining the frequency indication of the number of occurrences of the pathogenic repeat sequence relative to the total number of occurrences of the plurality of repeat sequences is greater than a first status threshold; and (mathematical process, mental process).
determining the repeat expansion status at the locus of the gene of interest as pathogenic status (mathematical process, mental process).
Dependent claim 52 recites the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas:
wherein the subject has one allele of the gene of interest with repeat expansion at the locus of the gene of interest (mathematical process, mental process).
Dependent claim 58 recites the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas:
wherein the subject has zero allele with repeat expansion at the locus of the gene of interest, and wherein the repeat expansion status at the locus of the gene of interest is benign status (mathematical process, mental process).
Dependent claim 62 recites the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas:
wherein the repeat expansion status at the locus of the gene of interest is a pathogenic status, a carrier status, or a benign status (mathematical process, mental process).
Dependent claim 63 recites the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas:
wherein each of the plurality of repeat sequences has a number of occurrences greater than or equal to the first occurrence threshold with each occurrence having a number of bases each having a quality score greater than or equal to the first quality threshold (mathematical process, mental process).
Dependent claim 65 recites the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas:
wherein each of the occurrences has a number of bases each having a quality score greater than or equal to a second quality threshold (mathematical process, mental process).
Dependent claim 67 recites the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas:
wherein the repeat sequence representation is degenerate (mathematical process, mental process).
Dependent claim 69 recites the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas:
wherein the repeat sequence representation and/or each of the plurality of repeat sequences is at least 5 bases in length, optionally wherein the repeat sequence representation and/or each of the plurality of repeat sequences is 6 bases in length (mathematical process, mental process).
Dependent claim 70 recites the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas:
wherein the pathogenic repeat sequence has a GC content of at least 60% (mathematical process, mental process).
Dependent claim 71 recites the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas:
wherein the frequency indication of the number of occurrences of the pathogenic repeat sequence relative to the total number of occurrences of the plurality of repeat sequences is a percentage of the number of occurrences of the pathogenic repeat sequence out of the total number of occurrences of the plurality of repeat sequences or a ratio of the number of occurrences of the pathogenic repeat sequence over the total number of occurrences of the plurality of repeat sequences (mathematical process, mental process).
Dependent claim 72 recites the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas:
wherein the plurality of sequence reads is aligned to the locus of the gene of interest (mathematical process, mental process).
Dependent claim 73 recites the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas:
wherein receiving the plurality of sequence reads generated from the sample obtained comprises: aligning a second plurality of sequence reads comprising the plurality of sequence reads to a reference genome sequence; and (mathematical process, mental process)
selecting the plurality of sequence reads from the second plurality of sequence reads, wherein the plurality of sequence reads is aligned to the locus of the gene of interest (mathematical process, mental process).
Dependent claim 80 recites the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas:
wherein the hardware processor is programmed by the executable instructions to perform: receiving conformation of the repeat expansion status at the locus of the gene of interest of the subject determined using one or more diagnosis systems, optionally wherein the one or more diagnosis systems comprise polymerase chain reaction (PCR) and Sanger sequencing, southern blots, and linkage analysis (mathematical process, mental process).
The abstract ideas recited in the claims are evaluated under the broadest reasonable interpretation (BRI) of the claim limitations when read in light of and consistent with the specification. As noted in the foregoing section, the claims are determined to contain limitations that can practically be performed in the human mind with the aid of a pencil and paper, and therefore recite judicial exceptions from the mental process grouping of abstract ideas. Additionally, the recited limitations that are identified as judicial exceptions from the mathematical concepts grouping of abstract ideas are abstract ideas irrespective of whether or not the limitations are practical to perform in the human mind.
Therefore, claims 40, 41, 43-48, 52, 62-63, 65, 67, 69-73, 80 recite an abstract idea.
[Step 2A Prong One: YES]
Eligibility Step 2A Prong Two: In determining whether a claim is directed to a judicial exception, further
examination is performed that analyzes if the claim recites additional elements that when examined as a
whole integrates the judicial exception(s) into a practical application (MPEP 2106.04(d)). A claim that
integrates a judicial exception into a practical application will apply, rely on, or use the judicial exception
in a manner that imposes a meaningful limit on the judicial exception. The claimed additional elements
are analyzed to determine if the abstract idea is integrated into a practical application (MPEP
2106.04(d)(I); MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the abstract
idea, the claim fails to integrate the abstract idea into a practical application (MPEP 2106.04(d)(III)).
The judicial exceptions identified in Eligibility Step 2A Prong One are not integrated into a practical
application because of the reasons noted below.
The additional element in independent claim 40 includes:
A system for determining a repeat expansion status of a gene of interest comprising: non-transitory memory configured to store executable instructions; and a hardware processor in communication with the non-transitory memory, the hardware processor programmed by the executable instructions to perform
receiving a plurality of sequence reads generated from a sample obtained from a subject
The additional element in dependent claim 46 includes:
wherein the hardware processor is programmed by the executable instructions to perform
The additional element in dependent claim 80 includes:
wherein the hardware processor is programmed by the executable instructions to perform: receiving conformation of the repeat expansion status at the locus of the gene of interest of the subject determined using one or more diagnosis systems, optionally wherein the one or more diagnosis systems comprise polymerase chain reaction (PCR) and Sanger sequencing, southern blots, and linkage analysis.
