DETAILED ACTION
Applicant’s response, filed 11/18/2025, has been fully considered. Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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.
Restriction/Election
Applicant’s election without traverse of Group I (claims 21-22, 39, 72-73, and 94) in the reply filed on 03/20/2025 is acknowledged. Claims 16-17 and 19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claim Status
Claims 73, 94, and 99-120 are pending.
Claims 16-17 and 19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species, as described above.
Claims 1-72 and 74-93, and 95-98 are canceled.
Claims 99-120 are newly added.
Claims 73, 94, and 99-120 are rejected.
Priority
The instant Application claims domestic benefit to US provisional application 62/825499, filed 03/28/2019.
Applicant's claim for the benefit of a prior-filed application, PCT/US2020/025528, filed 03/27/2020, is acknowledged.
Accordingly, each of claims 1-4, 6-9, 12-13, 19, 21-22, 25-27, 30, 33-36, 38-39, 72-73, and 94 are afforded the effective filing date of 03/28/2019.
Drawings
The Drawings submitted 09/24/2021 are accepted.
Specification
The outstanding objections to the specification are withdrawn in view of the amendments submitted herein.
Claim Objections
The outstanding objections to the claims are withdrawn in view of the amendments submitted herein.
Claim Rejections- 35 USC § 112
The outstanding rejections to the claims are withdrawn in view of the cancelation of the claims submitted herein.
35 U.S.C. 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 105-110 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
The instant rejection is newly stated and is necessitated by claim amendment.
Claim 105, limitation, recites “wherein pixels within 10-300 kbp of a cis-chromosome diagonal of the 2D image from the subject are excluded”. It is unclear what the pixels are excluded from, therefore making the claim indefinite. Please amend to specify what the pixels would be excluded from. Claim(s) 106-110 is/are rejected for the same reason because they depend from claim 1, and does not resolve the indefiniteness issue in those claims.
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.
For the following rejections, underlined text indicates newly recited portions necessitated by claim amendment.
Claims 73, 94, and 99-120 are rejected under 35 U.S.C. 101 because the claimed invention is directed to one or more judicial exceptions without significantly more. Any newly recited portions are necessitated by claim amendment.
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 methods, i.e., a process, machine, or manufacture within the above 101 categories [Step 1: YES; See MPEP § 2106.03].
Step 2A, Prong One
With respect to Step 2A, Prong One, the claims recite judicial exceptions in the form of abstract ideas. The MPEP at 2106.04(a)(2) further explains that abstract ideas are defined as:
mathematical concepts (mathematical formulas or equations, mathematical relationships and mathematical calculations);
certain methods of organizing human activity (fundamental economic practices or principles, managing personal behavior or relationships or interactions between people); and/or
mental processes (procedures for observing, evaluating, analyzing/ judging and organizing information).
With respect to the instant claims, under the Step 2A, Prong One evaluation, the claims are found to recite abstract ideas that fall into the grouping of mental processes (in particular procedures for observing, analyzing and organizing information) and mathematical concepts (in particular mathematical relationships and formulas) are as follows:
Independent claims 73 and 94:
representing the contact matrix as a two-dimensional (2D) image, wherein an intensity of each pixel in the 2D image represents a density of links between two genomic locations in the contact matrix;
applying an edge and/or corner detection algorithm to the 2D image; to detect chromosomal structural variants in the subject.
Dependent claim 101:
applying a global normalization to the 2D image;
applying a first threshold to the normalized 2D image;
identifying sub regions of the normalized 2D image corresponding to chromosome comparisons;
applying a second threshold to each sub region; and de-noising each sub region
applying at least one filter to remove false positives;
determining the genomic locations of all chromosomal structural variants in the 2D image.
Dependent claim 102:
applying the edge and/or corner detecting algorithm to each sub region
Dependent claim 103:
fitting a matrix of weights to the 2D image.
Dependent claim 105:
generating a contact matrix from a healthy sample;
representing the contact matrix from the healthy subject as a 2D image from a healthy subject;
subtracting the 2D image from the healthy subject from the 2D image from the subject, wherein pixels within 10-300 kbp of a cis-chromosome diagonal of the 2D image from the subject are excluded.
