DETAILED ACTION
The Applicant’s response, received 13 February 2026, has been fully considered. 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 .
Status of the Claims
Claims 16-38 are pending.
Claims 16-38 are rejected.
Priority
This application is a CON of 15/898,145, filed 15 February 2018,
which is a CON of 14/692,703, filed 21 April 2015 (PAT 10,179,937),
which claims benefit of 61/982,245, filed 21 April 2014,
and claims benefit of 61/987,407, filed 01 May 2014,
and claims benefit of 61/994,791, filed 16 May 2014,
and claims benefit of 62/066,514, filed 21 October 2014,
and claims benefit of 62/146,188, filed 10 April 2015,
and claims benefit of 62/147,377, filed 14 April 2015,
and claims benefit of 62/148,173, filed 15 April 2015.
The Applicant’s claim for the benefit of a prior-filed application:
U.S. Non-Provisional Application Nos. 15/898,145, filed 15 February 2018; 14/692,703, filed 21 April 2015; and
U.S. Provisional Application Nos. 61/982,245, filed 21 April 2014; 61/987,407, filed 01 May 2014; 61/994,791 filed 16 May 2014; 62/066,514, filed 21 October 2014; 62/146,188, filed 10 April 2015; 62/147,377, filed 14 April 2015; and 62/148,173, filed 15 April 2015;
under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c), is acknowledged.
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application Nos. 61/982,245, filed 21 April 2014; 61/987,407, filed 01 May 2014; 61/994,791 filed 16 May 2014; 62/066,514, filed 21 October 2014; 62/146,188, filed 10 April 2015; 62/147,377, filed 14 April 2015; and 62/148,173, filed 15 April 2015; fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
Independent claim 16 and dependent claims 17-33 are not given the benefit of priority to Application Nos. 61/982,245, filed 21 April 2014; 61/987,407, filed 01 May 2014; 61/994,791 filed 16 May 2014; 62/066,514, filed 21 October 2014; 62/146,188, filed 10 April 2015; 62/147,377, filed 14 April 2015; and 62/148,173, filed 15 April 2015, because there is not support for the limitation reciting “the sequencing has a depth of read of at least 25,000 per target locus” (independent claim 16 and dependent claims 17-33) or the limitation reciting “the sequencing has a depth of read of at least 50,000 per target locus” (dependent claim 17).
Dependent claims 17-33 are construed as incorporating by reference all the limitations of the claim from which they depend (claim 16), thereby requiring a depth of read of at least 25,000 per target locus.
U.S. Patent Application No. 14/692,703, filed 21 April 2015, provides support for the limitations reciting “the sequencing has a depth of read of at least 25,000 per target locus” (claims 16 and 17-33) and the limitation reciting “the sequencing has a depth of read of at least 50,000 per target locus” (claim 17) (e.g., at ¶ [00353] in the specification).
Therefore, the effective filing date of the claimed invention is 21 April 2015.
Information Disclosure Statement
The information disclosure statement (IDS) received 11 February 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claim Interpretation
The claim interpretations in the Office action mailed 19 November 2025 have been maintained in view of the amendment received 13 February 2026.
Claim 16 is interpreted to recite a product-by-process limitation of “sequencing nucleic acids from a tumor sample of a subject,” with the product being the nucleic acids, and not requiring the process of performing the active steps of producing the product (e.g., obtaining a tumor sample, isolating nucleic acid, and purifying the nucleic acid).
Claim 16 is further interpreted to recite a product-by-process limitation of “cell-free DNA isolated from a plasma sample of the subject or in nucleic acids derived therefrom,” with the product being the cell-free DNA or nucleic acids, and not requiring the process of performing the active steps of producing the product (e.g., sample collection and processing, cfDNA extraction, and cfDNA quantification).
Claim 34 is interpreted to recite a product-by-process limitation of “sequencing a genetic material from a subject,” with the product being the genetic material, and not requiring the process of performing the active steps of producing the product (e.g., obtaining a sample from a subject, and nucleic acid isolation and purification).
Claim 34 is further interpreted to recite a product-by-process limitation of “isolating cell-free DNA (cfDNA) from a plasma sample from the subject,” with the product being the cell-free DNA, and not requiring the process of performing the active steps of producing the product (e.g., obtaining a sample from the subject, and processing the sample to separate the plasma, which contains the cfDNA, from the blood cells).
Claim Objections
The objection to claim 34 in the Office action mailed 19 November 2025 has been withdrawn in view of the amendment received 13 February 2026.
Claim Rejections - 35 USC § 112
The rejection of claims 16-33 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, in the Office action mailed 19 November 2025 is withdrawn in view of the amendment received 13 February 2026.
Claim Rejections - 35 USC § 101
The rejection of claims 16-38 under 35 U.S.C. 101 in the Office action mailed 19 November 2025 is maintained with modification in view of the amendment received 13 February 2026.
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 16-38 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claims recite: (a) mental processes, i.e., concepts performed in the human mind (e.g., observation, evaluation, judgement, opinion); and (b) mathematical concepts (e.g., mathematical relationships, formulas or equations, mathematical calculations).
Subject matter eligibility evaluation in accordance with MPEP 2106.
Eligibility Step 1: Step 1 of the eligibility analysis asks: Is the claim to a process, machine, manufacture or composition of matter?
Claims 16-33 are directed to a method (i.e., a process); and claims 34-38 are directed to a method for generating a deoxyribonucleic acid (DNA) preparation (i.e., a process).
Therefore, the claims are encompassed by the categories of statutory subject matter, and thus, satisfy the subject matter eligibility requirements under Step 1.
[Step 1: YES]
Eligibility Step 2A: First it is determined in Prong One whether a claim recites a judicial exception, and if so, then it is determined in Prong Two whether the recited judicial exception is integrated into a practical application of that exception.
Eligibility Step 2A Prong One: In determining whether a claim is directed to a judicial exception, examination is performed that analyzes whether the claim recites a judicial exception, i.e., whether a law of nature, natural phenomenon, or abstract idea is set forth or described in the claim.
Independent claim 16 recites the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas:
identifying a plurality of different tumor-specific single nucleotide variants SNVs in the sequenced nucleic acids (i.e., mental processes); and
identifying one or more of the different tumor-specific SNVs present in the cell-free DNA based on the sequence reads (i.e., mental processes).
Independent claim 34 recites the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas:
identifying a plurality of variant alleles in said genetic material (i.e., mental processes);
selecting 10 to 500 different variant alleles identified in the genetic material (i.e., mental processes); and
identifying the selected variant alleles from the sequence reads, wherein the limit of detection is less than or equal to 0.015% (i.e., mental processes and mathematical concepts).
Dependent claims 19-21, 23, 26, 28, 30, and 31 further recite the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas, as noted below.
Dependent claim 19 further recites:
the SNVs comprise one or more clonal SNVs (i.e., mental processes).
Dependent claim 20 further recites:
the SNVs comprise one or more subclonal SNVs (i.e., mental processes).
Dependent claim 21 further recites:
the SNVs comprise one or more clonal SNVs and one or more subclonal SNVs (i.e., mental processes).
Dependent claim 23 further recites:
determining clonal heterogeneity of the tumor sample (i.e., mental processes).
Dependent claim 26 further recites:
designing PCR primers or hybrid capture probes targeting the plurality of different SNVs identified in the tumor sample (i.e., mental processes).
Dependent claim 28 further recites:
detecting recurrence and/or metastases of the tumor from the SNVs identified in the cell-free DNA (i.e., mental processes).
Dependent claim 30 further recites:
capable of detecting one or more SNVs at a limit of detection of less than or equal to 0.05% (i.e., mental processes and mathematical concepts).
