DETAILED ACTION
Applicant’s response, filed Mar 12 2026, 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 Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn.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.
Claim Status
Claims 1, 3, 6-7, 9-11, 14-15, 17-25, 33, and 39-42 are pending.
Claims 10-11 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species, as set forth in the Non-Final Office Action dated Sep 7 2023.
Claims 2, 4-5, 8, 12-13, 16, 26-32, and 34-38 are canceled.
Claims 22 and 24 are objected to.
Claims 1, 3, 6-7, 9, 14-15, 17-25, 33, and 39-42 are rejected.
Priority
The instant Application claims domestic benefit to US provisional application 62/398,354, filed Sep 22 2016, and 62/447,065, filed Jan 17 2017.
Applicant's claim for the benefit of a prior-filed application, PCT/US2017/052766, filed Sep 21 2017, is acknowledged.
However, the priority applications do not provide support for the limitations in claim 1 of “wherein said sequencing request comprises analyzing multiple different samples simultaneously in the same sequencing run, thereby reducing sequencing depth of coverage per sample” claim 24 of “wherein acquiring the sequencing data comprises analyzing multiple different samples simultaneously in the same sequencing run, thereby reducing sequencing depth of coverage per sample”.
Accordingly, each of claims 1, 3, 6-7, 9, 14-15, 17-25, 33, and 39-42 are afforded the effective filing date of Mar 15 2019.
Information Disclosure Statement
The information disclosure statement (IDS) filed on Feb 17 2026 is in compliance with the provisions of 37 CFR 1.97 and has therefore been considered. A signed copy of the IDS document is included with this Office Action.
Claim Objections
The outstanding objections to the claims are withdrawn in view of the amendments submitted herein.
The claims are objected to because of the following informalities. The instant objection is newly stated and is necessitated by claim amendment.
Claim 22 recites “wherein the new sequencing data was acquired using an exome sequencing panel”. As claim 1, from which claim 22 depends, has been amended to include an active step of “sequencing the new biological sample”, claim 22 should be amended to include similar language, such as “wherein sequencing the new biological sample comprises using an exome sequencing panel”.
The three ”wherein” limitations in claim 24, first limitation, which appear after the semicolon should be on new lines, and the “and” separating the first two “wherein” limitations should be removed.
The ninth limitation in claim 24 should be indented less because it is assumed to be a substep of “normalizing the sequencing data” and not a substep of “wherein the plurality of baseline median sequencing read counts”.
Claim Interpretation
In claim 7, the terms “low median” and “large median sequence coverage absolute deviation” are interpreted in light of the specification to provide enough certainty to one of skill in the art when read in the context of the invention to be definite (see MPEP 2173.05(b)). The specification provides examples of a low median (0.25) and large median sequence coverage absolute deviation (CV of 0.2) at [0063] that can be used to measure a degree even without a precise numerical measurement.
Claim Rejections- 35 USC § 112
Unless otherwise indicated, the outstanding 35 USC 112(a) and (b) rejections to the claims are withdrawn in view of the amendments submitted herein.
35 USC § 112(a)
Claims 1, 3, 6-7, 9, 14-15, 17-25, 33, and 39-42 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. The rejection is newly stated and is based on claim amendment.
Claim 1, second limitation, recites “wherein said sequencing request comprises analyzing multiple different samples simultaneously in the same sequencing run, thereby reducing sequencing depth of coverage per sample”. Claim 24, first limitation, recites “wherein acquiring the sequencing data comprises analyzing multiple different samples simultaneously in the same sequencing run, thereby reducing sequencing depth of coverage per sample”.
Applicant points to [0056] of the specification as originally filed for support of the amendments. However, [0056] discusses only general sequencing technologies.