Dependent claim 109:
minimizes a sum of each row and each column of pixels of the 2D image from the subject.
Dependent claim 110:
calculating a balanced interaction density for each pixel by normalizing and correcting an interaction density for one or more of sequencing coverage, sequence features such as restriction enzyme or other motifs, abundance, background signal, noise, or variation.
Dependent claims 99-100, 104, 106-108, and 111-120 recite further steps that limit the judicial exceptions in independent claim 73 and, as such, also are directed to those abstract ideas. For example, claims 99 and 100 further limits the pixel of claim 73, claim 104 further limits the cell of claim 103, claim 106 further limits the contact matrix of claim 105, claim 107 further limits the healthy tissue of claim 105, claim 108 further limits the contact matrix of claim 105, claim 111 further limits the first threshold of claim 105, claim 112 further limits the threshold of claim 111, claim 113 further limits the algorithm of claim 73, claim 114 further limits the at least one filter of claim 101, claim 115 further limits the chromosomal structure variants of claim 73, claim 116 further limits the disease of claim 73, claim 117 further limits the chromosome conformation analysis of claim 73, claim 118 further limits subject of claim 73, claim 119 further limits the sample of claim 118, and claim 120 further limits the tumor of claim 119.
The abstract ideas recited in the claims are evaluated under the Broadest Reasonable Interpretation (BRI) and determined to each cover performance either in the mind and/or by mathematical operation because the method only requires a user to manually filter, represent a 2D image, normalize, identify, determining, fitting, subtracting and minimizing . Without further detail as to the methodology involved in “representing the contact matrix as a two-dimensional (2D) image”, “applying an edge and/or corner detection algorithm”, “applying a global normalization”, “identifying sub regions”, “applying a second threshold”, “applying at least one filter”, “determining the genomic locations”, “fitting a matrix of weights”, “generating a contact matrix”, “representing the contact matrix from the healthy subject as a 2D image”, under the BRI, one may simply, for example, use pen and paper to produce a karyotype.
Therefore, claim 73, 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 73:
receiving a contact matrix, wherein the contact matrix is produced by a chromosome conformation analysis technique applied to a sample from the subject
The claims also include non-abstract computing elements. For example, independent claim 94 includes a non-transitory computer readable storage media and processor.
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”, 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 computer readable storage media, processor” 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)).
With respect to the limitations of known chromosomal structural variants are generated by a chromosome conformation analysis technique is well-understood, routine, and conventional in the art. The claims discloses the chromatin conformation capture (3C), circularized chromatin conformation capture (4C), carbon copy chromosome conformation capture (5C), chromatin immunoprecipitation (ChIP), ChIP-Loop, Hi-C, combined 3C-ChIP-cloning (6C), Capture-C, Split-pool barcoding (SPLiT-seq), Nuclear Ligation Assay (NLA), Single-cell Hi-C (scHi-C), Combinatorial Single-cell Hi-C, Concatamer Ligation Assay (COLA), Cleavage Under Targets and Release Using Nuclease (CUT& RUN), in vitro proximity ligation (Chicago®), in situ proximity ligation (in situ Hi-C), proximity ligation followed by sequencing on an Oxford Nanopore machine (Pore-C), proximity ligation sequenced on a Pacific Biosciences machine (SMRT-C), DNase Hi-C, Micro-C or Hybrid Capture Hi-C. The process of performing an chromosome conformation analysis is well known and may be performed using 3C, 4-C, and 5-C Hi-C, (Sati, Satish, and Giacomo Cavalli. "Chromosome conformation capture technologies and their impact in understanding genome function." Chromosoma 126 (2017)).
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 claim 94 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 [125-128]. 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).
With respect to chromosome conformation analysis technique, the additional elements of the claims do not integrate the judicial exceptions into a practical application for the following reasons. Those steps directed to chromosome conformation analysis techniques do not impose any meaningful limitations on the abstract idea, or on how the abstract idea is performed. These steps are insignificant extra-solution activity to the judicial exception (MPEP 2106.05(g)(2))
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.
Response to Applicant Arguments
Applicant submits the claimed method does not merely recite the abstract idea of using mathematical concepts for representing a contact matrix as a 2D image [p. 15, par. 1].
