DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1-14 and 16-22 are pending and under examination.
Claims 1-14 and 16-22 are rejected.
Claim 15 is canceled.
Claims 1-2, 8, 10-12, 16, 20 and 22 are amended.
Claim 1 is independent.
No claims are allowed, new, or withdrawn.
Office Action Outline
Rejections applied
Abbreviations
112/b Indefiniteness
PHOSITA
"a Person Having Ordinary Skill In The Art before the effective filing date of the claimed invention"
112/b "Means for"
BRI
Broadest Reasonable Interpretation
112/a Enablement,
Written description
CRM
"Computer-Readable Media" and equivalent language
112 Other
IDS
Information Disclosure Statement
X
102, 103
JE
Judicial Exception
X
101 JE(s)
112/a
35 USC 112(a) and similarly for 112/b, etc.
101 Other
N:N
page:line
X
Double Patenting
MM/DD/YYYY
date format
Priority
As detailed in the 01-30-2026 filing receipt, this application is a CON of 19/098,448, filed 04/02/2025, which is a CON of 16/678,060, filed 11/08/2019, which is a CON of PCT/US2018/033038, filed 05/16/2018, which claims benefit of U.S. Provisional 62/507,127, filed 05/16/2017.
Claims 1-14 and 16-20 are being examined with an effective filing date of 05/16/2017.
Claims 21 and 22 recite "tumor mutation burden" and/or "TMB." Claim 22 further recites "using...the identified antigenic somatic mutation to calculate the TMB...;" these recitations are not supported by the disclosure of U.S. Provisional Application No. 62/507,127, filed on 05/16/2017. The Provisional Specification discloses "tumor burden" at [0044-46, 0066, 0183, and 0235], however "tumor mutation burden" is not disclosed, nor is "antigenic somatic mutation", nor "calculate the TMB." Therefore claims 21 and 22 will be examined with an effective filing date of 05/16/2018, the date of parent PCT/US2018/033038.
Overview of Withdrawal/Revision of Objections/Rejections
In view of the amendment and remarks received 07/17/2026:
• The objection to the Specification is withdrawn.
• The claim objections are withdrawn.
• The 112(a) and 112(b) rejections are withdrawn.
• The 101 rejection is maintained with revision.
• The 102 rejection is withdrawn (reasons given below in 102 section).
• The 103 rejections are withdrawn and new 103 rejections necessitated by amendment are applied below.
• The Non-Statutory Double Patenting rejection is maintained with revision.
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 1-14 and 16-22 are rejected under 35 U.S.C. 101 because the claimed invention is directed to one or more judicial exceptions without significantly more.
MPEP 2106 details the following framework to analyze Subject Matter Eligibility:
• Step 1: Are the claims directed to a category of statutory subject matter (a process, machine, manufacture, or composition of matter)? (see MPEP § 2106.03)
• Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e. an abstract idea, a law of nature, or a natural phenomenon? (see MPEP §§ 2106.04(a), 2106.04(a)(2), & 2106.04(b)).
• Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application? (see MPEP § 2106.04(d))
• Step 2B: If the claims do not integrate the judicial exception, do the claims provide an inventive concept? (see MPEP § 2106.05)
Step 1:
Claims 1-14 and 16-22 are directed to a 101 process, here a method, which falls under a category of statutory subject matter. (See MPEP § 2106.03). (Step 1: Yes.)
Step 2A, Prong One:
The claims are found to recite abstract ideas in the form of mental processes and mathematical concepts, as well as a law of nature, as follows:
Mental processes and mathematical concepts: Each type of judicial exception is recited in the claims as follows:
• claim 1, step (c): obtain allele fractions (AFs) for genetic variants
• claim 1, step (d): identifying the genetic variant as cancer mutation by comparing AFs
• claim 8 further limits the confidence level of claim 1, step (c)
• claims 9-12 further limit the AF (frequency) of the genetic variant in plasma of claim 1
• claims 13-14 and 16 further limit the genetic variant or cancer of claim 1
• claim 17: determining a tissue of origin of the genetic variant
• claim 18: detecting a presence or absence of residual cancer in the subject
• claim 19: determining methylation profiles
• claim 20: filtering out a portion of reads
• claim 21: determining tumor mutation burden (TMB)
• claim 22: identifying the genetic variant as an antigenic somatic mutation; and calculating the TMB using the somatic mutations including the identified antigenic somatic mutation.
Law of nature: Additionally, each of claims 1 and 16 recites a law of nature in the correlation between the naturally occurring genetic variant in a subject and cancer in a subject.
