DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claim Status
Claims 1-2, 6-12, 14-16, 19-22, 25, 27-28, and 33 are pending.
Claims 3-5, 13, 17-18, 23-24, 26, 29-32, and 34-66 are canceled.
Claims 1-2, 6-12, 14-16, 19-22, 25, 27-28, and 33 are under examination.
Claims 1-2, 6-12, 14-16, 19-22, 25, 27-28, and 33 are rejected.
Priority
The instant Application claims domestic benefit to US provisional application 63/332107, filed 04/18/2022. Accordingly, each of claims 1-2, 6-12, 14-16, 19-22, 25, 27-28, and 33 are afforded the effective filing date of the 04/18/2022.
Information Disclosure Statement
The information disclosure statements (IDS) filed on 05/17/2023 and 7/23/2024 are in compliance with the provisions of 37 CFR 1.97 and have therefore been considered. Signed copies of the IDS documents are included with this Office Action.
Drawings
The Drawings submitted 04/17/2023 are accepted.
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 1-2, 6-12, 14-16, 19-22, 25, 27-28, and 33 are rejected under 35 U.S.C. 101 because the claimed invention is directed to one or more judicial exceptions without significantly more.
MPEP 2106 organizes judicial exception analysis into Steps 1, 2A (Prongs One and Two) and 2B as follows below. MPEP 2106 and the following USPTO website provide further explanation and case law citations: uspto.gov/patent/laws-and-regulations/examination-policy/examination-guidance-and-training-materials.
Framework with which to Evaluate Subject Matter Eligibility:
Step 1: Are the claims directed to a process, machine, manufacture, or composition of matter;
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e. a law of nature, a natural phenomenon, or an abstract idea;
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application (Prong Two); and
Step 2B: If the claims do not integrate the judicial exception, do the claims provide an inventive concept.
Framework Analysis as Pertains to the Instant Claims:
Step 1
With respect to Step 1: yes, the claims are directed to method and system, i.e., a process, machine, or manufacture within the above 101 categories [Step 1: YES; See MPEP § 2106.03].
Step 2A, Prong One
With respect to Step 2A, Prong One, the claims recite judicial exceptions in the form of abstract ideas. The MPEP at 2106.04(a)(2) further explains that abstract ideas are defined as:
mathematical concepts (mathematical formulas or equations, mathematical relationships and mathematical calculations);
certain methods of organizing human activity (fundamental economic practices or principles, managing personal behavior or relationships or interactions between people); and/or
mental processes (procedures for observing, evaluating, analyzing/ judging and organizing information).
With respect to the instant claims, under the Step 2A, Prong One evaluation, the claims are found to recite abstract ideas that fall into mathematical concepts (in particular mathematical relationships and formulas) are as follows:
Independent claims 1 and 33:
aligning the plurality of sequence reads to a reference genome sequence to obtain a plurality of aligned sequence reads comprising sequence reads aligned to a gene in the reference genome sequence, wherein the gene comprises a plurality of regions, wherein two copy number variants (CNVs) of a plurality of CNVs of the gene each comprises one or more regions of the plurality of regions and differ by at least one region of the plurality of regions;
determining a number of the sequence reads aligned to each region of the plurality of regions of the gene in the reference genome sequence;
determining a number of copies of each region of the plurality of regions based on the number of the sequence reads aligned to the region; and
determining two alleles of the gene of the subject, each comprising one or more regions of the plurality of regions, based on the number of copies of each region of the plurality of regions and all CNVs of the plurality of CNVs comprising the region.
Dependent claim 16:
determining the number of copies of each region of the plurality of regions using the number of the sequence reads aligned to the region based on a normalized and/or GC-corrected number of the sequence reads aligned to each region of the plurality of regions of the gene in the reference genome sequence.
Dependent claim 20:
determining a difference in the number of copies of each region of the plurality of regions, relative to a reference number of copies of the region, based on the number of the sequence reads aligned to the region, and wherein determining the two alleles of the gene of the subject comprises:
determining the two alleles of the gene of the subject using the difference in the number of copies of each region of the plurality of regions, relative to the reference number of copies of the region, and all CNVs of the plurality of CNVs comprising the region.