It is respectfully found not persuasive. The process of taking numbers and putting them into a contact matrix is a mental activity and therefore a judicial exception.
Applicant submits the application of edge and/or corner detection algorithms to a 2D-image based representation of a contact matrix in order to detect chromosomal structural variants is an improvement that integrates the contact matrix representation into a practical application.
It is respectfully found not persuasive. There are no additional elements in claim 73 to integrate into a practical application. Claim 94 has the use of conventional elements such as processor and non-transitory media. It is important to keep in mind that an improvement in the abstract idea itself (e.g. a recited fundamental economic concept) is not an improvement in technology. Furthermore, it is important to note, the judicial exception alone cannot provide the improvement. The improvement can be provided by one or more additional elements or by the additional element(s) in combination with the recited judicial exception. See MPEP 2106.05(a).
Claim Rejections - 35 USC § 102
The outstanding rejections to the claims are withdrawn in view of the amendments and cancelation of the claims submitted herein.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
For the following rejections, instantly claimed elements which are considered to be equivalent to the prior art teachings are described in bold for all claims, and underlined text indicates newly recited portions necessitated by claim amendment.
A. Claims 73, 94, 99, 101-104, 110-112, and 114-120 are rejected under 35 U.S.C. 103 as being unpatentable over Harewood et al. (Harewood, Louise, et al. "Hi-C as a tool for precise detection and characterization of chromosomal rearrangements and copy number variation in human tumours." Genome biology 18 (2017), cited on IDS dated 07/25/2023) in view of Saiyod et al. (Saiyod, Saiyan, and Pichet Wayalun. "A new technique for edge detection of chromosome g-band images for segmentation." Advanced Approaches to Intelligent Information and Database Systems. Cham: Springer International Publishing, 2014. 315-323, newly cited).
The instant rejection is newly stated and is necessitated by claim amendment.
Claim 73 is directed to a method of identifying chromosomal structural variants in a subject comprising: a) receiving a contact matrix, wherein the contact matrix is produced by a chromosome conformation analysis technique applied to a sample from the subject;
Harewood discloses to detect chromosomal rearrangements and determine accuracy of breakpoint identification they performed in-nucleus Hi-C on two human lymphoblastoid cell lines with known chromosomal translocations [p. 2, col. 1, par. 2]. Harewood further discloses Hi-C interrogates spatial proximity within the nucleus by analyzing contacts between genomic regions [p. 2, col. 1, par. 2].
(b) representing the contact matrix as a two-dimensional (2D) image, wherein an intensity of each pixel in the 2D image represents a density of links between two genomic locations in the contact matrix; and
Harewood discloses a heatmap and partial heatmap of tumor GB180 showing a balanced translocation between chromosomes 3 and 13 [p. 4, fig. 2]. Harewood further discloses heatmaps were colored by the number of interactions with the color gradient scaled linearly from ten (blue) to 50 (red) [p. 4, fig. 2]. Harewood also discloses bins containing less than ten interactions are not represented. Harewood further discloses the small red arrows indicate amplified regions [p. 4, fig. 2]. Harewood also discloses determine whether they could confirm the presence of rearrangements using an approach other than visual inspection of the number of interactions on a Hi-C heatmap, generated linkage density plots for the Hi-C data [p. 5, col. 2, par. 2 and fig. 4]. The contact matrix is represented as an image.
(c) applying an edge and/or corner detection algorithm to the 2D image; thereby detecting to detect chromosomal structural variants in the subject.
Harewood discloses that Hi-C can detect novel chromosomal rearrangements in cell lines [p. 2, col. 2, par. 2] but is silent on an edge and/or corner detection algorithm.
However, Saiyod discloses a new technique for edge detection of chromosome g-band images for segmentation [title]. Saiyod further discloses the chromosome image flowchart showing a threshold preprocessing, edge detection, and segmentation [p. 319, fig. 5] which reads on an edge detection algorithm. Saiyod also discloses that it also was observed that on incorporating using the flood-fill and erosion further results in improved performance [p.322, par. 2] which implies that the method can be used without the flood-fill and erosion portions. Saiyod further discloses comparing the proposed method to the algorithm Sobel which is listed as an example in the specification [167].