The additional element of a system for determining a repeat expansion status of a gene of interest comprising: non-transitory memory configured to store executable instructions; and a hardware processor in communication with the non-transitory memory, the hardware processor programmed by the executable instructions to perform (claim 40) and wherein the hardware processor is programmed by the executable instructions to perform (claim 46) merely invokes a computer as a tool and does not improve the technology of a generic computer (see MPEP 2106.05(a)). The additional element of receiving a plurality of sequence reads generated from a sample obtained from a subject (claim 40) is an insignificant extra-solution activity that are part of the data gathering process used in the recited judicial exceptions (see MPEP 2106.05(g)). The additional element of wherein the hardware processor is programmed by the executable instructions to perform: receiving conformation of the repeat expansion status at the locus of the gene of interest of the subject determined using one or more diagnosis systems, optionally wherein the one or more diagnosis systems comprise polymerase chain reaction (PCR) and Sanger sequencing, southern blots, and linkage analysis merely invokes a computer as a tool and does not improve the technology of a generic computer (see MPEP 2106.05(a)) and is an insignificant extra-solution activity that are part of the data gathering process used in the recited judicial exceptions (see MPEP 2106.05(g)).
Claims 41, 43, 44, 45, 47 48, 52, 62-63, 65, 67, 69-73, 80 do not recite any elements in addition to the judicial exception, and thus are part of the judicial exception.
Thus, the additionally recited elements merely invoke a computer as a tool, and/or amount to insignificant extra-solution data gathering activity, and as such, when all limitations in claims 40, 46, 80. have been considered as a whole, the claims are deemed to not recite any additional elements that would integrate a judicial exception into a practical application, and therefore claims 40, 41, 43-48, 52, 62-63, 65, 67, 69-73, 80 are directed to an abstract idea (MPEP 2106.04(d)).
[Step 2A Prong Two: NO]
Eligibility Step 2B: Because the claims recite an abstract idea, and do not integrate that abstract idea into a practical application, the claims are probed for a specific inventive concept. The judicial exception alone cannot provide that inventive concept or practical application (MPEP 2106.05). Identifying whether the additional elements beyond the abstract idea amount to such an inventive concept requires considering the additional elements individually and in combination to determine if they amount to significantly more than the judicial exception (MPEP 2106.05A i-vi).
The claims do not include any additional elements that are sufficient to amount to significantly more than the judicial exception(s) because of the reasons noted below.
The additional elements recited in independent claim 40 and dependent claims 46 and 80 are identified above, and carried over from Step 2A: Prong Two along with their conclusions for analysis at Step 2B. Any additional element or combination of elements that was considered to be insignificant extra-solution activity at Step 2A: Prong Two was re-evaluated at Step 2B, because if such re-evaluation finds that the element is unconventional or otherwise more than what is well-understood, routine, conventional activity in the field, this finding may indicate that the additional element is no longer considered to be insignificant; and all additional elements and combination of elements were evaluated to determine whether any additional elements or combination of elements are other than what is well-understood, routine, conventional activity in the field, or simply append well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, per MPEP 2106.05(d).
The additional elements of a system for determining a repeat expansion status of a gene of interest comprising: non-transitory memory configured to store executable instructions; and a hardware processor in communication with the non-transitory memory, the hardware processor programmed by the executable instructions to perform (claim 40) and wherein the hardware processor is programmed by the executable instructions to perform (claim 46) are conventional. Evidence for conventionality is shown by Dolzhenko and Bennet et al. which teaches ExpansionHunter Denovo (EHdn) is a computer program capable of determining repeat expansion status of a gene of interest. Additional evidence for conventionality is shown by Dolzhenko and Deshpande et al. teaches ExpansionHunter a program used to identify repeat expansions. Additional evidence for conventionality is shown by Koboldt et al. which also teaches a computer program for analyzing DNA information.
In addition, the limitations of non-transitory memory configured to store executable instructions; and a hardware processor in communication with the non-transitory memory, the hardware processor programmed by the executable instructions to perform (claim 40) and wherein the hardware processor is programmed by the executable instructions to perform (claim 46) are insignificant extra solution activity conventional merely invokes a computer as a tool and does not improve the technology of a generic computer (see MPEP 2106.05(a)). The additional element of receiving a plurality of sequence reads generated from a sample obtained from a subject (claim 40) is conventional and is part of the data gathering process used in the recited judicial exceptions (see MPEP 2106.05(g)).
Claims 41, 43, 44, 45, 47 48, 52, 62-63, 65, 67, 69-73, 80 do not recite any elements in addition to the judicial exception.
Therefore, when taken alone, all additional elements in claims 40, 41, 43-48, 52, 62-63, 65, 67, 69-73, 80 do not amount to significantly more than the above-identified judicial exception(s). Even when evaluated as a combination, the additional elements fail to transform the exception(s) into a patent-eligible application of that exception. Thus, claims 40, 41, 43-48, 52, 62-63, 65, 67, 69-73, 80 are deemed to not contribute an inventive concept, i.e., amount to significantly more than the judicial exception(s) (MPEP 2106.05(II)).