Dependent claim 25:
determining (i) a number of copies a first CNV in a first allele of the two alleles of the gene of the subject and (ii) a number of copies of a second CNV in a second allele of the two alleles of the gene of the subject such that (a) the number of copies of a region of the plurality of regions in the first CNV and not the second CNV is the number of copies of the first CNV, (b) the number of copies of a region of the plurality of regions in the first CNV and the second CNV is the sum of the number of copies of the first CNV and the number of copies of the second CNV, and/or (c) the number of copies of a region of the plurality of regions in the second CNV and not the first CNV is the number of copies of the second CNV.
Dependent claim 27:
determining the plurality of regions using the plurality of CNVs, optionally wherein receiving the plurality of CNVs comprises determining the plurality of CNVs
Dependent claims 2,6-12, 14-15, 19 and 21-22 recite further steps that limit the judicial exceptions in independent claim 1 and, as such, also are directed to those abstract ideas. For example, claims 2, 6-12, 14-15, 19 and 21-22 further limits the CVNs of claim 1.
Under the BRI, the instant claims recite judicial exceptions that are an abstract idea of a “mathematical concept”, such as mathematical relationships and mathematical equations.
The claims recite a mathematical concept of aligning the plurality of sequence reads, determining a number of the sequence reads aligned, determining a number of copies of each region, determining two alleles of the gene of the subject, determining a difference in the number of copies of each region of the plurality of regions, relative to a reference number of copies of the region, determining the number of copies of each region of the plurality of regions using the number of the sequence reads aligned to the region based on a normalized and/or GC-corrected, and determining (i) a number of copies a first CNV in a first allele of the two alleles of the gene of the subject and (ii) a number of copies of a second CNV in a second allele of the two alleles of the gene of the subject.
Therefore, claim 1 and those claims dependent therefrom recite an abstract idea [Step 2A, Prong 1: YES; See MPEP § 2106.04].
Step 2A, Prong Two
Because the claims do recite judicial exceptions, direction under Step 2A, Prong Two, provides that the claims must be examined further to determine whether they integrate the judicial exceptions into a practical application (MPEP 2106.04(d)). A claim can be said to integrate a judicial exception into a practical application when it applies, relies on, or uses the judicial exception in a manner that imposes a meaningful limit on the judicial exception. This is performed by analyzing the additional elements of the claim to determine if the judicial exceptions are integrated into a practical application (MPEP 2106.04(d).I.; MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the judicial exceptions, the claim is said to fail to integrate the judicial exceptions into a practical application (MPEP 2106.04(d).III).
Additional elements, Step 2A, Prong Two
With respect to the instant recitations, the claims recite the following additional elements:
Independent claim 1:
receiving a plurality of sequence reads generated from a sample obtained from a subject
Dependent claim 27:
receiving the plurality of CNVs
Dependent claim 28:
creating a file or a report
The claims also include non-abstract computing elements. For example, independent claim 33 includes a non-transitory memory and system.
Considerations under Step 2A, Prong Two
With respect to Step 2A, Prong Two, the additional elements of the claims do not integrate the judicial exceptions into a practical application for the following reasons. Those steps directed to data gathering, such as “receiving” and “acquiring”, and to data outputting, such as “creating a file”, perform functions of collecting the data needed to carry out the judicial exceptions. Data gathering and outputting do not impose any meaningful limitation on the judicial exceptions, or on how the judicial exceptions are performed. Data gathering and outputting steps are not sufficient to integrate judicial exceptions into a practical application (MPEP 2106.05(g)).
Further steps directed to additional non-abstract elements of “non-transitory memory and system” do not describe any specific computational steps by which the “computer parts” perform or carry out the judicial exceptions, nor do they provide any details of how specific structures of the computer, such as the computer-readable recording media, are used to implement these functions. The claims state nothing more than a generic computer which performs the functions that constitute the judicial exceptions. Hence, these are mere instructions to apply the judicial exceptions using a computer, and therefore the claim does not integrate that judicial exceptions 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 (MPEP 2106.05(f)).