Dependent claim 31 further recites:
capable of detecting one or more SNVs at a limit of detection of less than or equal to 0.015% (i.e., mental processes and mathematical concepts).
Dependent claim 38 further recites:
designing PCR primers or hybrid capture probes targeting the selected variant alleles (i.e., mental processes).
The abstract ideas recited in the claims are evaluated under the broadest reasonable interpretation (BRI) of the claim limitations when read in light of and consistent with the specification. As noted in the foregoing section, the claims are determined to contain limitations that can practically be performed in the human mind with the aid of a pen and paper (e.g., comparing sequence read data to a reference sequence to identify one or more variations), and therefore recite judicial exceptions from the mental process grouping of abstract ideas. Additionally, the recited limitations that are identified as judicial exceptions from the mathematical concepts grouping of abstract ideas (e.g., calculating the limit of detection for single nucleotide variants (e.g., see Example 6 in the Specification at paras. [0689] – [0695]) are abstract ideas irrespective of whether or not the limitations are practical to perform in the human mind.
Therefore, claims 16-38 recite an abstract idea.
[Step 2A Prong One: YES]
Eligibility Step 2A: Prong Two: In determining whether a claim is directed to a judicial exception, further examination is performed that analyzes if the claim recites additional elements that when examined as a whole integrates the judicial exception(s) into a practical application (MPEP 2106.04(d)). A claim that integrates a judicial exception into a practical application will apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception. The claimed additional elements are analyzed to determine if the abstract idea is integrated into a practical application (MPEP 2106.04(d)(I); MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the abstract idea, the claim fails to integrate the abstract idea into a practical application (MPEP 2106.04(d)(III)).
The judicial exceptions identified in Eligibility Step 2A Prong One are not integrated into a practical application because of the reasons noted below.
The additional elements in independent claim 16 include:
sequencing nucleic acids from a tumor sample of a subject;
amplifying 10 to 500 target loci encompassing some portion of the plurality of different tumor-specific SNVs in cell-free DNA isolated from a plasma sample of the subject or in nucleic acids derived therefrom and obtaining amplicons having a length of 50 to 150 bases,
wherein the target loci are amplified together in the same reaction volume; and
sequencing the amplicons with a depth of read of at least 25,000 per target locus.
The additional elements in independent claim 34 include:
sequencing a genetic material from a subject;
isolating cell-free DNA (cfDNA) from a plasma sample from the subject;
performing targeted multiplex amplification of the cfDNA to obtain amplicons comprising the selected different variant alleles identified in the genetic material,
wherein the targeted multiplex amplification is performed in the same reaction volume; and
sequencing all or a portion of the obtained amplicons to obtain sequence reads.
The additional elements in dependent claims 17, 18, 22, 24, 25, 27, 29, 32, 33, and 35-37 include:
the depth of read is at least 50,000 per target locus (claim 17);
the cell-free DNA comprises circulating tumor DNA (claim 18);
the tumor sample of the subject is a tumor tissue sample (claim 22);
step (b) comprises amplifying 20 to 50 target loci each encompassing a different tumor-specific SNV (claim 24);
step (b) comprises amplifying 50 to 100 target loci each encompassing a different tumor-specific SNV (claim 25);
performing barcoding PCR prior to sequencing in step c) (claim 27);
the tumor is colorectal cancer, lung cancer, bladder cancer, or breast cancer (claim 29);
the nucleic acids from the tumor sample are sequenced by whole-genome sequencing (claim 32);
the nucleic acids from the tumor sample are sequenced by whole-exome sequencing (claim 33);
the genetic material is from a human (claim 35);
the genetic material is from a tumor (claim 36); and
the sequencing of the genetic material comprises whole exome sequencing or whole genome sequencing (claim 37).
The additional elements of sequencing nucleic acids from a tumor sample of a subject (claim 16); sequencing a genetic material from a subject (claim 34); sequencing the amplicons with a depth of read of at least 25,000 per target locus (claim 16); sequencing all or a portion of the obtained amplicons to obtain sequence reads (claim 34); the depth of read is at least 50,000 per target locus (claim 17); performing barcoding PCR prior to sequencing in step c) (claim 27); the nucleic acids from the tumor sample are sequenced by whole-genome sequencing (claim 32); the nucleic acids from the tumor sample are sequenced by whole-exome sequencing (claim 33); and the sequencing of the genetic material comprises whole exome sequencing or whole genome sequencing (claim 37); are merely pre-solution activities (e.g., gathering data for use in the claimed process) – nominal or tangential additions to the claims that do not meaningfully limit the claims, and therefore do not add more than insignificant extra-solution activity to the judicial exceptions (MPEP 2106.05(g)).
The additional elements of amplifying 10 to 500 target loci encompassing some portion of the plurality of different tumor-specific SNVs in cell-free DNA isolated from a plasma sample of the subject or in nucleic acids derived therefrom and obtaining amplicons having a length of 50 to 150 bases (claim 16); performing targeted multiplex amplification of the cfDNA to obtain amplicons comprising the selected different variant alleles identified in the genetic material (claim 34); wherein the target loci are amplified together in the same reaction volume (claim 16) and wherein the targeted multiplex amplification is performed in the same reaction volume (claim 34); step (b) comprises amplifying 20 to 50 target loci each encompassing a different tumor-specific SNV (claim 24); and step (b) comprises amplifying 50 to 100 target loci each encompassing a different tumor-specific SNV (claim 25); are merely pre-solution activities (e.g., gathering data for use in the claimed process) – nominal or tangential additions to the claims that do not meaningfully limit the claims, and therefore do not add more than insignificant extra-solution activity to the judicial exceptions (MPEP 2106.05(g)).
The additional elements of isolating cell-free DNA (cfDNA) from a plasma sample from the subject (claim 34); the cell-free DNA comprises circulating tumor DNA (claim 18); the tumor sample of the subject is a tumor tissue sample (claim 22); the tumor is colorectal cancer, lung cancer, bladder cancer, or breast cancer (claim 29); the genetic material is from a human (claim 35); and the genetic material is from a tumor (claim 36); are merely pre-solution activities (e.g., gathering data for use in the claimed process) – nominal or tangential additions to the claims that do not meaningfully limit the claims, and therefore do not add more than insignificant extra-solution activity to the judicial exceptions (MPEP 2106.05(g)).
Thus, the additionally recited elements amount to insignificant extra-solution data gathering activity, and as such, when all limitations in claims 16-38 have been considered as a whole (i.e., the analysis takes into consideration all the claim limitations and how those limitations interact and impact each other when evaluating whether the exception is integrated into a practical application), the claims are deemed to not recite any additional elements that would integrate a judicial exception into a practical application, and therefore claims 16-38 are directed to an abstract idea (MPEP 2106.04(d)).
[Step 2A Prong Two: NO]
Eligibility Step 2B: Because the claims recite an abstract idea, and do not integrate that abstract idea into a practical application, the claims are probed for a specific inventive concept. The judicial exception alone cannot provide that inventive concept or practical application (MPEP 2106.05). Identifying whether the additional elements beyond the abstract idea amount to such an inventive concept requires considering the additional elements individually and in combination to determine if they amount to significantly more than the judicial exception (MPEP 2106.05A i-vi).
The claims do not include any additional elements that are sufficient to amount to significantly more than the judicial exception(s) because of the reasons noted below.
Dependent claims 19-21, 23, 26, 28, 30, 31, and 38 do not recite any elements in addition to the judicial exception(s).