Step 2A Prong One Summary: The claims recite mental processes and mathematical concepts. When considering the broadest reasonable interpretation (BRI) of the claims, the mental processes recited in independent claim 1 (e.g., analyzing sequence reads; obtaining allele fraction; comparing allele fraction (AF) measures, etc.) are directed to processes that may be performed in the human mind, or with pen and paper, as there are no particular limitations recited in claim 1 which would prevent the mental processes from being performed in the human mind or with pen and paper. The claims recite inherent mathematical processes in e.g., obtaining allele fractions, confidence intervals/levels, calculating a tumor mutation burden (TMB), etc.; while details of the mathematical processes are not explicitly shown in the claims, they are discussed in the Specification, e.g., at [0006], [0008], [0086], [0090-91], etc. Such analysis performed mentally, or with paper and pencil, may take considerable time and effort, and although a general-purpose computer can perform these calculations at a rate and accuracy that can far exceed the mental performance of a skilled artisan, the nature of the activity is essentially the same, and therefore constitutes an abstract idea. Further, a law of nature is recited in the correlation between the naturally occurring genetic variant in a subject and cancer in a subject. Therefore, the claims recite elements that constitute a judicial exception in the form of abstract ideas and law of nature. (Step 2A, Prong One: Yes.)
Step 2A, Prong Two:
In Step 2A, Prong One above, claim steps and/or elements were identified as part of one or more judicial exceptions (JEs). Here at Step 2A, Prong Two, any remaining steps and/or elements not identified as JEs are therefore in addition to the identified JE(s), and are considered additional elements. Because the claims have been interpreted as being directed to judicial exceptions (abstract ideas in this instance) then Step 2A, Prong Two provides that the claims be examined further to determine whether the judicial exception is integrated into a practical application [see 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.
MPEP § 2106.04(d)(I) lists the following five example considerations for evaluating whether a judicial exception is integrated into a practical application:
(1) An improvement in the functioning of a computer or an improvement to other technology or another technical field, as discussed in MPEP §§ 2106.04(d)(1) and 2106.05(a).
(2) Applying or using a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition, as discussed in MPEP § 2106.04(d)(2).
(3) Implementing a judicial exception with, or using a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim, as discussed in MPEP § 2106.05(b).
(4) Effecting a transformation or reduction of a particular article to a different state or thing, as discussed in MPEP § 2106.05(c).
(5) Applying or using the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception, as discussed in MPEP § 2106.05(e).
The claims recite additional elements as follows:
Additional elements of data gathering, inputting, and outputting steps: Claim 1 recites additional elements of a buffy coat specimen including genomic DNA, and a plasma sample including cfNA (cell-free RNA in claim 2); claim 1 further recites additional elements of sequencing (exome and whole transcriptome sequencing in claims 3 and 4, and at different read depths in claims 5-7). Data gathering steps are additional elements which perform functions of inputting, collecting, and outputting the data needed to carry out the abstract idea. These steps are considered insignificant extra-solution activity, and are not sufficient to integrate an abstract idea into a practical application as they do not impose any meaningful limitation on the abstract idea or how it is performed, nor do they provide an improvement to technology (see MPEP § 2106.04(d)(I)).
Step 2A Prong Two summary: The claims have been further analyzed with respect to Step 2A, Prong Two, and no additional elements have been found, alone or in combination, that would integrate the judicial exception into a practical application. At this point in examination, it is not yet the case that any of the Step 2A Prong Two considerations enumerated above clearly demonstrates integration of the identified JE(s) into a practical application. Referring to the considerations above, none of: (1) an improvement, (2) a treatment, (3) a particular machine, or (4) a transformation is clear in the record. For example, regarding the first consideration for improvement at MPEP 2106.04(d)(1), the record, including the Specification, does not yet clearly disclose an explanation of improvement over the previous state of the technology field, and the claims do not yet clearly result in such an improvement. (Step 2A, Prong Two: No).
Step 2B analysis:
Because the additional claim elements do not integrate the abstract idea or law of nature into a practical application, the claims are further examined under Step 2B, which evaluates whether the additional elements, individually and in combination, amount to significantly more than the judicial exception itself by providing an inventive concept. An inventive concept is furnished by an element or combination of elements that is recited in the claim in addition to the judicial exception, and is sufficient to ensure that the claim, as a whole, amounts to significantly more than the judicial exception itself (see MPEP § 2106.05).