[Step 2B: NO]
Response to Arguments
Examiner finds applicants arguments regarding eligibility under 101 unpersuasive and have kept the rejection. Examiner disagrees that the additional elements integrate the abstract idea into a practical application. The abstract ideas in the claim are all capable of being done in the human mind. Under the broadest reasonable interpretation there is no requirement that these steps are not performed in the human mind. The additional element of a system for determining a repeat expansion status of a gene of interest comprising: non-transitory memory configured to store executable instructions; and a hardware processor in communication with the non-transitory memory, the hardware processor programmed by the executable instructions to perform (claim 40) and wherein the hardware processor is programmed by the executable instructions to perform (claim 46) merely invokes a computer as a tool and does not improve the technology of a generic computer (see MPEP 2106.05(a)). The additional element of receiving a plurality of sequence reads generated from a sample obtained from a subject (claim 40) is an insignificant extra-solution activity that are part of the data gathering process used in the recited judicial exceptions (see MPEP 2106.05(g)). The additional element of wherein the hardware processor is programmed by the executable instructions to perform: receiving conformation of the repeat expansion status at the locus of the gene of interest of the subject determined using one or more diagnosis systems, optionally wherein the one or more diagnosis systems comprise polymerase chain reaction (PCR) and Sanger sequencing, southern blots, and linkage analysis merely invokes a computer as a tool and does not improve the technology of a generic computer (see MPEP 2106.05(a)) and is an insignificant extra-solution activity that are part of the data gathering process used in the recited judicial exceptions (see MPEP 2106.05(g)). Accordingly, the "mental processes" abstract idea grouping is defined as concepts performed in the human mind, and examples of mental processes include observations, evaluations, judgments, and opinions. A discussion of concepts performed in the human mind, as well as concepts that cannot practically be performed in the human mind and thus are not "mental processes", is provided below with respect to point A. The courts do not distinguish between mental processes that are performed entirely in the human mind and mental processes that require a human to use a physical aid (e.g., pen and paper or a slide rule) to perform the claim limitation. See, e.g., Benson, 409 U.S. at 67, 65, 175 USPQ at 674-75, 674 (noting that the claimed "conversion of [binary-coded decimal] numerals to pure binary numerals can be done mentally," i.e., "as a person would do it by head and hand."); Synopsys, Inc. v. Mentor Graphics Corp., 839 F.3d 1138, 1139, 120 USPQ2d 1473, 1474 (Fed. Cir. 2016) (holding that claims to a mental process of "translating a functional description of a logic circuit into a hardware component description of the logic circuit" are directed to an abstract idea, because the claims "read on an individual performing the claimed steps mentally or with pencil and paper"). Nor do the courts distinguish between claims that recite mental processes performed by humans and claims that recite mental processes performed on a computer. As the Federal Circuit has explained, "[c]ourts have examined claims that required the use of a computer and still found that the underlying, patent-ineligible invention could be performed via pen and paper or in a person’s mind." Versata Dev. Group v. SAP Am., Inc., 793 F.3d 1306, 1335, 115 USPQ2d 1681, 1702 (Fed. Cir. 2015). See also Intellectual Ventures I LLC v. Symantec Corp., 838 F.3d 1307, 1318, 120 USPQ2d 1353, 1360 (Fed. Cir. 2016) (‘‘[W]ith the exception of generic computer-implemented steps, there is nothing in the claims themselves that foreclose them from being performed by a human, mentally or with pen and paper.’’); Mortgage Grader, Inc. v. First Choice Loan Servs. Inc., 811 F.3d 1314, 1324, 117 USPQ2d 1693, 1699 (Fed. Cir. 2016) (holding that computer-implemented method for "anonymous loan shopping" was an abstract idea because it could be "performed by humans without a computer"). Mental processes recited in claims that require computers are explained further below with respect to point C. Because both product and process claims may recite a "mental process", the phrase "mental processes" should be understood as referring to the type of abstract idea, and not to the statutory category of the claim. The courts have identified numerous product claims as reciting mental process-type abstract ideas, for instance the product claims to computer systems and computer-readable media in Versata Dev. Group. v. SAP Am., Inc., 793 F.3d 1306, 115 USPQ2d 1681 (Fed. Cir. 2015). This concept is explained further below with respect to point D. The MPEP also states the following are mental process. The comparing BCRA sequences is very similar to what applicant is doing.
claim to "collecting information, analyzing it, and displaying certain results of the collection and analysis," where the data analysis steps are recited at a high level of generality such that they could practically be performed in the human mind, Electric Power Group v. Alstom, S.A., 830 F.3d 1350, 1353-54, 119 USPQ2d 1739, 1741-42 (Fed. Cir. 2016); [AltContent: rect]
claims to "comparing BRCA sequences and determining the existence of alterations," where the claims cover any way of comparing BRCA sequences such that the comparison steps can practically be performed in the human mind, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 763, 113 USPQ2d 1241, 1246 (Fed. Cir. 2014); Each additional element is only recited at a high level of generality. Examiner disagrees that examples given are analogous art. Examiner asserts that the claimed invention is similar to "comparing BRCA sequences and determining the existence of alterations," which is a mental process under MPEP 2106.04(a). In addition, the MPEP takes priority over the examples.
Regarding the applicant’s arguments regarding 2B. Examiner believes the additional elements are conventional as even whole genome sequence is well established, routine, and conventional at the earliest priority date. Examiner asserts that Exergen is not analogous art as "comparing BRCA sequences and determining the existence of alterations," is an abstract idea and whole genome sequencing including on the single cell level is routine.