The additional elements recited in independent claims 16 and 34 and dependent claims 17, 18, 22, 24, 25, 27, 29, 32, 33, and 35-37 are identified above, and carried over from Step 2A: Prong Two along with their conclusions for analysis at Step 2B. Any additional element or combination of elements that was considered to be insignificant extra-solution activity at Step 2A: Prong Two was re-evaluated at Step 2B, because if such re-evaluation finds that the element is unconventional or otherwise more than what is well-understood, routine, conventional activity in the field, this finding may indicate that the additional element is no longer considered to be insignificant; and all additional elements and combination of elements were evaluated to determine whether any additional elements or combination of elements are other than what is well-understood, routine, conventional activity in the field, or simply append well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, per MPEP 2106.05(d).
The additional elements of sequencing nucleic acids from a tumor sample of the subject (claim 16); sequencing a genetic material from a subject (claim 34); performing barcoding PCR prior to sequencing in step c) (claim 27); the nucleic acids from the tumor sample are sequenced by whole-genome sequencing (claim 32); the nucleic acids from the tumor sample are sequenced by whole-exome sequencing (claim 33); and the sequencing of the genetic material comprises whole exome sequencing or whole genome sequencing (claim 37); are conventional. Evidence for the conventionality is shown by:
Shendure et al. (Nature Biotechnology, 2012, Vol. 30, No. 11, pp. 1084-1094, as cited in the Office action mailed 19 November 2025).
Shendure et al. reviews the expanding scope of DNA sequencing (Title; and Abstract), and shows the basic workflow structure of sequencing experiments including the modification and tagging of extracted nucleic acids, e.g., barcoding (Figure 2(b)); and further shows sample indexing or molecular tagging by appending a synthetic index or barcode subsequence to all molecules in a given sequencing library (page 1090, col. 2, para. 3); and further shows an application of next-generation DNA sequencing to determine the functional consequences of genetic variation wherein the genetic manipulation included process steps of barcoding and PCR prior to sequencing (Table I, Ex. reference 93). Shendure et al. further shows that genome sequencing and exome sequencing are being used to identify de novo mutations that may be risk factors (page 1086, col. 1, para. 2); and that whole-genome sequencing of tumor DNA from individual patients yields information for clinical decisions (page 1087, col. 2, para. 3).
The additional elements of amplifying 10 to 500 target loci encompassing some portion of the plurality of different tumor-specific SNVs in cell-free DNA isolated from a plasma sample of the subject or in nucleic acids derived therefrom and obtaining amplicons having a length of 50 to 150 bases (claim 16); performing targeted multiplex amplification of the cfDNA to obtain amplicons comprising the selected different variant alleles identified in the genetic material (claim 34); wherein the target loci are amplified together in the same reaction volume (claim 16) and wherein the targeted multiplex amplification is performed in the same reaction volume (claim 34); step (b) comprises amplifying 20 to 50 target loci each encompassing a different tumor-specific SNV (claim 24); and step (b) comprises amplifying 50 to 100 target loci each encompassing a different tumor-specific SNV (claim 25); are conventional. Evidence for the conventionality is shown by:
Koboldt et al. (Cell, 2013, Vol. 155, pp. 27-38, as cited in the Office action mailed 19 November 2025);
Beaulieu et al. (US 2005/0079521, as cited in the Information Disclosure Statement (IDS) received 03 May 2022, as cited in the Office action mailed 19 November 2025);
Leamon et al. (US 2012/0295819, as cited in the Information Disclosure Statement (IDS) received 03 May 2022, as cited in the Office action mailed 19 November 2025);
Deciu et al. (US 2013/0338933, as cited in the Office action mailed 19 November 2025); and
Bianchi et al. (Clinical Chemistry, 2014 (Published 19 Nov. 2013), Vol 60(1), pp. 78-87, as cited in the Office action mailed 19 November 2025).
Koboldt et al. reviews the next-generation sequencing (NGS) revolution and its impact on genomics (Title; and Abstract) and shows the selective capture of circulating tumor cells (CTCs) or the amplification and sequencing of circulating tumor DNA (ctDNA), and that this so-called “liquid biopsy” approach using plasma can detect the predominant somatic mutations for that tumor type, or if chromosomal translocations or structural variants already are known from prior characterization of the cancer genome, PCR primers can be designed to amplify the tumor-specific products for NGS and analysis (page 33, col. 2, para. 2).
Beaulieu et al. shows methods for performing multiplexed detection of a plurality of sequence variations and for performing multiplexed amplification of target nucleic acid (Abstract); and that multiplex polymerase chain reaction (PCR) is a variant of PCR in which two or more target sequences can be amplified by including more than one pair of primers in the same reaction (para. [0030]).
Leamon et al. shows methods and compositions for multiplex PCR (Title) of one or more nucleic acids present in a sample, and in particular, using various target-specific primers that allow for the selective amplification of one or more target sequences associated with cancer (Abstract); and further shows that in some embodiments, the target-specific primers can be provided in one or more aliquots of target-specific primer pairs that can be pooled prior to performing the multiplex PCR reaction in a single amplification vessel or reaction chamber (para. [0198]).
Deciu et al. shows methods and processes for non-invasive assessment of genetic variations (Title; and Abstract); and further shows performing multiplex PCR of 67 SNPs and sequencing the ccf DNA from the plasma of a pregnant mother (para. [0119]; and FIG. 165); and the amplification reaction is performed in a single vessel (e.g., tube, container, well on a plate) which sometimes is referred to as multiplexed amplification (paras. [0270] & [1170]).
Bianchi et al. shows targeted sequencing with amplification of 192 loci that contain SNPs (p. 79, col. 2, para. 2).
The additional elements of sequencing the amplicons with a depth of read of at least 25,000 per target locus (claim 16); sequencing all or a portion of the obtained amplicons to obtain sequence reads (claim 34); and the depth of read is at least 50,000 per target locus (claim 17); are conventional. Evidence of conventionality is shown by:
Rieneck et al. (Transfusion, 2013, Vol. 53, pp. 2892-2898, as cited in the Office action mailed 19 November 2025);
Narayan et al. (Cancer Research, 2012, Vol. 72(14), pp. 3492-3498, as cited in the Information Disclosure Statement (IDS) received 03 May 2022, as cited in the Office action mailed 19 November 2025);
Zhang et al. (WO 2012/125848, as cited in the Office action mailed 19 November 2025);
Kukita et al. (PLoS ONE, 2013, Vol. 8(11): e81468. doi: 10.1371/journal.pone.0081468, pp. 1-10, as cited in the Office action mailed 19 November 2025);
Patel (WO 2013/138510, as cited in the Information Disclosure Statement (IDS) received 03 May 2022, as cited in the Office action mailed 19 November 2025);
Ciccarelli et al. (WO 2010/019588, as cited in the Office action mailed 19 November 2025); and
Leamon et al. (WO 2006/110855, as cited in the Information Disclosure Statement (IDS) received 03 May 2022, as cited in the Office action mailed 19 November 2025).
Rieneck et al. shows using next-generation sequencing on cell-free fetal DNA from maternal plasma (Title; and Abstract) and further shows amplification and subsequent deep sequencing and identification of all SNPs at a given position (page 2895, col. 2, para. 1) and a sequencing depth of approximately 100,000 reads (page 2895, col. 2, para. 2); and further shows sequencing results with the number of reads at the KEL1/2 SNP base position that range from hundreds of reads per SNP base to more than one million reads per SNP base position (Table 3).
Narayan et al. shows ultrasensitive measurement of hotspot mutations in tumor DNA in blood using error-suppressed multiplexed deep sequencing (Title; and Abstract) and further shows obtaining a median depth of 108,467 read pairs per mutation site per sample (page 3494, col. 2, para. 1).