The specification as published discloses that the request includes a selected pre-existing sequencing panel and/or a customized sequencing panel based on desired regions of interest in the genomic DNA of the sample, and may include customer information, biological sample organism information, biological sample type information (e.g. information identifying whether the sample is fresh, frozen, or preserved), tissue type, desired sequencing assay type, nucleic acids sequences for desired probes of a sequencing panel and/or nucleic acid sequences of regions of interest in a genome that may be used by the provider to design and/or generate probes for a targeted sequencing panel [0048]. The specification as published generally discloses “a targeted sequencing run” at [0006; 0043; 0083]. The specification as published discusses sequencing depth as a source of bias that can affect sample to sample variation (TABLE 1; [0055]).
However, there is not support within the specification, nor has Applicant provided such support, for either a sequencing request for or a general discussing of analyzing multiple different samples simultaneously in the same sequencing run, thereby reducing sequencing depth of coverage per sample, as instantly claimed. Therefore, the limitation introduces new matter. Claims 3, 6-7, 9, 14-15, 17-23, 25, 33, and 39-42 are rejected based on their dependency from claims 1 and 24.
35 USC § 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 24-25 and 33 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 or is maintained from the previous Office Action and updated based on amendment.
Claim 24, fifth limitation, recites “wherein the plurality of baseline median sequencing read counts are generated by performing the following steps…”. It is unclear whether the wherein clause of the fifth through eighth limitations is intended to require generating the baseline median sequencing read count within the metes and bounds of the claimed invention, or if it is only further limiting the baseline median sequencing read count such that performing the steps involved in generating are not required within the metes and bounds of the invention. As set forth in MPEP 2111.04.I, “wherein” clauses raise the question as to the limiting effect of the language in a claim. As the claims do not recite an active performance of the generating prior to the wherein clause, the metes and bounds of the claims are unclear. For compact examination, it is assumed that the generating and subsequent steps are required to be performed. The rejection may be overcome by clarifying what steps are required to be performed. For example, if Applicant intends for the limitations to not be required to be performed, it is recommended to amend the claim to recite “wherein the plurality of baseline median sequencing read counts [[are]] were generated by performing the following steps…”. If Applicant intends for the limitations to be required to be performed, it is recommended to amend the claim to recite “generating
Response to Applicant Arguments
At p. 10-11, Applicant submits that the rejections under 35 USC 112(b) have been addressed through amendment. It is submitted that the amendment for claim 24 regarding the “wherein” clause for generating the plurality of baseline median sequencing read counts has not addressed the previous rejection, but has rather reworded the limitation to recite a similar issue. The rejection is therefore maintained.
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, 3, 6-7, 9, 14-15, 17-25, 33, and 39-42 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 claim 1: generating copy number normalization information for a hypothetical matched reference sample by:
determining… a plurality of copy number baselines for a region of interest of the one or more regions of interest by:
determining a bin count comprising sequencing reads in each individual bin of the plurality of individual bins within the region of interest of each baseline biological sample of the plurality of samples;
clustering the plurality of baseline biological samples to identify different clusters with the plurality of samples based on the bin count; and
generating a copy number baseline for each cluster using a median bin count of a respective cluster, wherein the plurality of copy number baselines comprises the copy number baselines of the clusters; and
using the plurality of copy number baselines to generate the copy number normalization information.
Dependent claim 6: determining one or more of a median sequencing read count, median absolute deviation, GC content, and size for each bin of the plurality of bins.
Dependent claim 7: eliminating or masking bins from the plurality of bins with one or more of a low median, large median sequence coverage absolute deviation, GC content outside of a predetermined range, or a size below a size threshold from the baseline sequencing data before determining the copy number normalization information such that the copy number normalization information is determined using only remaining bins after the eliminating or the masking.
Dependent claim 17: determining a copy number variation for normalized new sequence data of a region of interest in the new sequencing data, generating an indication of the variation.
Dependent claim 19: masking outlier bins in the new sequencing data before determining that the new sequencing data comprises the variation from the copy number baseline in the region of interest.
Dependent claim 20: applying loess regression to the new sequencing data to eliminate GC bias after masking the outlier bins.
Dependent claim 21: fitting the new sequencing data to a curve after masking the outlier bins.