Thus, none of the claims recite additional elements which would integrate a judicial exception into a practical application, and the claims are directed to one or more judicial exceptions [Step 2A, Prong 2: NO; See MPEP § 2106.04(d)].
Step 2B (MPEP 2106.05.A i-vi)
According to analysis so far, the additional elements described above do not provide significantly more than the judicial exception. A determination of whether additional elements provide significantly more also rests on whether the additional elements or a combination of elements represents other than what is well-understood, routine, and conventional. Conventionality is a question of fact and may be evidenced as: a citation to an express statement in the specification or to a statement made by an applicant during prosecution that demonstrates a well-understood, routine or conventional nature of the additional element(s); a citation to one or more of the court decisions as discussed in MPEP 2106(d)(II) as noting the well-understood, routine, conventional nature of the additional element(s); a citation to a publication that demonstrates the well-understood, routine, conventional nature of the additional element(s); and/or a statement that the examiner is taking official notice with respect to the well-understood, routine, conventional nature of the additional element(s).
With respect to the instant claims, the courts have found that receiving and outputting data are well-understood, routine, and conventional functions of a computer when claimed in a merely generic manner or as insignificant extra-solution activity (see Symantec, 838 F.3d at 1321, 120 USPQ2d at 1362 (utilizing an intermediary computer to forward information), buySAFE, Inc. v. Google, Inc., 765 F.3d 1350, 1355, 112 USPQ2d 1093, 1096 (Fed. Cir. 2014) (computer receives and sends information over a network), Versata Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1334, 115 USPQ2d 1681, 1701 (Fed. Cir. 2015), and OIP Techs., 788 F.3d at 1363, 115 USPQ2d at 1092-93, as discussed in MPEP 2106.05(d)(II)(i)).
As such, the claims simply append well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception (MPEP2106.05(d)). The data gathering steps as recited in the instant claims constitute a general link to a technological environment which is insufficient to constitute an inventive concept which would render the claims significantly more than the judicial exception (MPEP2106.05(g)&(h)).
With respect to claims 33 and those claims dependent therefrom, the computer-related elements or the general purpose computer do not rise to the level of significantly more than the judicial exception. The claims state nothing more than a generic computer which performs the functions that constitute the judicial exceptions. Hence, these are mere instructions to apply the judicial exceptions using a computer, which the courts have found to not provide significantly more when recited in a claim with a judicial exception (see MPEP 2106.06(A)). The specification also notes that computer processors and systems, as example, are commercially available or widely used at [0046, 0066-0067, and 0079]. The additional elements are set forth at such a high level of generality that they can be met by a general purpose computer. Therefore, the computer components constitute 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 judicial exceptions (see MPEP 2106.05(b)I-III).
Taken alone, the additional elements do not amount to significantly more than the above-identified judicial exception(s). Even when viewed as a combination, the additional elements fail to transform the exception into a patent-eligible application of that exception. Thus, the claims as a whole do not amount to significantly more than the exception itself [Step 2B: NO; See MPEP § 2106.05].
Therefore, the instant claims are not drawn to eligible subject matter as they are directed to one or more judicial exceptions without significantly more. For additional guidance, applicant is directed generally to the MPEP § 2106.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-2, 6-12, 14-16, 19-22, 25, 27-28, and 33 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chen et al. (Chen, Hao, et al. "Allele-specific copy number estimation by whole exome sequencing." The annals of applied statistics 11.2 (2017), cited on IDS dated 07/23/2024).
Claims 1 and 33 are directed to a method for determining alleles of a gene of a subject comprising: under control of a hardware processor:
Chen proposes a bivariate binomial mixture model with site-specific background bias to estimate allele-specific copy number from whole exome sequencing data [p. 3, par. 2]. Chen further discloses the data input to our model consists of sequencing coverage for a tumor sample and its matched normal sample from the same patient which reads on a subject [p. 5, par. 2].