Zhang et al. shows a method for comprehensive sequence analysis using deep sequencing technology (Title; and Abstract) and further shows a clinically applicable deep sequencing technique using Next Generation Sequencing (NGS) in clinical diagnosis that demonstrates uniform coverage of each of the 16,569 bases of the mitochondrial genome at over 100,000-fold average reads per nucleotide, for example (paras. [0003] & [0010]).
Kukita et al. shows quantitative identification of mutant alleles derived from lung cancer in plasma cell-free DNA using deep sequencing data (Title; and Abstract) and further shows that read depth for one assay mostly exceeded 100,000 (page 8., col. 2, para. 2).
Patel shows measurement of nucleic acid variants using highly-multiplexed error-suppressed deep sequencing (Title; and Abstract) and further shows performing massively parallel sequencing on PCR amplicons derived from plasma DNA fragments and obtaining a median depth of 108,467 read pairs per mutation site per sample (page 35, para. 2).
Ciccarelli et al. shows a method for detecting or diagnosing genomic instability (Title; and Abstract) and further shows the average depth of coverage of sequencing (reads/base pair) in various samples ranging from 45,370 to 52,530 (para. [0008]).
Leamon et al. shows methods for determining sequence variants using ultra-deep sequencing (Title; and Abstract) and further shows a method to determine the nucleotide sequence of a polynucleotide region of interest at great depth, i.e., the number of individual sequence reads spanning a given region of interest, and that the depth may range from about 10 to about 1 million (page 4, lines 24-33).
The additional elements of isolating cell-free DNA (cfDNA) from a plasma sample from the subject (claim 34); the cell-free DNA comprises circulating tumor DNA (claim 18); the tumor sample of the subject is a tumor tissue sample (claim 22); the tumor is colorectal cancer, lung cancer, bladder cancer, or breast cancer (claim 29); the genetic material is from a human (claim 35); and the genetic material is from a tumor (claim 36); are conventional. Evidence for the conventionality is shown by:
Heitzer et al. (Clinical Chemistry, 2015 (Published online 2014), Vol. 61:1, pp. 112-123, as cited in the Office action mailed 19 November 2025).
Heitzer et al. reviews circulating tumor DNA as a liquid biopsy for cancer (Title: and Abstract), and shows that there are many conventional methods for the isolation of cfDNA, including directly from blood (page 116, col. 2, para. 2).
Therefore, when taken alone, all additional elements in claims 16-38 do not amount to significantly more than the above-identified judicial exception(s). Even when evaluated as an ordered combination, the additional elements fail to transform the exception(s) into a patent-eligible application of that exception. Thus, claims 16-38 are deemed to not contribute an inventive concept, i.e., amount to significantly more than the judicial exception(s) (MPEP 2106.05(II)).
[Step 2B: NO]
Response to Arguments
The Applicant’s arguments/remarks received 13 February 2026 have been fully considered, but are not persuasive.
The Applicant states on page 6/12 (para. 5) of the Remarks (as originally numbered) that as currently amended, the claims are not directed to a judicial exception, but to a method comprising tangible steps of amplifying and sequencing, which is a patent eligible process under the decision in Illumina v. Ariosa Diagnostics, 952 F.3d 1367 (Fed. Cir. 2020). The Applicant further states that in Illumina v. Ariosa Diagnostics, the Federal Circuit held that a claim reciting “[a] method for preparing a deoxyribonucleic acid (DNA) fraction from a pregnant human female useful for analyzing a genetic locus involved in a fetal chromosomal aberration, comprising (a) extracting DNA…; (b) producing a fraction of DNA extracted in (a)…; and (c) analyzing a genetic locus produced in (b)” is patent eligible because it is considered a method of preparation and not a method of diagnosis. The Applicant further states that the Federal Circuit stated “we conclude at step one of the Alice/Mayo test that the claims are not directed to a patent-ineligible concept, and we need not reach step two of the test.” The Applicant further states (para. 6) that similar to the claim found patent eligible by the Federal Circuit in Illumina v. Ariosa Diagnostics, the present claims 16-38 are directed to a method for preparing amplicons (claim 16) or method of generating a DNA preparation (claim 34), and recite tangible steps such as sequencing, and performing targeted multiplex amplification to prepare amplicons. The Applicant further states that accordingly, consistent with the Federal Circuit decision in Illumina v. Ariosa Diagnostics, the amended claims of the instant application are directed to patent eligible processes, and are not directed to a patent-ineligible concept at step one of the Alice/Mayo test, and it is unnecessary to reach step two of the test discussed at pages 15-21 of the Office action mailed 19 November 2025.
These arguments are not persuasive, because first, the fact patterns differ between Illumina v. Ariosa Diagnostics and the instant application, at least in that the dispute in Illumina v. Ariosa Diagnostics was regarding whether the claims of the disputed patents were “directed to” a natural phenomenon, i.e., whether they claimed the discovered natural phenomenon itself versus eligible subject matter that exploits the discovery of the natural phenomenon. In contrast, and as noted in the above rejection, the instant claims are not determined to recite any law of nature or natural phenomenon at Step 2A Prong One of the eligibility analysis, but rather, are determined to recite mental processes and/or mathematical concepts at Step 2A Prong One, which necessitates further analysis at Step 2A Prong Two of the eligibility analysis, and because at Prong Two the claims are determined to not integrate the recited judicial exceptions into a practical application of those judicial exceptions, the additional elements identified at Prong Two are carried over to Step 2B for further evaluation, as noted and discussed in the above rejection.
The Applicant states on page 7/12 (para. 2) of the Remarks that nevertheless, that Applicant notes that none of the references cited in the Office action (mailed 19 November 2025) at pages 15-21, including Deciu discussed below, can provide evidence that the presently claimed method is conventional when viewed as a whole. The Applicant further states that the Federal Circuit has explained that the claims must be considered as a whole, and it is inappropriate to dissect the clams into disintegrated elements when assessing if the claimed methods are well-understood, routine, and conventional in the field. The Applicant further states that the U.S. Supreme Court in Diehr started the entirety analysis, “[t]hose steps [in Diehr’s patent] included steps that sound utterly old and routine…. Indeed, even the Arrhenius equation was well-known in the art, but in combination was eligible.” The Applicant further states that the combinatorial approach was later endorsed by the Court – “[A] new combination of steps in a process may be patentable even though all the constituents of the combination were well known and in common use before the combination was made.” The Applicant further states (para. 3) that the present claims, when considered as a whole, form a non-routine and unconventional method for determining the presence or absence of one or more tumor-specific single nucleotide variants, which is performed in a non-invasive manner based on a combined biochemical and bioinformatics analysis of cell-free DNA, in sharp contrast to conventional art. The Applicant further states that in particular, the steps of performing sequencing on nucleic acids from a tumor sample of a subject and identifying a plurality of tumor-specific SNVs, amplifying 10 to 500 target loci from cell-free DNA isolated from a plasma sample of the same subject, sequencing the amplicons with a depth of read of at least 25,000 per target locus, and identifying one or more of the tumor-specific SNVs present in the cell-free DNA from the sequence reads, when taken as a whole, were not routine, conventional, or well-known in genetic testing technology at the priority date of the present application.