Claim 94 is directed to a system of claim 73.
Harewood discloses the use of code that requires a system to use [p. 10, par. 4].
Claim 99 is directed to the method of claim 73, wherein each pixel represents 5-500 kilobase pairs (kbp) of a genome of the subject.
Harewood discloses Hi-C interaction heatmap generated using 500 kb probe size [p. 6, col. 2, fig. 4].
Claim 101 is directed to the method of claim 73, further comprising, prior to step (c):applying a global normalization to the 2D image; applying a first threshold to the normalized 2D image;
Harewood discloses each bin of interaction matrix was normalized by the number of HindIII restriction sites in each bin and plotted to generate linkage density plots [p. 9, col. 2, par. 5]. Harewood further discloses for the six tumor samples, two different thresholds of exclusion were applied to the data – namely the 99.9th and 99.5th percentiles [p. 7, col. 1, par. 3].
identifying sub regions of the normalized 2D image corresponding to chromosome comparisons;
Harewood discloses two different thresholds of exclusion were applied to the data – namely the 99.9th and 99.5th percentiles – with all values above these being excluded from correlation analyses [p. 7, col. 1, par. 3] which reads on a sub region or chromosome comparison after each application of the threshold.
applying a second threshold to each sub region; and
Harewood discloses two different thresholds of exclusion were applied to the data – namely the 99.9th and 99.5th percentiles – with all values above these being excluded from correlation analyses [p. 7, col. 1, par. 3] which reads on a sub region or chromosome comparison after each application of the threshold.
de-noising each sub region, and
Harewood discloses once the heatmap was generated, the Min Absolute count was increased to ten to reduce background noise on the heatmaps and to enrich for interaction blocks over single interactions [p. 9, col. 1, par. 2].
after step (c):applying at least one filter to remove false positives; and
Harewood is silent on applying at least one filter to remove false positives.
However, Saiyod discloses Non-Maximum suppression is scanned along the image gradient direction [p. 318, par. 3] which is one of the listed examples of the least one filter to remove false positives in the specification [167].
determining the genomic locations of all chromosomal structural variants in the 2D image.
Harewood discloses Hi-C as a tool for precise detection and characterization of chromosomal rearrangements and copy number variation in human tumors [title]. As Hi-C data is fundamentally about genomic location as it provides precise spatial coordinated for DNA segments it is obvious that is would include the genomic locations or all variants in the 2D image.
Claim 102 is directed to the method of claim 101, wherein applying the edge and/or corner detection algorithm comprises applying the edge and/or corner detecting algorithm to each sub region.
Harewood discloses two different thresholds of exclusion were applied to the data – namely the 99.9th and 99.5th percentiles – with all values above these being excluded from correlation analyses [p. 7, col. 1, par. 3] which reads on a sub region or chromosome comparison after each application of the threshold. Harewood is silent on applying the egde algorithm to each sub region.
Saiyod further discloses the chromosome image flowchart showing a threshold preprocessing, edge detection, and segmentation [p. 319, fig. 5] which reads on an edge detection algorithm. Saiyod also discloses that it also was observed that on incorporating using the flood-fill and erosion further results in improved performance [p.322, par. 2] which implies that the method can be used without the flood-fill and erosion portions. Saiyod further discloses comparing the proposed method to the algorithm Sobel which is listed as an example in the specification [167].
Claim 103 is directed to the method of claim 101, wherein the global normalization comprises fitting a matrix of weights to the 2D image.
Harewood is silent on fitting a matric of weights.
However, Saiyod discloses the use of Canny operator that includes a 2-D Gaussian function (kernel) as a filter [p. 318, par. 3].
Claim 104 is directed to the method of claim 103, wherein each cell in the matrix of weights corresponds to a pixel in the 2D image.
Harewood is silent on each cell in the matrix of weights corresponds to a pixel in the 2D image.
However, Saiyod discloses the use of Canny operator that includes a 2-D Gaussian function (kernel) as a filter [p. 318, par. 3]. The Canny operator also has a convolute function that corresponds to a neighboring pixel relative to the center pixel being processed [p. 319, par. 1].