receiving a plurality of sequence reads generated from a sample obtained from a subject; aligning the plurality of sequence reads to a reference genome sequence to obtain a plurality of aligned sequence reads comprising sequence reads aligned to a gene in the reference genome sequence,
Chen discloses the data input to our model consists of sequencing coverage for a tumor sample and its matched normal sample from the same patient [p. 5, par. 2] together with the lllumina Genome Analyzer produces fixed length genome sequences, called reads, that cover the exon targets [p. 4, par. 3]. Chen further discloses these reads are mapped to a reference template, where the number of reads that cover a position is called the "coverage" at that position [p. 4, par. 3] which reads on reads for a tumor sample from a patient, which are mapped, i.e. aligned, to a reference template, i.e. a reference genome sequence . Since the input data is exome data, it is implied that the reads are aligned to a gene.
wherein the gene comprises a plurality of regions,
Chen discloses in Step 2, the matched normal sample is used to identify all of the heterozygous sites in the individual, using existing software [p. 5, par. 3]. Chen further discloses these heterozygous sites are the inherited heterozygous sites and are the basic units in our model [p. 5, par. 3] which reads on heterozygous sites as the basic units in the model of Chen, which are a plurality of regions.
wherein two copy number variants (CNVs) of a plurality of CNVs of the gene each comprises one or more regions of the plurality of regions and differ by at least one region of the plurality of regions;
Chen discloses the allele-specific copy number estimates from Falcon-X (top panel) and Falcon (bottom panel) under 35% tumor purity with signals spanning 200 inherited heterozygous sites [p. 22, fig. 4]. Chen further discloses the two colored lines represent the estimates of the two allele-specific copy numbers (Ca and Cb), and the two lines overlap when the two estimates are the same [p. 22, fig. 4]. Chen also discloses losses are shown in blue and gains are shown in red. Normal copy number is shown in green [p. 22, fig. 4]. Chen further discloses dotted black lines show the true allele-specific copy numbers in the spike-in set [p. 22, fig. 4] which reads on two copy number variants, i.e. two alleles with differing copy numbers, which comprise one or more regions, i.e. heterozygous sites and differ by at least one region (see e.g. the simultaneous loss in one allele and gain in the other allele in the top panel at a heterozygous loci index between 2500 and 3000).
determining a number of the sequence reads aligned to each region of the plurality of regions of the gene in the reference genome sequence;
Chen discloses a number of sequence reads aligned to each region, i.e. heterozygous site [p. 20, fig. 2 and p. 21, fig. 3].
determining a number of copies of each region of the plurality of regions based on the number of the sequence reads aligned to the region; and
Chen discloses in Step 5, the allele-specific coverage at these heterozygous positions in the tumor and the normal control, along with the total coverage bias estimates from CODEX, are taken as input to the Falcon-X model to estimate the allele-specific copy number at these heterozygous positions [p. 5, par. 3] which reads on determining coverage, i.e. number of aligned sequences reads, and copy numbers ate heterozygous positions, i.e. of each region.
determining two alleles of the gene of the subject, each comprising one or more regions of the plurality of regions, based on the number of copies of each region of the plurality of regions and all CNVs of the plurality of CNVs comprising the region.
Chen discloses two alleles determined by their respective copy numbers [p. 22, fig. 4]. Since the underlying data set is a whole exome sequencing data set, each data point in Figure 4 maps to a gene.
Claims 2, 6-12, 14, and 21-22 are directed to the genetic structure of the sample to be probed in terms of numbers and structure of copy number variants involved. They are obvious variants of input data or as the intended result.
Claim 15 is directed to the method of claim 1, wherein the number of the sequence reads aligned to each region of the plurality of regions of the gene comprises a raw number or a normalized and/or GC-corrected number of the sequence reads aligned to each region of the plurality of regions of the gene.
Chen discloses in Step 5, the allele-specific coverage at these heterozygous positions in the tumor and the normal control, along with the total coverage bias estimates from CODEX, are taken as input to the Falcon-X model to estimate the allele-specific copy number at these heterozygous positions [p. 5, par. 3 and p. 20, fig. 2].
Claim 16 is directed to the method of claim 1, wherein determining the number of copies of each region of the plurality of regions comprises: determining the number of copies of each region of the plurality of regions using the number of the sequence reads aligned to the region based on a normalized and/or GC-corrected number of the sequence reads aligned to each region of the plurality of regions of the gene in the reference genome sequence.