Dependent claims 9, 13, 18, and 41 recite further steps that limit the judicial exceptions in independent claim 1 and, as such, also are directed to those abstract ideas. For example, claim 9 further limits eliminating or masking the bins; claim 13 further limits determining copy number baselines; claim 18 further limits generating the indication; and claim 41 further limits the copy number variation.
Independent claim 24: normalizing the sequencing data…, wherein the normalizing comprises:
for each region of interest of the plurality of regions of interest, comparing a raw sequencing read count of one or more bins representative of a portion of a region of interest of the plurality of regions of interest of the biological sample to a plurality of baseline median sequencing read counts selected based on the sample preparation type;
wherein the plurality of baseline median sequencing read counts are generated by performing the steps of:
training an algorithm using baseline sequencing data from a plurality of unmatched biological samples to select the one or more bins of the plurality of unmatched samples;
clustering the baseline sequencing data to identify different read count clusters for the selected one or more bins of the plurality of unmatched samples on a per-bin basis; and
using a median bin count of each cluster of the different read count clusters to generate the baseline median sequencing read count for a respective cluster, wherein the plurality of baseline median sequencing read counts comprises the baseline median sequencing read count for each cluster;
using the plurality of baseline median counts for a plurality of clusters to generate a normalized sequencing read count for each region of interest;
determining copy number variation in each region of interest based on the normalized sequencing read count of the one or more bins in each region of interest; and
determining a clinical status of the biological sample based on the copy number variation in each region of interest of the plurality of regions of interest, wherein the clinical status comprises a designation of tumor or normal.
Dependent claim 33: removing or masking outlier bins in the sequencing data before normalizing the sequencing data.
Dependent claims 25 recites further steps that limit the judicial exceptions in independent claim 24 by further limiting the region of interest and, as such, also is directed to those abstract ideas.
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 determine copy number normalization and copy number variation. Without further detail as to the methodology involved in “generating”, “determining”, “clustering”, “using”, “normalizing”, “comparing”, “training”, “removing”, “eliminating”, and “masking”, under the BRI, one may simply, for example, use pen and paper to determine copy number normalization information by determining a sequence read bin count, clustering the samples based on the bin count, and generating the normalization information based on the median value of the clusters, and then normalize the sequencing data with the normalization information, determine copy number variation in the normalized data, and finally determine a clinical status of the biological sample based on the copy number variation. Some of these steps, such as “normalizing”, determining a median bin count, “clustering”, and “removing” GC bias and those recited in the dependent claims require mathematical techniques as the only supported embodiments, as is disclosed in the specification as published at: [0046; 0062-0064; 0071-0075].
Therefore, claims 1 and 24 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, at a processor, a sequencing request from a user to sequence at a first sequencing depth one or more regions of interest in a biological sample comprising a particular tissue type and prepared using a particular sample preparation technique, wherein the new biological sample is a somatic sample, and wherein the first sequencing depth provides a coverage level for variant detection at a certain degree of confidence in the one or more regions of interest;
sequencing the new biological sample, wherein said sequencing request comprises analyzing multiple different samples simultaneously in the same sequencing run, thereby reducing sequencing depth of coverage per sample;
acquiring baseline sequencing data using a sequencing device and a panel of probes that hybridize to individual nucleic acid sequences in the one or more regions of interest from a plurality of baseline biological samples that are not matched to the new biological sample and that are from the same particular tissue type and prepared using the same particular sample preparation technique, the one or more regions of interest comprising a plurality of individual bins, each individual bin comprising a contiguous nucleic acid region corresponding to a portion of the region of interest; and
providing the copy number normalization information to the user to normalize new sequencing data of the new biological sample acquired at the first sequencing depth using the panel of probes that hybridize to individual nucleic acids in the one or more regions of interest in the new sample, the new sequencing data comprising bin counts of sequencing reads in each individual bin of the plurality of bins within the region of interest of the new sample, wherein copy number variations for each region of interest are characterized with the certain degree of confidence in the normalized new sequencing data.
Dependent claim 17: providing the indication to the user.