Claim 110 is directed to the method of claim 105, further comprising calculating a balanced interaction density for each pixel by normalizing and correcting an interaction density for one or more of sequencing coverage, sequence features such as restriction enzyme or other motifs, abundance, background signal, noise, or variation.
Harewood discloses the output of QDNAseq is read counts per bin, which have been corrected, filtered, normalized and log2-transformed [p. 7, col. 1, par. 1].
Claim 111 is directed to the method of claim 101, wherein the first threshold is applied over the entirety of the 2D image.
Harewood discloses each bin of interaction matrix was normalized by the number of HindIII restriction sites in each bin and plotted to generate linkage density plots [p. 9, col. 2, par. 5]. Harewood further discloses for the six tumor samples, two different thresholds of exclusion were applied to the data – namely the 99.9th and 99.5th percentiles [p. 7, col. 1, par. 3].
Claim 112 is directed to the method of claim 111, wherein the threshold applied over the entirety of the 2D image is based on the balanced density interaction for each pixel.
Harewood discloses the output of QDNAseq is read counts per bin, which have been corrected, filtered, normalized and log2-transformed [p. 7, col. 1, par. 1]. Harewood discloses each bin of interaction matrix was normalized by the number of HindIII restriction sites in each bin and plotted to generate linkage density plots [p. 9, col. 2, par. 5]. Harewood further discloses for the six tumor samples, two different thresholds of exclusion were applied to the data – namely the 99.9th and 99.5th percentiles [p. 7, col. 1, par. 3].
Claim 114 is directed to the method of claim 101, wherein the at least one filter to remove false positives comprises a Diagonal Path Finder, non-maximum suppression filter, Neighbor threshold or a combination thereof.
Harewood is silent on applying at least one filter to remove false positives.
However, Saiyod discloses Non-Maximum suppression is scanned along the image gradient direction [p. 318, par. 3] which is one of the listed examples of the least one filter to remove false positives in the specification [167].
Claim 115 is directed to the method of claim 73, wherein the chromosomal structural variants include a balanced translocation, an unbalanced translocation, an inversion, an insertion, a deletion, a repeat expansion or a combination thereof.
Harewood discloses the use of Hi-C as a tool for detection of both balanced and unbalanced chromosomal rearrangements in primary human tumor samples [abstract].
Claim 116 is directed to the method of claim 73, wherein the subject has a disease or disorder caused by at least one of the chromosomal structural variants.
Harewood discloses the use of Hi-C as a tool for detection of both balanced and unbalanced chromosomal rearrangements in primary human tumor samples [abstract].
Claim 117 is directed to the method of claim 73, wherein the chromosome conformation analysis technique chromatin conformation capture (3 C), circularized chromatin conformation capture, carbon copy chromosome conformation capture, chromatin immunoprecipitation (ChIP), ChIP- Loop, Hi-C, combined 3C-ChIP-cloning, Capture-C, Split-pool barcoding, Nuclear Ligation Assay, Single-cell Hi-C, Combinatorial Single-cell Hi-C, Concatamer Ligation Assay, Cleavage Under Targets and Release Using Nuclease, in vitro proximity ligation, in situ proximity ligation (in situ Hi-C), DNase Hi-C, Micro-C or Hybrid Capture Hi-C.
Harewood discloses the use of Hi-C as a tool for detection of both balanced and unbalanced chromosomal rearrangements in primary human tumor samples [abstract].
Claim 118 is directed to the method of claim 73, wherein the subject has cancer.
Harewood discloses the potential of Hi-C as a method to detect and characterize unknown chromosomal rearrangements in clinical material, we performed Hi-C on six human brain tumors: five glioblastomas (GB) and one anaplastic astrocytoma (AA) [p. 2, col. 2, par. 3].
Claim 119 is directed to the method of claim 118, wherein the sample from the subject is from a tumor associated with the cancer.
Harewood discloses the potential of Hi-C as a method to detect and characterize unknown chromosomal rearrangements in clinical material, we performed Hi-C on six human brain tumors: five glioblastomas (GB) and one anaplastic astrocytoma (AA) [p. 2, col. 2, par. 3].