Chen discloses in Step 5, the allele-specific coverage at these heterozygous positions in the tumor and the normal control, along with the total coverage bias estimates from CODEX, are taken as input to the Falcon-X model to estimate the allele-specific copy number at these heterozygous positions [p. 5, par. 3 and p. 20, fig. 2].
Claim 19 is directed to the method of claim l wherein the number of copies of each region comprises the number of copies of each region relative to a reference number of copies of the region, optionally wherein the reference number of copies of the region is 2.
Chen discloses detect copy number variation because coverage of any given region reflects the relative quantity of the DNA from that region in the sample [p. 4, par. 4].
Claim 20 is directed to the method of claim 1,wherein determining the number of copies of each region of the plurality of regions comprises: determining a difference in the number of copies of each region of the plurality of regions, relative to a reference number of copies of the region, based on the number of the sequence reads aligned to the region, and wherein determining the two alleles of the gene of the subject comprises: determining the two alleles of the gene of the subject using the difference in the number of copies of each region of the plurality of regions, relative to the reference number of copies of the region, and all CNVs of the plurality of CNVs comprising the region.
Chen discloses detect copy number variation because coverage of any given region reflects the relative quantity of the DNA from that region in the sample [p. 4, par. 4]. Chen further discloses sequenced reads are aligned to the reference template, resulting in bam then, the matched normal sample is used to identify all of the heterozygous sites in the individual, using existing software such as GATK, then these heterozygous sites are the inherited heterozygous sites and are the basic units in our model, followed by the total and allele-specific coverage at these sites are extracted from the tumor sample as well as all of the samples in the normal control cohort, next the matrix of total coverage at the union of all germline heterozygous loci across all samples is used by CODEX to estimate the background total coverage bias for the tumor and matched normal sample, finally the allele-specific coverage at these heterozygous positions in the tumor and the normal control, along with the total coverage bias estimates from CODEX, are taken as input to the Falcon-X model to estimate the allele-specific copy number at these heterozygous positions [p. 5, par. 3 and p. 20, fig. 2].
Claim 25 is directed to the method of claim l, wherein determining the two alleles of the gene of the subject comprises: determining (i) a number of copies a first CNV in a first allele of the two alleles of the gene of the subject and (ii) a number of copies of a second CNV in a second allele of the two alleles of the gene of the subject such that (a) the number of copies of a region of the plurality of regions in the first CNV and not the second CNV is the number of copies of the first CNV, (b) the number of copies of a region of the plurality of regions in the first CNV and the second CNV is the sum of the number of copies of the first CNV and the number of copies of the second CNV, and/or (c) the number of copies of a region of the plurality of regions in the second CNV and not the first CNV is the number of copies of the second CNV.
Chen discloses overview of the proposed analysis steps for estimating allele-specific copy number from whole exome sequencing of tumor and matched normal samples*CODEX is applied to the union of heterozygous sites across all samples using the tumor-normal option [p. 20, fig. 4] which reads on the determination of two alleles with limitations a-c.
Claim 27 is directed to the method of claim l, further comprising: receiving the plurality of CNVs; and determining the plurality of regions using the plurality of CNVs, optionally wherein receiving the plurality of CNVs comprises determining the plurality of CNVs.
Chen discloses the Falcon-X results clearly indicate that there are genome regions that are more frequently altered than others [p. 14, par. 3].
Claim 28 is directed to the method of claim l, further comprising: creating a file or a report and/or generating a user interface (UI) comprising a UI element representing or comprising alleles of the gene of the subject and/or the one or more regions of the plurality of regions in each of the two alleles.
Chen discloses a graphical estimation of the allele-specific copy number estimates from Falcon-X [p. 22, fig. 4] which reads on a report.
Conclusion
No claims are allowed.
Inquiries
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Dawn M. Bickham whose telephone number is (703)756-1817. The examiner can normally be reached M-Th 7:30 - 4:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Olivia Wise can be reached at 571-272-2249. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/D.M.B./Examiner, Art Unit 1685
/Soren Harward/Primary Examiner, TC 1600
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