Dependent claims 3, 14-15, 22-23, 39-40, and 42 recite steps that further limit the recited additional elements in claim 1. For example, claims 3 and 22 further limit acquiring the baseline sequencing data; claims 14-15 further limits the biological sample and the baseline biological samples; and claim 23 further limits providing the copy number baseline information to the user; claim 39 further limits the first depth the of sequencing requested from a user; claim 40 further limits the sequencing data; and claim 42 further limits the panel of probes.
Independent claim 24: acquiring sequencing data at a first sequencing depth from a biological sample associated with a sample preparation type using a sequencing device and using a panel of probes that hybridize to individual nucleic acid sequences, wherein acquiring the sequencing data comprises analyzing multiple different samples simultaneously in the same sequencing run, thereby reducing sequencing depth of coverage per sample; wherein the sequencing data comprises a plurality of raw sequencing read counts for a respective plurality of regions of interest, and wherein the biological sample is a somatic sample, and wherein the first sequencing depth provides a coverage level for variant detection at a certain degree of confidence in the one or more regions of interest; and
receiving an input of the sample preparation type.
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” or “acquiring” samples and data, as in claims 1 and 24, and “sequencing” or “acquiring sequencing data” as in claims 1 and 24, and to data outputting, such as “providing” results, as in claims 1 and 17, perform functions of collecting the data needed to carry out the judicial exceptions. It is noted that in claim 1, the limitation directed to “providing the copy number normalization information” requires only the act of providing, where everything after “to normalize new sequencing data” is interpreted as an intended use or action and is not required to be actively performed. Data gathering and outputting do not impose any meaningful limitation on the judicial exceptions, or on how the judicial exceptions are performed. Data gathering and outputting steps are not sufficient to integrate judicial exceptions into a practical application (MPEP 2106.05(g)).
The specification discloses “a need for improved detection of variants in sequencing data” at [0003], and that, in the current method, “the raw sequencing data coverage from a targeted sequencing run is normalized to reduce technical and biological noise to improve CNV detection” at [0006] (see also [0080]), but does not provide a clear explanation for how the additional elements provide these improvements. Therefore, the additional elements do not clearly improve the functioning of a computer, or comprise an improvement to any other technical field. Further, the additional elements do not clearly affect a particular treatment; they do not clearly require or set forth a particular machine; they do not clearly effect a transformation of matter; nor do they clearly provide a nonconventional or unconventional step (MPEP2106.04(d)).
Thus, none of the claims recite additional elements which would integrate a judicial exception into a practical application, and the claims are directed to one or more judicial exceptions [Step 2A, Prong 2: NO; See MPEP § 2106.04(d)].
Step 2B (MPEP 2106.05.A i-vi)
According to analysis so far, the additional elements described above do not provide significantly more than the judicial exception. A determination of whether additional elements provide significantly more also rests on whether the additional elements or a combination of elements represents other than what is well-understood, routine, and conventional. Conventionality is a question of fact and may be evidenced as: a citation to an express statement in the specification or to a statement made by an applicant during prosecution that demonstrates a well-understood, routine or conventional nature of the additional element(s); a citation to one or more of the court decisions as discussed in MPEP 2106(d)(II) as noting the well-understood, routine, conventional nature of the additional element(s); a citation to a publication that demonstrates the well-understood, routine, conventional nature of the additional element(s); and/or a statement that the examiner is taking official notice with respect to the well-understood, routine, conventional nature of the additional element(s).