Claim 120 is directed to the method of claim 119, wherein the tumor is a solid tumor or a liquid tumor.
Harewood discloses the potential of Hi-C as a method to detect and characterize unknown chromosomal rearrangements in clinical material, we performed Hi-C on six human brain tumors: five glioblastomas (GB) and one anaplastic astrocytoma (AA) as fresh frozen tissue with between 75% and 90% tumor content [p. 2, col. 2, par. 3].
In regards to claim(s) 73, 94, 99, 101-104, 110-112, and 114-120, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine, Harewood with Saiyod as they both are directed to chromosome rearrangement and karyotyping. The motivation would have been to combine the Hi-C data output of Harewood and to process it with the edge detection algorithm of Saiyod to develop an algorithm to computationally detect these rearrangements as disclosed by Harewood [p. 6, col. 1, par. 1], a finding that one of ordinary skill in the art would have recognized that the results of the combination were predictable.
B. Claim 100 are rejected under 35 U.S.C. 103 as being unpatentable over Harewood in view of Saiyod, as applied to claims 73, 94, and 99 as above, and in further view of Zhao et al. (US 2018/0282801 A1, published on 10/04/2018, cited on IDS dated 03/20/2025).
Claim 100 is directed to the method of claim 73, wherein each pixel represents 40 kbp of a genome of the subject.
Harewood discloses Hi-C interaction heatmap generated using 500 kb probe size [p. 6, col. 2, fig. 4] and for six tumor samples a bin size of 100(kb) [p. 7, col.1, par. 3]. Harewood and Saiyod are silent on 40 kbp.
However, Zhao discloses a portion is based on a particular length of genomic sequence that can be about 40 kb in length [0159].
Claim 105 is directed to the method of claim 103, wherein fitting the matrix of weights comprises generating a contact matrix from a healthy sample; representing the contact matrix from the healthy subject as a 2D image from a healthy subject; and subtracting the 2D image from the healthy subject from the 2D image from the subject, wherein pixels within 10-300 kbp of a cis-chromosome diagonal of the 2D image from the subject are excluded.
Harewood discloses in order to exclude any regions that showed consistent large changes between the two sets of results, the difference between Hi-C and sWGS output values was determined for each bin and the total difference (i.e. the sum of the differences for all six tumours) calculated [p. 7, col. 1, par. 3]. Harewood is silent on wherein pixels within 10-300 kbp of a cis-chromosome diagonal of the 2D image from the subject are excluded, but does disclose two different thresholds of exclusion were applied to the data – namely the 99.9th and 99.5th percentiles – with all values above these being excluded from correlation analyses [p. 7, col. 1, par. 3] which reads on excluding certain regions that show consistent large changes between the two sets. Harewood and Saiyod are silent on a healthy subject.
However, Zhao discloses the discrimination of tumor and normal patient DNA can be performed using the compositions and processes of the present technology alone or in combination with other discriminating factors[0065].
Claim 106 is directed to the method of claim 105, wherein the contact matrix from the healthy sample is generated using a simulated set of reads, a theoretical set of reads or a set of reads experimentally determined from a healthy tissue.
Harewood discloses partial heatmaps for chromosomes 11 and 22 generated from two sets of Hi-C data performed on human cell lines from an Emanuel syndrome patient and balanced translocation carrier [p. 3, fig. 1] which reads on a simulated set of reads. Harewood is silent on healthy sample
However, Zhao discloses the discrimination of tumor and normal patient DNA can be performed using the compositions and processes of the present technology alone or in combination with other discriminating factors[0065].
Claim 107 is directed to the method of claim 105, wherein the healthy tissue comprises tissue from the subject that does not have a disease or disorder.
Harewood is silent on healthy sample
However, Zhao discloses the discrimination of tumor and normal patient DNA can be performed using the compositions and processes of the present technology alone or in combination with other discriminating factors[0065]. Zhao further discloses the term "normal" refers to the predominate karyotype or banding pattern found in healthy individuals of a particular species [0404].
Claim 108 is directed to the method of claim 105, wherein the contact matrix from the healthy sample comprises a reference matrix.