Examiner disagrees with determining the acts of aligning a plurality of sequence reads to a sequence graph, determining occurrences of a plurality of repeat sequences using quality and occurrence thresholds, computing a frequency indication of a pathogenic repeat sequence relative to all repeat sequences, determining allele count (zero, one, or two), and classifying the repeat expansion status as pathogenic, carrier, or benign are not a mental process. Although these sequences could be very long there and the applicant claims their process is faster, those limitations do not exist in the claim thus could be a mental process under BRI. See above for more detail.
Examiner also disagrees with the claims being directed to a mathematical concept. MPEP states that organizing information and manipulating information through mathematical correlations, Digitech Image Techs., LLC v. Electronics for Imaging, Inc., 758 F.3d 1344, 1350, 111 USPQ2d 1717, 1721 (Fed. Cir. 2014). The patentee in Digitech claimed methods of generating first and second data by taking existing information, manipulating the data using mathematical functions, and organizing this information into a new form. The court explained that such claims were directed to an abstract idea because they described a process of organizing information through mathematical correlations, like Flook's method of calculating using a mathematical formula. 758 F.3d at 1350, 111 USPQ2d at 1721. Examiner asserts that ligning the plurality of sequence reads to a sequence graph to generate a plurality of aligned sequence reads", "determining a number of occurrences of a plurality of repeat sequences in aligned sequence reads of the plurality of aligned sequence reads using a first occurrence threshold and a first quality threshold", and "determining a frequency indication of a number of occurrences of a pathogenic repeat sequence relative to a total number of occurrences of the plurality of repeat sequence" are simply ways of organizing and manipulating data using mathematical concepts.
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 40, 46, 63, 65, 67, 71, 72, 73 are rejected under 35 U.S.C. 103 as being unpatentable by Dolzhenko and Bennet et al. (Dolzhenko, E., Bennett, M.F., et al. Genome Biol 21, 102 (2020)) in view of Dolzhenko and Deshpande et al. (Egor Dolzhenko, Viraj Deshpande, et al., Bioinformatics, Volume 35, Issue 22, November 2019, Pages 4754–4756,) in view of Cortese et al. (RFC1 CANVAS / Spectrum Disorder, Andrea Cortese, November 25, 2020., EurpoeMC)
Regarding the limitations of independent claim 40,
A system for determining a repeat expansion status of a gene of interest comprising: non-transitory memory configured to store executable instructions; and a hardware processor in communication with the non-transitory memory, the hardware processor programmed by the executable instructions to perform;
Dolzhenko and Bennet et al. teaches ExpansionHunter Denovo (EHdn) is a computer program capable of determining repeat expansion status of a gene of interest. (Background 4th paragraph, pg. 2)
(a) receiving a plurality of sequence reads generated from a sample obtained from a subject;
Dolzhenko and Bennet et al. teaches ExpansionHunter Denovo, which performs a genome-wide search in BAM/CRAM files containing read alignments. (Results – Overview 1st paragraph, pg. 3)
(c) determining a number of occurrences of a plurality of repeat sequences in aligned sequence reads of the plurality of aligned sequence reads using a first occurrence threshold and a first quality threshold;
Dolzhenko and Bennet et al. teaches quality thresholds, which are disclosed in the putative repeat unit which was used to calculate a weighted-purity (WP) score of a read. It is assumed that a read is an IRR if it achieves a WP score of at least 0.9. The WP score lowers the penalty for low-quality mismatches in order to account for the possibility of an increased basecall error rate that may occur in highly repetitive regions of the genome (Identification of IRRs 1st paragraph, pg. 10). Dolzhenko and Bennet et al. also teaches occurrence thresholds by considering loci where EHdn identified at least five anchored IRRs (The landscape of long repeats within a control population 1st paragraph, pg. 7).
Regarding the limitations of dependent claim 63,
wherein each of the plurality of repeat sequences has a number of occurrences greater than or equal to the first occurrence threshold with each occurrence having a number of bases each having a quality score greater than or equal to the first quality threshold.
Dolzhenko and Bennet et al. teaches teaches quality thresholds, which are disclosed in the putative repeat unit which was used to calculate a weighted-purity (WP) score of a read. It is assumed that a read is an IRR if it achieves a WP score of at least 0.9. The WP score lowers the penalty for low-quality mismatches in order to account for the possibility of an increased basecall error rate that may occur in highly repetitive regions of the genome (Identification of IRRs 1st paragraph, pg. 10). Dolzhenko and Bennet et al. also teaches occurrence thresholds by considering loci where EHdn identified at least five anchored IRRs (The landscape of long repeats within a control population 1st paragraph, pg. 7).
Regarding the limitations of dependent claim 65,
wherein each of the occurrences has a number of bases each having a quality score greater than or equal to a second quality threshold.
Dolzhenko and Bennet et al. teaches quality thresholds, which are disclosed in the putative repeat unit which was used to calculate a weighted-purity (WP) score of a read. It is assumed that a read is an IRR if it achieves a WP score of at least 0.9. The WP score lowers the penalty for low-quality mismatches in order to account for the possibility of an increased basecall error rate that may occur in highly repetitive regions of the genome (Identification of IRRs 1st paragraph, pg. 10). Dolzhenko and Bennet et al. also teaches occurrence thresholds by considering loci where EHdn identified at least five anchored IRRs (The landscape of long repeats within a control population 1st paragraph, pg. 7).