With respect to the instant claims, the prior art review to Liu et al. (Oncotarget, 2013, 4(11):1868-1881; cited on the 15 Mar 2019 IDS) discloses computational methods for detecting copy number variations in cancer genomes using next generation sequencing, and discloses that using probes to enrich specific regions of the genome for sequencing (p. 1869, col. 1, par. 2 and col. 2, par. 2) and modeling across samples (i.e., baseline biological samples) (p. 1875, col. 2, par. 3) are well-understood, routine, and conventional activity in the art. Further, the prior art review to Mason-Suares (Curr Genet Med Rep, June 8 2016, 4:74-85; newly cited) discloses a review of sequencing and bioinformatics approaches to determine copy number variants, stating that clinical diagnostic laboratories have started to implement CNV detection from targeted NGS gene panels and whole exome sequencing data (abstract; entire document is relevant). Mason-Suarez cites multiple references which disclose targeted panels of greater than 500 genes or exons which are then multiplex sequenced, normalized to controls, and used to determine copy number variations (Pugh et al., Genetics in Medicine, July 2016, 18(7):712-719, newly cited: abstract, p. 712, col. 1, par. 2, and p. 713, col. 1, par. 2; Feng et al., Genetics in Medicine, 2015, 17(2):99-107, newly cited: abstract, p. 100, col. 1, par. 5 and col. 2, par. 2; Bansal et al., PLOS One, 2014, 9(1):e85375: abstract and p. 3, col. 1, par. 1). The Mar 15 2019 IDS reference US 2015/0347676 also discloses enriching samples with probe arrays [0100], performing multiplex sequencing [0131], and detecting copy number variations (abstract). The instant specification discloses that acquiring sequencing data using a sequencing device may be implemented according to any sequencing technique, including those in the art and performed by commercially available sequencing devices [0056].
Further, 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 and outputting steps as recited in the instant claims constitute a general link to a technological environment which is insufficient to constitute an inventive concept which would render the claims significantly more than the judicial exception (MPEP2106.05(g)&(h)).
Taken alone, the additional elements do not amount to significantly more than the above-identified judicial exception(s). Even when viewed as a combination, the additional elements fail to transform the exception into a patent-eligible application of that exception. Thus, the claims as a whole do not amount to significantly more than the exception itself [Step 2B: NO; See MPEP § 2106.05].
Therefore, the instant claims are not drawn to eligible subject matter as they are directed to one or more judicial exceptions without significantly more. For additional guidance, applicant is directed generally to the MPEP § 2106.
Response to Applicant Arguments
At p. 11-12, par. 1, Applicant submits that the claims are patent eligible at Step 2A, Prong 1, because the claims do not recite an abstract idea. Applicant submits that the claims are instructions that are performed on a processor, not mental processes. Applicant further submits that the instructions recited in the claims cannot be performed mentally because high quantities of sequence data obtained from probes, especially an exome panel as in claim 22, at sequencing depth for variant detection cannot practically be performed mentally. Applicant points to the August 4 2025 Memorandum. Applicant submits that claims that merely involve a judicial exception are distinguished from claims that recite a judicial exception.
It is respectfully submitted that this is not persuasive. 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 MPEP 2104(a)(2), III: 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"). The instant claims merely recite the application of the judicial exception to a computer, as described in the above rejection.
Further, it is considered that the claims includes limitations which encompass purely mental actions and do not merely rely on a judicial exception, as set forth in the above rejection. In MPEP 2106.04(a)(2), section III(A), examples that cannot practically be performed in the mind are provided, and include a method for calculating an absolute position of a GPS receiver and an absolute time of reception of satellite signals, detecting suspicious activity by using network monitors and analyzing network packets, specific data encryption method for computer communication involving a several-step manipulation of data, a method for rendering a halftone image of a digital image where the method required the manipulation of computer data structures and the output of a modified computer data structure. In contrast, the MPEP notes that the limitations that can practically be performed in the human mind, including for example, observations, evaluations, judgments, and opinions. The MPEP therefore makes clear that limitations which cannot practically be performed in the mind are those in which the human mind is not equipped to perform the claim limitations. The term practical is not meant to indicate that as a matter of practicality, one would perform a method preferentially on a computer rather than mentally. The MPEP makes clear that “practical” indicates that a human mind is not capable of performing the recited action. That the performance of such a task would be cumbersome or take a large amount of time because of the scale of the data to be analyzed is not changed by the fact that the human mind is capable of performing the task. Such analysis is supported in the August Memorandum, which sets forth that “a claim recites a mental process when it contains limitation(s) that can practically be performed in the human mind, including, for example, observations, evaluations, judgments, and opinions. On the other hand, a claim does not recite a mental process when it contains limitation(s) that cannot practically be performed in the human mind, for instance when the human mind is not equipped to perform the claim limitation(s)”. It is considered that a human mind is equipped to count sequences in a bin, even if the number of sequences is large. It is further noted that the Memorandum and the MPEP give no guidance in regards to the manipulation of large numbers. Further, the use of a physical aid, such as a computer, does not negate the mental and mathematical nature of said limitations at Step 2A, Prong 1 (see MPEP 2106.05(f)).