These arguments are not persuasive, because first, the Applicant appears to be conflating aspects of the eligibility analysis at both Step 2A Prong Two and Step 2B (e.g., by stating “the present claims, when considered as a whole, form a non-routine and unconventional method for determining the presence or absence of one or more tumor-specific single nucleotide variants, which is performed in a non-invasive manner based on a combined biochemical and bioinformatics analysis of cell-free DNA, in sharp contrast to conventional art”). Second, and as noted and discussed in the above rejection, at Step 2A Prong Two of the eligibility analysis, when all limitations in claims 16-38 have been considered as a whole (i.e., the analysis takes into consideration all the claim limitations (i.e., judicial exceptions and additional elements) and how those limitations interact and impact each other when evaluating whether the exception is integrated into a practical application), the claims are deemed to not recite any additional elements that would integrate a judicial exception into a practical application, using one or more of the considerations introduced in subsection I at 2106.04(d) of the MPEP, and discussed in more detail in MPEP §§ 2106.04(d)(1), 2106.04(d)(2), 2106.05(a) through (c) and 2106.05(e) through (h), and therefore claims 16-38 are directed to an abstract idea at Step 2A Prong Two. Third, because the claims are directed to an abstract idea at Step 2A Prong Two, the eligibility analysis proceeds to Step 2B, which asks the question: Does the claim recite additional elements that amount to significantly more than the judicial exception? Examiners should answer this question by first identifying whether there are any additional elements (features/limitations/steps) recited in the claim beyond the judicial exception(s), and then evaluating those additional elements individually and in combination to determine whether they contribute an inventive concept (i.e., amount to significantly more than the judicial exception(s)). Thus, the bioinformatics analysis elements of the instant claims (e.g., identifying a plurality of different tumor-specific single nucleotide variants SNVs in the sequenced nucleic acids; and identifying one or more of the different tumor-specific SNVs present in the cell-free DNA based on the sequence reads) comprise limitations that are judicial exceptions that are not carried over to Step 2B for further evaluation. Fourth, when taken alone (i.e., individually), all additional elements in claims 16-38 do not amount to significantly more than the above-identified judicial exception(s). Even when evaluated as an ordered combination, the additional elements fail to transform the exception(s) into a patent-eligible application of that exception. Thus, claims 16-38 are deemed to not contribute an inventive concept, i.e., do not amount to significantly more than the judicial exception(s).
Claim Rejections - 35 USC § 103
The Applicant’s amendment received 13 February 2026 has been fully considered, however after further consideration, the rejection of claims 16-38 under 35 U.S.C. 103 as being unpatentable over Diehn et al. in view of Zimmermann et al. in view of Deciu et al. in the Office action mailed 19 November 2025 is maintained in view of the amendment.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
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.
Claims 16-38 are rejected under 35 U.S.C. 103 as being unpatentable over Diehn et al. (US 2014/0296081, as cited in the Information Disclosure Statement (IDS) received 03 May 2022) in view of Zimmermann et al. (US 2013/0123120, as cited in the Information Disclosure Statement (IDS) received 03 May 2022) in view of Deciu et al. (US 2013/0338933).
Regarding independent claims 16 and 34, Diehn et al. shows an ultrasensitive and specific strategy for analysis of cancer-derived cfDNA that can simultaneously detect single nucleotide variants (SNVs) (para. [0122]); obtaining a tumor nucleic acid sample and a genomic nucleic acid sample from a subject with a specific cancer (para. [0026]); sequencing a plurality of target regions in the tumor nucleic acid sample and in the genomic nucleic acid sample to obtain a plurality of tumor nucleic acid sequences and a plurality of genomic nucleic acid sequences (para. [0027]); comparing the plurality of tumor nucleic acid sequences to the plurality of genomic nucleic acid sequences to identify a patient-specific genetic alteration in the tumor nucleic acid sample (para. [0028]); obtaining a cell-free nucleic acid sample from a subject (para. 0049]); isolating the cell-free DNA (para. [0141]); enriching the plurality of target regions in the cell-free nucleic acid sample (para. [0046]) using hybrid selection followed by amplification and sequencing of the multiplexed libraries (para. [0146]); sequencing a plurality of target regions in the cell-free sample to obtain a plurality of cell-free nucleic acid reads (para. [0050]); the plurality of target regions are selected from a plurality of genomic regions that are recurrently mutated in the specific cancer (para. [0052]); the plurality of genomic regions comprises at least 25 to at least 500 different genomic regions (para. [0055]); identifying a cancer-specific genetic alteration in the cell-free sample (para. [0051]); and detection of somatic SNVs (para. [0185]) with a detection limit of <0.01% (para. [0082]).
Regarding independent claims 16 and 34, Diehn et al. does not show obtaining amplicons having a length of 50 to 150 bases; the target loci are amplified together in the same reaction volume; or the sequencing has a depth of read of at least 25,000 per target locus.
Regarding independent claims 16 and 34, Zimmermann et al. shows methods for simultaneously amplifying multiple nucleic acid regions of interest in one reaction volume as well as methods for selecting a library of primers for use in such amplification methods (Abstract); and the length of the target amplicons is between 50 and 100 nucleotides (para. [0010]).
Regarding independent claims 16 and 34, Diehn et al. in view of Zimmermann et al. does not show the sequencing has a depth of read of at least 25,000 per target locus.
Regarding independent claims 16 and 34, Deciu et al. shows sequencing amplicon libraries from plasma samples that generated reads such that the after-alignment coverage per SNP (i.e., read depth) was as high as 71,619 reads per SNP (para. [1177]); and in certain embodiments a genetic variation for which the presence or absence is identified for a subject is associated with a medical condition (para. [0648]).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method shown by Diehn et al. by incorporating methods for targeted multiplex amplification, as shown by Zimmermann et al., and discussed above. One of ordinary skill in the art would have been motivated to combine the methods of Diehn et al. with the methods of Zimmermann et al., because Zimmermann et al. shows methods for highly multiplexed amplification and analysis of hundreds to thousands or even millions of loci in a single reaction, from a single sample. This modification would have had a reasonable expectation of success given that both Diehn et al. and Zimmermann et al. disclose methods for targeting and analyzing multiple genomic regions in a nucleic acid sample.
It would have been further obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method shown by Diehn et al. in view of Zimmermann et al. by incorporating methods for high depth of read coverage at targeted loci, as shown by Deciu et al., and discussed above. One of ordinary skill in the art would have been motivated to combine the methods of Diehn et al. in view of Zimmermann et al. with the methods of Deciu et al. because Zimmermann et al. shows that if the depth of read is too small, the stochastic noise can be too high for the data to be useful. This modification would have had a reasonable expectation of success given that both Diehn et al. in view of Zimmermann et al. and Deciu et al. disclose methods for targeting of specific genomic loci for detection of genetic variation.
Regarding dependent claim 18, Diehn et al. further shows the identification and use of circulating tumor markers (Title) and a method for the noninvasive detection and monitoring of circulating tumor DNA (para. [0075]).
Regarding dependent claims 19, 20, 21, and 23, Diehn et al. further shows detection and monitoring of the fractional abundance of a dominant clone (para. [0075]) and a sub-clonal population (para. [0135]) and further shows detecting clinically relevant subclones and monitoring clonal dynamics (Ibid.).
Regarding dependent claim 22, Diehn et al. further shows a tissue biopsy for generating mapped tumor/normal sequence reads (Figure 2).
Regarding dependent claims 24 and 25, Diehn et al. further shows methods for measuring tumor-derived nucleic acids (Abstract) by identifying a plurality of genomic regions from a group of genomic regions that are recurrently mutated in a specific cancer (para. [0012]) and the plurality of genomic regions comprises at least 25, at least 50, at least 100, at least 150, at least 200, or at least 500 different genomic regions (para. 0016]); and detecting single nucleotide variants (SNVs) in cancer-derived cfDNA (para. [0122]).
Regarding dependent claim 28, Diehn et al. further shows a strategy to identify and prioritize genomic regions using a “Recurrence Index” to measure patient-level recurrence frequency at the exon level (para. [0169]).