Regarding the limitations of dependent claim 73,
wherein receiving the plurality of sequence reads generated from the sample obtained comprises: aligning a second plurality of sequence reads comprising the plurality of sequence reads to a reference genome sequence; and selecting the plurality of sequence reads from the second plurality of sequence reads, wherein the plurality of sequence reads is aligned to the locus of the gene of interest.
Dolzhenko and Bennet et al. teaches EHdn which scans the existing alignments of one or many sequencing libraries implying the reference alignment has occurred which is then used for further analysis (Background 4th paragraph, pg. 4)
Dolzhenko and Bennet et al. does not explicitly teach
(b) aligning the plurality of sequence reads to a sequence graph to generate a plurality of aligned sequence reads, wherein the sequence graph represents a locus of a gene of interest and comprises a repeat sequence representation flanked by non-repeat sequences of the locus of the gene, and wherein the plurality of aligned sequence reads comprises the plurality of sequence reads and alignments of the plurality of sequence reads to the sequence graph; (Claim 40)
determining a frequency indication of a number of occurrences of a pathogenic repeat sequence relative to a total number of occurrences of the plurality of repeat sequence (Claim 40)
determining a repeat expansion status at the locus of the gene of interest of the subject using the frequency indication of the number of occurrences of the pathogenic repeat sequence relative to the total number of occurrences of the plurality of repeat sequences. (Claim 40)
determining the subject has zero, one, or two alleles with a repeat expansion at the locus of the gene of interest using the plurality of aligned sequence reads (Claim 40)
wherein the hardware processor is programmed by the executable instructions to perform: determining the subject has zero, one, or two alleles with a repeat expansion at the locus of the gene of interest using the plurality of aligned sequence reads that are in-repeat reads or flanking reads (Claim 46)
wherein the repeat sequence representation is degenerate. (Claim 67)
wherein the frequency indication of the number of occurrences of the pathogenic repeat sequence relative to the total number of occurrences of the plurality of repeat sequences is a percentage of the number of occurrences of the pathogenic repeat sequence out of the total number of occurrences of the plurality of repeat sequences or a ratio of the number of occurrences of the pathogenic repeat sequence over the total number of occurrences of the plurality of repeat sequences (Claim 71).
wherein the plurality of sequence reads is aligned to the locus of the gene of interest (Claim 72)
Regarding the limitations of independent claim 40,
(b) aligning the plurality of sequence reads to a sequence graph to generate a plurality of aligned sequence reads, wherein the sequence graph represents a locus of a gene of interest and comprises a repeat sequence representation flanked by non-repeat sequences of the locus of the gene, and wherein the plurality of aligned sequence reads comprises the plurality of sequence reads and alignments of the plurality of sequence reads to the sequence graph;
Dolzhenko and Deshpande et al. teaches ExpansionHunter which for each locus, the program extracts relevant reads from a binary alignment/map file and realigns them using a graph-based model representing the locus structure. The realigned reads are then used to genotype each variant at the locus (Implementation 1st paragraph. pg. 4755, column 1)
determining the subject has zero, one, or two alleles with a repeat expansion at the locus of the gene of interest using the plurality of aligned sequence reads
Dolzhenko and Deshpande et al. teaches a diploid style genotyping framework at a locus of a gene of interest, where a sequence graph encodes possible alleles and genotyping evaluates presence or absence of constituent alleles from read alignments. The graph assembles different alleles and genotyping is performed by analyzing reads aligned to a sequence graph for the presence or absence of each constituent allele (implementation, pg. 4755, column 2). This method can be used to determine whether the subject has zero, one, or two alleles.
Regarding the limitations of dependent claim 46,
wherein the hardware processor is programmed by the executable instructions to perform: determining the subject has zero, one, or two alleles with a repeat expansion at the locus of the gene of interest using the plurality of aligned sequence reads that are in-repeat reads or flanking reads.
Dolzhenko and Deshpande et al. teaches a diploid style genotyping framework at a locus of a gene of interest, where a sequence graph encodes possible alleles and genotyping evaluates presence or absence of constituent alleles from read alignments. The graph assembles different alleles and genotyping is performed by analyzing reads aligned to a sequence graph for the presence or absence of each constituent allele (implementation, pg. 4755, column 2). This method can be used to determine whether the subject has zero, one, or two alleles.
Regarding the limitations of dependent claim 67,
wherein the repeat sequence representation is degenerate.
Dolzhenko and Deshpande et al. teaches that ExpansionHunter can handle multi-allelic or ‘degenerate’ base symbols (Implementation, pg. 4755, column 2)
Regarding the limitations of dependent claim 72,
wherein the plurality of sequence reads is aligned to the locus of the gene of interest.
Dolzhenko and Deshpande et al. teaches for each locus reads are extracted and realigned using a graph-based model representing the locus structure (Implementation, pg. 4755, column 1)
Regarding the limitations of independent claim 40,
(d) determining a frequency indication of a number of occurrences of a pathogenic repeat sequence relative to a total number of occurrences of the plurality of repeat sequence
(e) determining a repeat expansion status at the locus of the gene of interest of the subject using the frequency indication of the number of occurrences of the pathogenic repeat sequence relative to the total number of occurrences of the plurality of repeat sequences
Cortese et al. teaches the determination of pathogenic repeats by their frequency in a total amount of repeat sequences in RFC1 CANVAS. This would lead a person of ordinary skill in the art to use a frequency indicator to help diagnose similar disorders. (Establishing the Diagnosis)
Regarding the limitations of dependent claim 71,
wherein the frequency indication of the number of occurrences of the pathogenic repeat sequence relative to the total number of occurrences of the plurality of repeat sequences is a percentage of the number of occurrences of the pathogenic repeat sequence out of the total number of occurrences of the plurality of repeat sequences or a ratio of the number of occurrences of the pathogenic repeat sequence over the total number of occurrences of the plurality of repeat sequences.