Even if, supposing that the initial processing of the sequencing data could not be performed mentally, Applicant has not provided any support that further claim limitations could not then be performed mentally. Although Applicant has not provided any arguments for which specific limitation they consider as not being able to be performed mentally, it is assumed that Applicant intends that those limitations directed to “determining a bin count” in claim 1 could not be performed mentally. It is noted that no such similar limitation exists in claim 24. However, such an action, if considered an additional element, would serve at Step 2A, Prong 2, as merely a data gathering element for the other judicial exceptions in the claim, and would not provide significantly more at Step 2B. Therefore, even if Applicant’s arguments regarding the limitation as being one that could not be practically performed mentally were convincing, the claims would still not be patent eligible.
At p. 12, par. 2, Applicant submits that the claims do not recite mathematical concepts because the claims do not recite mathematical relationships, formulas, equations, or calculations, which are required to recite a mathematical concept. Applicant submits that the claims as a whole are directed to normalizing copy number for sequencing data.
It is respectfully submitted that this is not persuasive. At Step 2A, Prong 1, the claims are analyzed such that the specific claim limitations which recite a judicial exception are identified (see MPEP 2106.04(I)). Therefore, when examining independent claims 1 and 24, for example, those steps directed to “normalizing”, determining a median bin count, “clustering”, and “removing” GC bias are considered to recite mathematical concepts, as well as mental processes as set forth in the above rejection. While these limitations do not recite mathematical symbols, it is important to note that a mathematical concept need not be expressed in mathematical symbols. The instant claims recite words operating on data to solve a problem, which serves the same purpose as a formula (see MPEP 2106.04(a)(2)). Finally, the limitations require the use of mathematical concepts as their only embodiment for performance. There is no way to normalize a number in comparison to another number (i.e., dividing the numbers), determine a median bin count, cluster similar numbers, and remove GC bias without using mathematical concepts, as is supported by the specification as published at [0046; 0062-0064; 0071-0075]. Ultimately, at Step 2A, Prong 2, the claim is directed to a method for determining normalizing information from a plurality of reference samples and using that data to normalize sequencing data from a test sample, similarly to the assertion by Applicant. Applicant’s arguments that the claims recite concepts which are only based on mathematical concepts is unpersuasive because the claims recite steps which require the performance of mathematical concepts, described in words, as their only embodiment.
Applicant is reminded that at Step 2A, Prong 1, the claims are examined limitation by limitation to identify whether the claimed concept (the specific claim limitation(s) that recite an exception) aligns with at least one judicial exception (see MPEP 2106.04(I)). That the claims recite limitations which are not considered to align with a judicial exception does not negate that the claim also recites other limitations which do align. The claims are not examined as a whole at Step 2A, Prong 1. Therefore, it is maintained that the claims recite a judicial exception at Step 2A, Prong 1.
At p. 12, par. 3 through p. 15, par. 4, Applicant submits that the claim as a whole is patent eligible at Step 2A, Prong 2, because the judicial exception is integrated into a practical application of improved variant calling. Applicant refers to the Declaration under 37 CFS 1.132 filed Aug 8 2024 that sets forth evidence that the claimed methods have enabled improvements in sequencing efficiency for copy number normalization and variant calls. Applicant submits that raw, unnormalized data has a high amount of deviation from the mean, and that normalization reduces the noise such that fewer sequencing reads are required, permitting multiplexing during sequencing. Applicant submits that normalization therefore improves sequencing, pointing to the specification and the table from the Declaration:
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Applicant submits that the Declaration provides evidence that using the claimed normalization methods improves sequencing, as would be understood by one of ordinary skill in the art. Applicant points to the Dec 4 2025 Memorandum regarding Subject Matter Eligibility Declarations. Applicant submits that when examined as a whole, the claims provide an improvement and therefore are not directed to a judicial exception at Step 2A, Prong 2.