Regarding dependent claim 29, Diehn et al. further shows the specific cancer is a carcinoma, and the carcinoma is an adenocarcinoma, a non-small cell lung cancer, or a squamous cell carcinoma (para. [0023]).
Regarding dependent claims 30 and 31, Diehn et al. further shows a method for accurately quantifying circulating tumor DNA and identifying mutant alleles down to 0.025% with a detection limit of <0.01% (para. [0082]).
Regarding dependent claims 32 and 33, Diehn et al. further shows that some studies have proposed identifying patient-specific chromosomal rearrangements in tumors via whole genome sequencing (WGS) (para. [0002]); and further shows using whole exome sequencing (WES) data (para. [0124]).
Regarding dependent claims 17, 26, 27, and 38, Diehn et al. does not show the sequencing has a depth of read of at least 50,000 per target locus (claim 17); designing PCR primers or hybrid capture probes targeting the plurality of SNVs identified in the tumor sample (claims 26 and 38); or performing barcoding PCR prior to sequencing (claim 27).
Regarding dependent claims 26 and 38, Zimmermann et al. further shows a library of candidate primers is created by designing one or more primer pairs to candidate target loci such as SNPs (i.e., single nucleotide polymorphisms) (para. [0185]).
Regarding dependent claim 27, Zimmermann et al. further shows that the detection of the amplified DNA can be multiplexed such that tens to hundreds of samples can be multiplexed in one sequencing lane by using barcoding PCR (para. [0229]).
It would have been further obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method shown by Diehn et al. by incorporating methods for barcoding PCR, as shown by Zimmermann et al., and discussed above. One of ordinary skill in the art would have been motivated to combine the methods of Diehn et al. with the methods of Zimmermann et al., because Zimmermann et al. shows that this allows for a higher degree of multiplexing, allowing for hundreds of samples to be genotyped at thousands of SNPs in a single sequencing run. This modification would have had a reasonable expectation of success given that both Diehn et al. and Zimmermann et al. disclose methods for targeting and analyzing multiple genomic regions in a nucleic acid sample.
Regarding dependent claim 17, Deciu et al. further shows sequencing amplicon libraries from plasma samples that generated reads such that the after-alignment coverage per SNP (i.e., read depth) was as high as 71,619 reads per SNP (para. [1177]); and in certain embodiments a genetic variation for which the presence or absence is identified for a subject is associated with a medical condition (para. [0648]).
It would have been further obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method shown by Diehn et al. in view of Zimmermann et al. by incorporating methods for high depth of read coverage at targeted loci, as shown by Deciu et al., for the reasons discussed above.
Response to Arguments
The Applicant’s arguments/remarks received 13 February 2026 have been fully considered, but are not persuasive.
The Applicant states on page 8/12 (para. 3) of the Remarks (as originally numbered) that contrary to the cited references, the present claims 16-38 are directed to a personalized method for identifying tumor-specific SNVs in a tumor sample of a subject suffering from cancer and performing targeted multiplex amplification to amplify 10 to 500 target loci encompassing different members of the plurality of tumor-specific SNVs from cell-free DNA isolated from a plasma sample of the same subject. The Applicant further states (para. 4) that Diehn fails to teach or suggest these personalized features of the present claims, and instead, Diehn’s disclosure is directed to a methodology that is not tumor-specific and does not require designing a personalized panel specific to each cancer patient, and that in this regard, Diehn repeatedly criticizes the prior art for being patient-specific and for requiring a personalized assay to be designed for each patient, e.g., at para. [0002], [0003] & [0122]. The Applicant further states on page 9/12 (para. 2) of the Remarks that against this background, Diehn teaches an off-the-shelf CAPP-Seq assay which is based libraries of recurrently mutated genomic regions created for a given type of cancer using one or more of the design phases discussed at para. [0091]. The Applicant further points to paras. [0124] & [0083], while emphasizing the term “recurrently mutated” as presented by Diehn. The Applicant further states (para. 3) that accordingly, Diehn does not use a patient-specific, but a fixed panel comprising a fixed set of target regions aimed at recurrent mutations and fusions identified from a population of cancer patients, and that consistent with off-the-shelf design, Diehn emphasizes that a key feature of the CAPP-Seq assay is that it does not require patient-specific optimization (Diehn at [0138]) and therefore, Diehn discourages and teaches away from the presently claimed method directed to a personalized method for identifying tumor-specific SNVs in the tumor sample of the subject suffering from the cancer and performing targeted multiplex amplification to amplify 10 to 500 target loci encompassing different members of the plurality of tumor-specific SNVs from cell-free DNA isolated from a plasma sample of the same subject.
These arguments are not persuasive, because first, Diehn does not actually criticize the prior art for being patient-specific, as alleged by the Applicant, but rather criticizes the prior art (e.g., paras. [0002] – [0009]) for not making use of optimized libraries of polymorphisms, such as, e.g., libraries containing recurrently-mutated genomic regions, as taught by Diehn. Second, Diehn at least teaches methods for analyzing a cancer-specific genetic alteration in a subject comprising steps of obtaining a tumor nucleic acid sample and a genomic nucleic acid sample from a subject with a specific cancer; sequencing a plurality of target regions in the tumor nucleic acid sample and the genomic nucleic acid sample to obtain a plurality of tumor nucleic acid sequences and a plurality of genomic nucleic acid sequences; and comparing the plurality of tumor nucleic acid sequences to the plurality of genomic nucleic acid sequences to identify a patient-specific genetic alteration in the tumor nucleic acid sample (e.g., paras. [0025] – [0029]). Third, Diehn’s invention, called CAPP-Seq, literally means CAncer Personalized Profiling by deep Sequencing, and is directed to the ultrasensitive detection of circulating tumor DNA in a subject. The problem in the art that Diehn addresses concerns the issue of vanishingly small quantities of tumor nucleic acid present in a cell-free sample (see Diehn at para. [0087]), and the fact that Diehn developed a library preparation method that does not need to be optimized for each patient because it incorporates recurrently mutated genomic regions (i.e., Diehn’s contribution over the prior art, as discussed at least at para. [0087]) does not mean or even suggest that Diehn “discourages and teaches away from the presently claimed method.”
The Applicant states on page 10/12 (para. 2) of the Remarks that the Office action also acknowledges that Diehn does not teach or suggest “obtaining amplicons having a length of 50 to 150 bases; the target loci are amplified together in the same reaction volume; or the sequencing has a depth of read of at least 25,000 per target locus,” and the Office action cites to Zimmermann for “teaching methods for simultaneously amplifying multiple nucleic acid regions of interest,” but Zimmermann is not referenced for providing the above-discussed missing teaching of Diehn. The Applicant further states (para. 3) that Deciu also fails to teach or suggest these personalized features of the presently claimed invention, nor is Deciu cited to for that purpose. The Applicant further states that Deciu is cited for teaching that the “after-alignment coverage per SNP (i.e., read depth) was as high as 71,619 reads per SNP, however, Deciu at para. [1177] teaches amplicon sequence coverage in the context of methods for fetal fraction estimation, and not for detecting one or more tumor-specific single nucleotide variants (SNVs) in a plasma sample as recited by the present claims. The Applicant further states that moreover, the present claims recite a sequencing depth of at least 25,000 per target locus, and while Deciu discloses that in some examples that coverage per SNP was a high as 71,619 reads per SNP (para. [1177]), the range of coverage was between 1413 and 71,619, and accordingly, Deciu does not teach a required minimum depth of read of at least 25,000 for detecting tumor-specific SNVs in a plasma sample. The Applicant further states (para. 4) that accordingly, the cited references, either alone, or in combination, fail to teach each and every step of the claimed invention, and at least Diehn teaches away from the present claims.