Cortese et al. teaches the determination of pathogenic repeats by their frequency in a total amount of repeat sequences in RFC1 CANVAS. They even specifically discuss different frequencies of common pathogenic and non pathogenic repeats as well as percentages. This would lead a person of ordinary skill in the art to use a frequency indicator to help diagnose similar disorders. (Establishing the Diagnosis)
A person having ordinary skill in the art would be motivated to combine ExpansionHunter Denovo (EHdn) (Dolzhenko and Bennet et al.) with ExpansionHunter 2019 (Dolzhenko and Deshpande et al.) because EHdn is an improvement on the earlier work and both are used to solve the same problem of identifying repeat expansions. Then to convert read-support evidence into a frequency/ quality indication with a clear status decision, a person of ordinary skill would use the knowledge of Cortese et al. that teaches that teaches read-count fraction+ threshold framework is used to diagnose RFC1 CANVAS. This would make it an obvious addition to add to a sequencing method for determining repeat sequences. There is a reasonable expectation of success because all methods are applied to sequencing data and combining EHdn with ExpansionHunter’s graph alignment and Cortese et al. frequency/ threshold yields a predictable, modular pipeline.
Claims 41, 43, 44, 45, 69 are rejected under 35 U.S.C. 103 as being unpatentable over Dolzhenko and Bennet et al. in view of Dolzhenko and Deshpande et al. in view of Cortese et al. as applied to claims 40, 46, 63, 65, 67, 71, 72, 73 above, and further in view of Akçimen et al. (Akçimen F, et al. Front Genet. 2019 Nov 22;10:1219. doi: 10.3389/fgene.2019.01219. PMID: 31824583; PMCID: PMC6884024)
As applied to independent claim 40 (detailed above), Dolzhenko and Bennet et al. in view of Dolzhenko and Deshpande et al. in view of Cortese et al. teaches a system for determining a repeat expansion status of a gene of interest.
Dolzhenko and Bennet et al. in view of Dolzhenko and Deshpande et al. in view of Cortese et al. does not explicitly teach:
wherein the gene of interest is replication factor C subunit 1 (RFC 1) (Claim 41)
wherein the repeat expansion is associated with or causes a disease, optionally wherein the disease is cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) (Claim 43)
wherein the repeat sequence representation is AARRG (Claim 44)
wherein the pathogenic repeat sequence is AAGGG or ACAGG (Claim 45)
Regarding the limitations of dependent claim 41,
wherein the gene of interest is replication factor C subunit 1 (RFC 1)
Akçimen et al. teaches that a biallelic pentanucleotide expansion in the RFC1 gene has been reported to be a common cause of late-onset ataxia (abstract).
Regarding the limitations of dependent claim 43,
wherein the repeat expansion is associated with or causes a disease, optionally wherein the disease is cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS).
Akçimen et al. teaches that a biallelic pentanucleotide expansion in the RFC1 gene has been reported to be a common cause of late-onset ataxia (abstract)
Regarding the limitations of dependent claim 44,
wherein the repeat sequence representation is AARRG.
Akçimen et al. teaches teaches a biallelic pentanucleotide expansion in the RFC1 gene has been reported to be a common cause of late-onset ataxia. In the general population, four different repeat conformations are observed: wild type sequence AAAAG (11 repeats) and longer expansions of either AAAAG, AAAGG or AAGGG sequences (abstract). R is a representation that can either be G or A.
Regarding the limitations of dependent claim 45,
wherein the pathogenic repeat sequence is AAGGG or ACAGG
Akçimen et al. teaches a biallelic pentanucleotide expansion in the RFC1 gene has been reported to be a common cause of late-onset ataxia. In the general population, four different repeat conformations are observed: wild type sequence AAAAG (11 repeats) and longer expansions of either AAAAG, AAAGG or AAGGG sequences (abstract)
Regarding the limitations of dependent claim 69,
wherein the repeat sequence representation and/or each of the plurality of repeat sequences is at least 5 bases in length, optionally wherein the repeat sequence representation and/or each of the plurality of repeat sequences is 6 bases in length.
Akçimen et al. teaches a biallelic pentanucleotide expansion in the RFC1 gene has been reported to be a common cause of late-onset ataxia. In the general population, four different repeat conformations are observed: wild type sequence AAAAG (11 repeats) and longer expansions of either AAAAG, AAAGG or AAGGG sequences (abstract).
The AAGGG is at least 5 bases in length.
Regarding the limitations of dependent claim 70,
wherein the pathogenic repeat sequence has a GC content of at least 60%.
Akçimen et al. teaches a biallelic pentanucleotide expansion in the RFC1 gene has been reported to be a common cause of late-onset ataxia. In the general population, four different repeat conformations are observed: wild type sequence AAAAG (11 repeats) and longer expansions of either AAAAG, AAAGG or AAGGG sequences (abstract).
The AAGGG has a GC content of at least 60%.