It is respectfully submitted that this is not persuasive. It is noted that the claims now recite “wherein the first sequencing depth provides a coverage level for variant detection at a certain degree of confidence in the one or more regions of interest… wherein said sequencing request comprises analyzing multiple different samples simultaneously in the same sequencing run, thereby reducing sequencing depth of coverage per sample” in claim 1 and “wherein acquiring the sequencing data comprises analyzing multiple different samples simultaneously in the same sequencing run, thereby reducing sequencing depth of coverage per sample… wherein the first sequencing depth provides a coverage level for variant detection at a certain degree of confidence in one or more of the plurality of regions of interest” in claim 24. However, the claims do not set forth any limitations regarding a specific sequencing depth or coverage required by the claims. The claims therefore read on sequencing only a biological sample at nearly any coverage or read depth, including very high read depths which would prohibit the levels of multiplexing and number of samples run per lane, as argued by Applicant, and do not realize an improvement in sample processing or a specific technical field of non-invasive prenatal testing. The claims require only that multiple different samples are sequenced simultaneously in the same run, but do not necessarily even require that the samples be multiplexed and sequenced in the same sequencing lane.
Further, while the improvements argued by Applicants are improvements in the sequencing of the samples, a step which recites an additional element, brought about by the normalization method, it is considered that any normalization method would likely result in the same improvements, as is supported by the data submitted by Applicant. The Declaration discusses several normalization methods, including CG normalization and another normalization method described as using a combination of global wave profile correction according to WO 20151894404 and GC additive correction and principal component analysis according to US 20170220735 (point 7, p. 4-5). The Declaration makes no such claim that the method according to the instant invention is examined. The Declaration makes apparent that GC normalization alone results in a fold reduction in the number of read counts required and an increase in the number of samples able to be sequenced per lane. Therefore, the improvements in sequencing as recited in the instant claims can be achieved by a technique that one of ordinary skill in the art in copy number variation detection would recognize as well-understood, routine, and conventional; therefore, such a reduction in sequencing depth and improvement in multiplexing is not an improvement to the state of the art. As the data that Applicant presents in points 7-8 of the Declaration to show the reduction in bin standard deviation and samples per sequencing lane was performed using a different normalization method than the one instantly claimed, such evidence supports that any normalization technique can provide the potential benefits purported by Applicant. However, as Applicant has not submitted any data regarding the theoretical effect/improvement from the claimed method, it is not possible to say that the claimed method provides any of the purported improvements.
When ascertaining the state of the art, the review to Mason-Suares et al. (Medicine Reports, 2016, 4(3):74-85) and the references cited therein make apparent that using panels of probes for targeted or exome enrichment of samples followed by multiplex sequencing and copy number determination are the state of the art in laboratory settings, and were even being adopted in the clinical setting at the time of filing. As the claims set no distinct limits for the required sequencing coverage or levels of multiplexing per lane per sequencing run, it is not possible to determine that the exact normalization methods recited in the claims provide an improvement to sequencing in comparison to the state of the art.
It is noted that the instant specification as published discloses the design, modification, and updated of a set of probes, including the evaluation of the generated probes according to a set of metrics, where if the metrics indicate that the panel yields poor normalization information, the panel may be discarded and the probes redesigned such that the new probes are retested until high quality normalization information is obtained, or that the metrics are obtained by applying the normalization information before identifying copy number variants in an internal sample, and that if the identified copy number variants across the sequenced regions deviate from an expected distribution, an output may be provided indicating that a new sequencing panel (e.g., a probe redesign) should be triggered [0052]. Such limitations have not been included in the instant claims and may provide a path towards a practical application of the judicial exceptions into improved probe design.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/JANNA NICOLE SCHULTZHAUS/Examiner, Art Unit 1685
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