These arguments are not persuasive, because first, as noted in the above rejection, Zimmermann et al. shows methods for simultaneously amplifying multiple nucleic acid regions of interest in one reaction volume as well as methods for selecting a library of primers for use in such amplification methods (Abstract); and the length of the target amplicons is between 50 and 100 nucleotides (para. [0010]). Second, regarding the Applicant’s argument that “while Deciu discloses that in some examples that coverage per SNP was a high as 71,619 reads per SNP (para. [1177]), the range of coverage was between 1413 and 71,619, and accordingly, Deciu does not teach a required minimum depth of read of at least 25,000 for detecting tumor-specific SNVs in a plasma sample,” it is noted that this range merely accounts for the various amounts of amplicon libraries that were used to demonstrate that allele frequency determinations can be made at varying levels of amplicon sequencing coverage, and it is further noted that one of skill in the art would recognize that a higher depth of coverage means that each base in a target genome or transcriptome is sequenced multiple times, thus yielding stronger statistical confidence, allowing researchers to accurately distinguish true genetic variants from random sequencing errors, detect low-frequency mutations in heterogeneous samples (like tumors), and successfully resolve complex, repetitive genomic regions. Thus, Deciu at least teaches methods that demonstrate that allele frequency determinations can be made at varying levels of after alignment coverage per SNP for each amplicon library ranging between 1413 and 71,619x per SNP. Therefore, the cited combination of references in the above rejection show that the instant claimed method would have been obvious to one of skill in the art before the effective filing date.
Double Patenting
The Applicant’s amendment received 13 February 2026 has been fully considered, however after further consideration, all rejections on the ground of nonstatutory double patenting in the Office action mailed 19 November 2025 are maintained in view of the amendment.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 16-38 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No. 11,530,454. Although the claims at issue are not identical, they are not patentably distinct from each other because:
claim 1 of the ‘454 patent recites “wherein the sequencing has a depth of read of at least 50,000 per target locus” which is a species of the instant claim 16 limitation reciting “wherein the sequencing has a depth of read of at least 25,000 per target locus,” and therefore claim 1 of the ‘454 patent anticipates instant claim 16; and
claim 14 of the ‘454 patent recites “wherein the method is capable of detecting an SNV mutation that is present in less than or equal to 0.015% of the cell-free DNA comprising the SNV locus” which is a species of the instant claim 34 limitation reciting “identifying the selected variant alleles from the sequence reads, wherein the limit of detection is less than or equal to 0.015%,” and therefore claim 14 of the ‘454 patent anticipates instant claim 34.
Regarding instant claim 17, claim 15 of the ‘454 patent shows this limitation.
Regarding instant claim 18, claims 2 and 16 of the ‘454 patent show these limitations.
Regarding instant claim 19, claims 3 and 17 of the ‘454 patent show these limitations.
Regarding instant claim 20, claims 4 and 18 of the ‘454 patent show these limitations.
Regarding instant claim 21, claims 5 and 19 of the ‘454 patent show these limitations.
Regarding instant claim 22, claims 6 and 20 of the ‘454 patent show these limitations.
Regarding instant claim 23, claims 7 and 21 of the ‘454 patent show these limitations.
Regarding instant claim 24, claims 8 and 22 of the ‘454 patent show these limitations.
Regarding instant claim 25, claims 9 and 23 of the ‘454 patent show these limitations.
Regarding instant claims 26 and 38, claims 10 and 24 of the ‘454 patent show these limitations.
Regarding instant claim 27, claim 25 of the ‘454 patent shows this limitation.
Regarding instant claim 28, claim 26 of the ‘454 patent shows this limitation.
Regarding instant claim 29, claim 27 of the ‘454 patent shows this limitation.
Regarding instant claims 30 and 31, claim 28 of the ‘454 patent shows these limitations.
Regarding instant claims 32, 33, and 37, claims 1 and 14 of the ‘454 patent show these limitations.
Regarding instant claims 35 and 36, claim 14 of the ‘454 patent shows this limitation.
Claims 16-38 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 12,203,142. Although the claims at issue are not identical, they are not patentably distinct from each other because:
Independent claims 1 and 16 of the ‘142 patent recite “performing whole exome sequencing or whole genome sequencing on nucleic acids” and “identifying 100 to 20,000 tumor biopsy-specific variants,” which are species of the instant independent claims 16 and 34 limitations reciting “sequencing a genetic material” and “identifying a plurality of SNVs,” respectively, and therefore independent claims 1 and 16 of the ‘142 patent anticipate independent claims 16 and 34 of the instant application.
Regarding instant claim 17, claims 2 and 30 of the ‘142 patent show this limitation.
Regarding instant claim 18, claim 5 of the ‘142 patent shows this limitation.
Regarding instant claims 19, 20, and 21, claim 6 of the ‘142 patent shows this limitation.
Regarding instant claim 22, claim 4 of the ‘142 patent shows this limitation.
Regarding instant claim 23, claim 7 of the ‘142 patent shows this limitation.
Regarding instant claims 24 and 25, claims 8 and 9 of the ‘142 patent are species of these limitations.
Regarding instant claim 26, claim 10 of the ‘142 patent shows this limitation.
Regarding instant claim 27, claim 11 of the ‘142 patent shows this limitation.
Regarding instant claim 28, claim 12 of the ‘142 patent shows this limitation.
Regarding instant claim 29, claim 14 of the ‘142 patent shows this limitation.
Regarding instant claims 30 and 31, claim 15 of the ‘142 patent shows these limitations.
Regarding instant claims 32 and 33, claims 1 and 16 of the ‘142 patent show these limitations.
Regarding instant claim 35, claim 13 of the ‘142 patent shows this limitation.
Regarding instant claim 36, claim 18 of the ‘142 patent shows this limitation.
Regarding instant claim 37, claims 1 and 16 of the ‘142 patent show these limitations.
Regarding instant claim 38, claim 10 of the ‘142 patent shows this limitation.
Claims 16-18, 22, and 24-38 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2-6, 8, 10, 13-17, 19, 20, and 24-30 of copending Application No. 19/028,651 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Independent claims 2, 17, and 20 of the copending Application recite “performing whole exome sequencing or whole genome sequencing on nucleic acids” and “identifying 100 to 20,000 tumor biopsy-specific variants,” which are species of the instant independent claims 16 and 34 limitations reciting “sequencing a genetic material” and “identifying a plurality of SNVs,” respectively, and therefore independent claims 2, 17, and 20 of the copending Application anticipate independent claims 16 and 34 of the instant application.
Regarding instant claim 17, claim 5 of the copending Application recites a species of this limitation.
Regarding instant claim 18, claim 8 of the copending Application recites this limitation.
Regarding instant claim 22, claim 6 of the copending Application recites this limitation.
Regarding instant claims 24 and 25, claims 2, 17, and 20 of the copending Application recite species of this limitation.
Regarding instant claim 26, claim 9 of the copending Application recites these limitations.
Regarding instant claim 27, claim 10 of the copending Application recites this limitation.
Regarding instant claim 28, claim 13 of the copending Application recites this limitation.
Regarding instant claim 29, claim 15 of the copending Application recites this limitation.
Regarding instant claims 30 and 31, claim 16 of the copending Application recites these limitations.
Regarding instant claims 32 and 33, claims 2, 17, and 20 of the copending Application recite these limitations.
Regarding instant claim 35, claim 14 of the copending Application recites this limitation.
Regarding instant claim 36, claim 24 of the copending Application recites this limitation.
Regarding instant claim 37, claims 2, 17, and 20 of the copending Application recites these limitations.