A person having ordinary skill in the art would be motivated to combine the system for determining a repeat expansion status of a gene of interest taught by Dolzhenko and Bennet et al. in view of Dolzhenko and Deshpande et al. in view of Cortese et al. with the knowledge of specific repeat expansions and how they relate to diseases in order to gain information on that repeat expansion. There is a reasonable expectation of success because the system taught by by Dolzhenko and Bennet et al. in view of Dolzhenko and Deshpande et al. in view of Cortese et al. is designed to work on genomic data that contains repeat expansions.
Claim 47 and 48 are rejected under 35 U.S.C. 103 as being unpatentable over Dolzhenko and Bennet et al. in view of Dolzhenko and Deshpande et al. in view of Cortese et al. as applied to claims 40, 46, 63, 65, 67, 71, 72, 73 above, and further in view of Al-Mahdawi et al. (Al-Mahdawi, et al, Large Interruptions of GAA Repeat Expansion Mutations in Friedreich Ataxia Are Very Rare. Frontiers in Cellular Neuroscience 2018, 12.)
As applied to independent claim 40 and dependent claims 46, 63, 65, 67, 71, 72, 73 (detailed above), Dolzhenko and Bennet et al. in view of Dolzhenko and Deshpande et al. in view of Cortese et al. teaches a system for determining a repeat expansion status of a gene of interest with a potential method of determining the frequency indication of the number of occurrences of the pathogenic repeat sequence relative to the total number of occurrences of the plurality of repeat sequences is greater than a first status threshold; and determining the repeat expansion status at the locus of the gene of interest as pathogenic status.
Regarding the limitations of dependent claim 48,
wherein determining the repeat expansion status at the locus of the gene of interest comprises: determining the frequency indication of the number of occurrences of the pathogenic repeat sequence relative to the total number of occurrences of the plurality of repeat sequences is greater than a first status threshold; and determining the repeat expansion status at the locus of the gene of interest as pathogenic status.
Dolzhenko and Bennet et al. in view of Dolzhenko and Deshpande et al. in view of Cortese et al. teaches a system that counts the number of occurrences of the pathogenic repeat. Computes a frequency threshold to determine if a sample has repeat-expansion classification.
Dolzhenko and Bennet et al. in view of Dolzhenko and Deshpande et al. in view of Cortese et al. does not explicitly teach:
wherein the subject has two alleles with repeat expansion at the locus of the gene of interest (Claim 47)
Regarding the limitations of dependent claim 47,
wherein the subject has two alleles with repeat expansion at the locus of the gene of interest.
Al-Mahdawi et al. teaches Friedreich ataxia is a multi-system autosomal recessive inherited disorder primarily caused by homozygous GAA repeat expansion mutations within intron 1 of the frataxin gene (abstract, introduction 2nd paragraph, pg. 2, column 1)
A person having ordinary skill in the art would be motivated to combine the system for determining a repeat expansion status of a gene of interest taught by Dolzhenko and Bennet et al. in view of Dolzhenko and Deshpande et al. in view of Cortese et al. with the knowledge of by homozygous GAA repeat expansion taught by Al-Mahdawi et al. because a person having ordinary skill in the art would be motivated to determine repeat expansion status of the frataxin gene to determine information on Friedreich ataxia. A person having ordinary skill in the art would have a reasonable expectation of success because the system taught by Dolzhenko and Bennet et al. in view of Dolzhenko and Deshpande et al. in view of Cortese et al. has been used to determine repeat expansion status of other diseases and can be applied to the frataxin gene taught by Al-Mahdawi et al.
Claim 52, 80 is rejected under 35 U.S.C. 103 as being unpatentable over Dolzhenko and Bennet et al. in view of Dolzhenko and Deshpande et al. in view of Cortese et al. as applied to claims 40, 46, 63, 65, 67, 71, 72, 73 above, and further in view of Monaghan et al. (Monaghan, K. et al. ACMG Standards and Guidelines for Fragile X Testing: A Revision to the Disease-Specific Supplements to the Standards and Guidelines for Clinical Genetics Laboratories of the American College of Medical Genetics and Genomics et al. Genetics in Medicine 2013, 15 (7), 575–586.)
As applied to independent claim 40 (detailed above), Dolzhenko and Bennet et al. in view of Dolzhenko and Deshpande et al. in view of Cortese et al. teaches a system for determining a repeat expansion status of a gene of interest.
Dolzhenko and Bennet et al. in view of Dolzhenko and Deshpande et al. in view of Cortese et al. does not explicitly teach:
wherein the subject has one allele of the gene of interest with repeat expansion at the locus of the gene of interest (Claim 52)
wherein the hardware processor is programmed by the executable instructions to perform: receiving conformation of the repeat expansion status at the locus of the gene of interest of the subject determined using one or more diagnosis systems, optionally wherein the one or more diagnosis systems comprise polymerase chain reaction (PCR) and Sanger sequencing, southern blots, and linkage analysis (Claim 80)
Regarding the limitations of dependent claim 52,
wherein the subject has one allele of the gene of interest with repeat expansion at the locus of the gene of interest.
Monaghan et al. teaches genetic testing for diagnostic testing and carrier detection (FX 2.9.2: Indications for testing, pg. 577, column 2) A carrier would only have 1 allele of a repeat expansion in the FMR1 gene for Fragile X syndrome.