Harewood is silent on healthy sample
However, Zhao discloses the discrimination of tumor and normal patient DNA can be performed using the compositions and processes of the present technology alone or in combination with other discriminating factors[0065]. Zhao further discloses the term "normal" refers to the predominate karyotype or banding pattern found in healthy individuals of a particular species [0404]. Zhao also discloses sequence reads, counts, levels, and profiles derived from a test subject ( e.g., a patient, a pregnant female) and/or from a reference subject can be further analyzed and processed to determine the presence or absence of a copy number variation [0356]. Zhao further discloses data or data sets can be organized into a matrix having two or more dimensions based on one or more features or variables [0356].
Claim 109 is directed to the method of claim 105, wherein subtracting the 2D image from the healthy subject from the 2D image from the subject minimizes a sum of each row and each column of pixels of the 2D image from the subject.
Harewood discloses in order to exclude any regions that showed consistent large changes between the two sets of results, the difference between Hi-C and sWGS output values was determined for each bin and the total difference (i.e. the sum of the differences for all six tumours) calculated [p. 7, col. 1, par. 3].
Claim 110 is directed to the method of claim 105, further comprising calculating a balanced interaction density for each pixel by normalizing and correcting an interaction density for one or more of sequencing coverage, sequence features such as restriction enzyme or other motifs, abundance, background signal, noise, or variation.
Harewood discloses the output of QDNAseq is read counts per bin, which have been corrected, filtered, normalized and log2-transformed [p. 7, col. 1, par. 1].
In regards to claim(s) 100 and 105-109, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine, Harewood and Saiyod with Zhao as they all are directed to chromosome rearrangement and karyotyping. The motivation would have been to include the 40kbp parameter of Zhao to the bin sizes of Harewood as Zhao discloses the use of 10-60 kb bin sizes as a design choice [p. 6, col. 1, par. 1], a finding that the substituted components and their functions were known in the art. It would also be obvious to substitute one of the contact matrixes from Harewood with the reference matrix of Saiyod as a design choice [p. 6, col. 1, par. 1], a finding that the substituted components and their functions were known in the art.
C. Claim 113 are rejected under 35 U.S.C. 103 as being unpatentable over Harewood in view of Saiyod, as applied to claims 73, 94, and 99 as above, and in further view of Dharampal et al. (Dharampal, Vikram Mutneja. "Methods of image edge detection: A review." J. Electr. Electron. Syst 4.2 (2015): 2332-0796, newly cited).
Claim 113 is directed to the method of claim 73, wherein the edge and/or corner detection algorithm comprises a Harris corner method, a Roberts cross method, a Hough transform or a combination thereof.
Harewood is silent on an edge and/or corner detection algorithm.
However, Saiyod discloses a new technique for edge detection of chromosome g-band images for segmentation [title]. Saiyod further discloses the chromosome image flowchart showing a threshold preprocessing, edge detection, and segmentation [p. 319, fig. 5] which reads on an edge detection algorithm. Saiyod also discloses that it also was observed that on incorporating using the flood-fill and erosion further results in improved performance [p.322, par. 2] which implies that the method can be used without the flood-fill and erosion portions. Saiyod further discloses comparing the proposed method to the algorithm Sobel which is listed as an example in the specification [167]. Saiyod is silent on the edge and/or corner detection algorithm comprises a Harris corner method, a Roberts cross method, a Hough transform or a combination.
However, Dharampal discloses methods of image edge detection: a review [title]. Dharampal further discloses this paper introduces the standard edge detection methods which are widely used in image processing such as Prewitt, Laplacian of Gaussian, Canny, Sobel, Robert [abstract].
In regards to claim(s) 113, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine, Harewood and Saiyod with Dharampal as Saiyod and Dharampal are directed to edge detection algorithms. The motivation would have been to substitute the Canny edge detection algorithm of Saiyod with the alternate edge detection algorithms of Dharampal including Sobel, Canny, and Robert as a design choice [p. 6, col. 1, par. 1], a finding that the substituted components and their functions were known in the art.
Conclusion
No claims are allowed.
The new grounds of rejection in this action were necessitated by Applicant’s amendments. Accordingly, THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/D.M.B./Examiner, Art Unit 1685 /Soren Harward/Primary Examiner, TC 1600