Regarding instant claim 38, claim 9 of the copending Application recites these limitations.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 16-18, 22, and 24-37 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2-6, 12-14, 18, 19, 21-23, and 27-29 of copending Application No. 19/028,506 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Independent claims 2 and 21 of the copending Application recite “selectively enriching 100 to 100,00 target loci” which are overlapping ranges of the instant independent claims 16 and 34 limitation “amplifying 10 to 500 target loci.”
Regarding instant claim 17, claims 2 and 21 of the copending Application recite this limitation.
Regarding instant claim 18, claim 5 of the copending Application recites this limitation.
Regarding instant claim 22, claim 3 of the copending Application recites this limitation.
Regarding instant claims 24 and 25, claims 2 and 21 of the copending Application recite species of these limitations.
Regarding instant claim 27, claim 14 of the copending Application recites this limitation.
Regarding instant claim 28, claim 16 of the copending Application recites this limitation.
Regarding instant claim 29, claim 13 of the copending Application recites this limitation.
Regarding instant claim 30, claim 21 of the copending Application recites this limitation.
Regarding instant claim 31, claim 22 of the copending Application recites this limitation.
Regarding instant claims 32 and 33, claims 28 and 29 of the copending Application show these limitations.
Regarding instant claim 35, claim 12 of the copending Application recites this limitation.
Regarding instant claim 36, claim 3 of the copending Application recites this limitation.
Regarding instant claim 37, claims 28 and 29 of the copending Application show these limitations.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 16, 17, 18, 22, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2, 3, 4, 6, 8, 9, 10, 13, 14, 15, 16, 17, 20 of copending Application No. 19/028,575 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Independent claims 2, 17, and 20 of the copending Application recite “performing whole exome sequencing or whole genome sequencing on nucleic acids” and “identifying 50 to 2,000 tumor biopsy-specific variants,” which are species of the instant independent claims 16 and 34 limitations reciting “sequencing a genetic material” and “identifying a plurality of SNVs,” respectively, and therefore independent claims 2, 17, and 20 of the copending Application anticipate independent claims 16 and 34 of the instant application.
Regarding instant claim 17, claim 3 of the copending Application recites this limitation.
Regarding instant claim 18, claim 6 of the copending Application recites this limitation.
Regarding instant claim 22, claim 4 of the copending Application recites this limitation.
Regarding instant claims 24 and 25, claim 8 of the copending Application recites an overlapping range of these limitations.
Regarding instant claim 26, claim 9 of the copending Application recites this limitation.
Regarding instant claim 27, claim 10 of the copending Application recites this limitation.
Regarding instant claim 28, claim 13 of the copending Application recites this limitation.
Regarding instant claim 29, claim 15 of the copending Application recites this limitation.
Regarding instant claims 30 and 31, claim 16 of the copending Application recites this limitation.
Regarding instant claims 32, 33, and 37, claims 2, 17, and 20 of the copending Application recites this limitation.
Regarding instant claim 35, claim 14 of the copending Application recites this limitation.
Regarding instant claim 36, claim 4 of the copending Application recites this limitation.
Regarding instant claim 38, claim 9 of the copending Application recites this limitation.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 8, 10, 12, 13, 14, 15, 16, 19, 20, 21, 22, 30 of copending Application No. 18/111,790 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Independent claims 1 and 16 of the copending Application recite “performing whole exome sequencing or whole genome sequencing on nucleic acids” and “enriching about 10 to 2,000 target loci,” which are species and overlapping ranges of the instant independent claims 16 and 34 limitations reciting “sequencing a genetic material” and “amplifying 10 to 500 target loci,” respectively, and therefore independent claims 1 and 16 of the copending Application anticipate independent claims 16 and 34 of the instant application.
Regarding instant claim 17, claim 30 of the copending Application recites this limitation.
Regarding instant claim 18, claim 20 of the copending Application recites this limitation.
Regarding instant claims 19, 20, and 21, claim 21 of the copending Application recites this limitation.
Regarding instant claim 22, claim 19 of the copending Application recites this limitation.
Regarding instant claim 23, claim 22 of the copending Application recites this limitation.
Regarding instant claims 24 and 25, claim 8 of the copending Application recites this limitation.
Regarding instant claims 26 and 38, claim 10 of the copending Application recites this limitation.
Regarding instant claim 27, claims 1 and 16 of the copending Application recite this limitation.
Regarding instant claim 28, claim 12 of the copending Application recites this limitation.
Regarding instant claim 29, claim 14 of the copending Application recites this limitation.
Regarding instant claim 30, claims 1 and 16 of the copending Application recite this limitation.
Regarding instant claim 31, claim 15 of the copending Application recites this limitation.
Regarding instant claims 32, 33, and 37, claims 1 and 16 of the copending Application recites these limitations.
Regarding instant claim 35, claim 13 of the copending Application recites this limitation.
Regarding instant claim 36, claim 4 of the copending Application recites this limitation.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 16, 17, 18, 22, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 36, 37, and 38 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 8, 11, 12, 13, 14, 16, 17, 20, 21, 28 of copending Application No. 18/753,991 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Independent claims 1 and 14 of the copending Application recite “performing whole exome sequencing or whole genome sequencing on a tumor sample” which are species of the instant independent claims 16 and 34 limitations reciting “sequencing nucleic acids derived from a tumor sample” and “sequencing a genetic material,” respectively, and therefore independent claims 1 and 14 of the copending Application anticipate independent claims 16 and 34 of the instant application.
Regarding instant claim 17, claim 16 of the copending Application recites this limitation.
Regarding instant claim 18, claim 17 of the copending Application recites this limitation.
Regarding instant claim 22, claim 2 of the copending Application recites this limitation.
Regarding instant claim 24, claim 20 of the copending Application recites this limitation.
Regarding instant claim 25, claim 21 of the copending Application recites this limitation.
Regarding instant claims 26, and 38, claim 8 of the copending Application recites this limitation.
Regarding instant claim 27, claim 11 of the copending Application recites this limitation.
Regarding instant claim 28, claim 12 of the copending Application recites this limitation.
Regarding instant claim 29, claim 13 of the copending Application recites this limitation.
Regarding instant claims 30 and 31, claim 28 of the copending Application recites these limitations.
Regarding instant claims 32, 33, and 37, claims 1 and 14 of the copending Application recites these limitations.
Regarding instant claim 36, claim 2 of the copending Application recites this limitation.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 16, 17, 18, 19, 20, 21, 22, 23, 26, 28, 29, 34, 36, are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 6, 7, 9, 10, 11, 14, 21, of copending Application No. 17/568,854 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Independent claims 1, 11, and 21 of the copending Application recite “performing whole exome sequencing on a tumor biopsy sample” which is a species of the instant independent claims 16 and 34 limitations reciting “sequencing nucleic acids derived from a tumor sample” and “sequencing a genetic material,” respectively, and therefore independent claims 1, 11, and 21 of the copending Application anticipate independent claims 16 and 34 of the instant application.
Regarding instant claim 17, claim 2 of the copending Application recites this limitation.
Regarding instant claim 18, claim 14 of the copending Application recites this limitation.
Regarding instant claims 19, 20, and 21, claim 6 of the copending Application recites these limitations.
Regarding instant claims 22 and 36, claim 1 of the copending Application recites these limitations.
Regarding instant claim 23, claim 7 of the copending Application recites this limitation.
Regarding instant claim 26, claims 1, 11, and 21 of the copending Application recite this limitation.
Regarding instant claim 28, claim 10 of the copending Application recites this limitation.
Regarding instant claim 29, claim 9 of the copending Application recites this limitation.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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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/S.W.B./Examiner, Art Unit 1687
/Joseph Woitach/Primary Examiner, Art Unit 1687
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