Regarding the limitations of dependent claim 80,
wherein the hardware processor is programmed by the executable instructions to perform: receiving conformation of the repeat expansion status at the locus of the gene of interest of the subject determined using one or more diagnosis systems, optionally wherein the one or more diagnosis systems comprise polymerase chain reaction (PCR) and Sanger sequencing, southern blots, and linkage analysis.
Monaghan et al. teaches the use of PCR and Southern Blot analysis in diagnostic workflows (FX 3: GUIDELINES, pg. 579, column 2)
A person having ordinary skill in the art would be motivated to combine the information taught by Monaghan et al. of clinical genetics routinely being used to distinguish carrier vs affected as well as the use of PCR and southern blot for confirmation and ExpansionHunter framework that classifies homozygous vs heterozygous via frequency threshold. There is a reasonable expectation of success because one expanded allele is equivalent to heterozygous expansion. In addition, success is expected because Dolzhenko and Bennet et al. in view of Dolzhenko and Deshpande et al. in view of Cortese et al. teaches a system for determining a repeat expansion status of a gene of interest which can detect 0,1 or 2 alleles that can be targeted. This can be applied to detect carriers of FMR1 gene for Fragile X syndrome where a carrier would only have 1 allele.
Claim 58 is rejected under 35 U.S.C. 103 as being unpatentable over Dolzhenko and Bennet et al. in view of Dolzhenko and Deshpande et al. in view of Cortese et al. as applied to claims 40, 46, 63, 65, 67, 71, 72, 73 above, and further in view of Dolzhenko and Vugt et al. (Dolzhenko E, van Vugt JJFA, et al. Detection of long repeat expansions from PCR-free whole-genome sequence data. Genome Res. 2017 Nov;27(11):1895-1903. doi: 10.1101/gr.225672.117. Epub 2017 Sep 8. PMID: 28887402; PMCID: PMC5668946.)
As applied to independent claim 40 (detailed above), Dolzhenko and Bennet et al. in view of Dolzhenko and Deshpande et al. in view of Cortese et al. teaches a system for determining a repeat expansion status of a gene of interest
Dolzhenko and Bennet et al. in view of Dolzhenko and Deshpande et al. in view of Cortese et al. does not explicitly teach:
wherein the subject has zero allele with repeat expansion at the locus of the gene of interest, and wherein the repeat expansion status at the locus of the gene of interest is benign status (Claim 58)
Regarding the limitations of dependent claim 58,
wherein the subject has zero allele with repeat expansion at the locus of the gene of interest, and wherein the repeat expansion status at the locus of the gene of interest is benign status.
Dolzhenko and Vugt et al. teaches a tool to detect repeat expansions against pathogenic threshold and include wild-type or non-expanded options, which is benign (abstract)
A person having ordinary skill in the art would be motivated to combine the system for determining a repeat expansion status of a gene of interest taught by Dolzhenko and Bennet et al. in view of Dolzhenko and Deshpande et al. in view of Cortese et al. with the knowledge of labeling no-expansion as benign because is routine clinical reporting once you have a pathogenic vs non-pathogenic classification taught by Dolzhenko and Vugt et al. There is a reasonable expectation of success because this is just reporting data with no technical barrier.
Claim 62 is rejected under 35 U.S.C. 103 as being unpatentable over Dolzhenko and Bennet et al. in view of Dolzhenko and Deshpande et al. in view of Cortese et al. in view of Monaghan et al. as applied to claims 52, 80 above, and further in view of in view of Dolzhenko and Vugt et al.
As applied to dependent claim 52 (detailed above), Dolzhenko and Bennet et al. in view of Dolzhenko and Deshpande et al. in view of Cortese et al. in view of Monaghan et al. teaches a system for determining a repeat expansion status of a gene of interest wherein the subject can have one allele of the gene of interest with repeat expansion at the locus of the gene of interest with one allele of the gene of interest being a carrier for the genetic disorder.
Dolzhenko and Bennet et al. in view of Dolzhenko and Deshpande et al. in view of Cortese et al. in view of Monaghan et al. does not explicitly teach
wherein the repeat expansion status at the locus of the gene of interest is a pathogenic status, a carrier status, or a benign status (Claim 62)
Regarding the limitations of dependent claim 62,
wherein the repeat expansion status at the locus of the gene of interest is a pathogenic status, a carrier status, or a benign status.
Dolzhenko and Vugt et al. teaches a tool to detect repeat expansions against pathogenic threshold and include wild-type or non-expanded options, which is benign (abstract)
A person having ordinary skill in the art would be motivated to combine the system for determining pathogenic repeat expansions (with the knowledge of a single allele being a carrier) taught by Dolzhenko and Bennet et al. in view of Dolzhenko and Deshpande et al. in view of Cortese et al. in view of Monaghan et al. with the knowledge pathogenic or benign status of a gene of interest taught by Dolzhenko and Vugt et al. in order to make effective clinical diagnosis. There is a reasonable expectation of success because it is simple a categorization on top of a functional pipeline for analyzing genomic data.
Response to Arguments
Examiner agrees that Koboldt does not teach the limitations of determining a frequency indication of a number of occurrences of a pathogenic repeat sequence relative to a total number of occurrences of the plurality of repeat sequence. Thus, Examiner has dropped that rejection. So, the previous rejection is moot. A new rejection has replaced the previous one.
Conclusion
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/C.H.B./Examiner, Art Unit 1687 /Karlheinz R. Skowronek/Supervisory Patent Examiner, Art Unit 1687
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