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite additional elements that are well-understood, routine, and conventional. Those additional elements are as follows:
Additional elements of data gathering, inputting, and outputting steps: The additional elements of in claim 1 for a buffy coat specimen including genomic DNA, and a plasma sample including cfNA (RNA in claim 2); and further for the claim 1 additional element of sequencing (exome and whole transcriptome sequencing in claims 3 and 4, and at different read depths in claims 5-7), do not cause the claims to rise to the level of significantly more than the judicial exception. The courts have recognized receiving or transmitting data over a network; storing and retrieving information in memory; determining the level of a biomarker in blood by any means; using polymerase chain reaction to amplify and detect DNA; detecting DNA or enzymes in a sample; analyzing DNA to provide sequence information or detect allelic variants; and amplifying and sequencing nucleic acid sequences, [see MPEP§2106.05(d)(II)], as well-understood, routine, conventional activity when they are claimed in a merely generic manner (e.g., at a high level of generality) or as extra-solution activity.
Additionally, the additional elements of samples and sequencing of claims 1-7 are shown to be conventional by the following reference(s):
Lennon, (Genome Medicine, vol. 8(1):112, pp. 1-10 (2016); cited on the attached form PTO-892), presents a review on genome guided diagnosis in the management of cancer, and shows buffy coat and plasma samples, and cfDNA (p.3, col.2); exome sequencing and transcriptome sequencing (p.5, table 2).
All limitations of claims 1-14 and 16-22 have been analyzed with respect to Step 2B, and none provides a specific inventive concept, as they all fail to rise to the level of significantly more than the identified judicial exception, and thus do not transform the judicial exception into a patent eligible application of the exceptions. (Step2B: NO.)
Therefore, the claims, when the limitations are considered individually and as a whole, are rejected under 35 U.S.C. § 101 as being directed to non patent-eligible subject matter.
Response to Applicant Arguments - 35 USC § 101
Applicant's arguments filed 07/17/2026 have been fully considered but they are not yet persuasive.
Applicant asserts the following (interpreted to be directed to Step 2A Prong Two):
• "The claim recites a method for treating a subject known to have a cancer comprising...administering a cancer therapeutic to the subject for treating the cancer. As a whole, the claim is directed to a method for treating a subject having a cancer rather than a judicial exception. " (p.14, ¶3.)
• "Since the claim is eligible in the Step 2A "directed to" part of the test, there is no need to conduct a Step 2B analysis." (bridging p.14-15.)
The arguments are not yet persuasive because claim 1 step (e) recites "administering a cancer therapeutic to the subject for treating the cancer," which is not informed by the judicial exception (JE). No nexus exists between the JE and administering a particular therapy at Step 2A Prong Two, and as such no practical application is yet recited in the claim. Additionally, if the step of "administering a cancer therapeutic to the subject for treating the cancer" were amended to be informed by the judicial exception, there will be further consideration as to if a particular therapy is recited (see MPEP § 2106.04(d)(2)).
Applicant asserts (regarding step 2B):
• " Lennon at p.3, col.2 only mentions buffy coat in the context of enriching circulating tumor cells (CTCs) and does not provide any teaching or suggestion of sequencing genomic DNA from a buffy coat specimen." (p.15, ¶2.)
The arguments are not persuasive first because Lennon performs genomic analysis on CTCs isolated from the buffy coat (Lennon, under "Liquid Biopsy", p.3, cols.1-2). There is no requirement in the claims that the genomic DNA from the buffy coat specimen is not from CTCs. Lennon continues on to discuss the buffy coat is the fraction of an anticoagulated blood sample that contains most of the white blood cells and platelets following density gradient centrifugation (Lennon, p.3, col.2, ¶ 3). A PHOSITA would understand buffy coat analysis is a well understood, conventional, and routinely used method for isolating certain cells of whole blood, e.g., white blood cells and CTCs, and that these isolated cells can then be used in genomic nucleic acid analysis. Therefore the additional element of a sequencing genomic DNA from a buffy coat specimen does not add significantly more than the JE, and does not result in an inventive concept at Step 2B of the 101 analysis.
Withdrawal of Claim Rejection under 35 USC § 102
The rejection of claims 1, 3, 5-6, 8-14 and 16, and 20 under 35 U..S.C. 102 (a)(1) in the 04/22/2026 Office action is withdrawn in view of Applicant's amendment and remarks. Claim 15 has been canceled.
Response to Applicant Arguments - 35 USC § 102
Applicant's arguments filed 07/17/2026 have been fully considered and are persuasive with regard to the following argument.
Applicant asserts:
• "...the Office has not articulated any teaching in Lanman of sequencing a plasma sample and a buffy coat specimen from the same subject known to have a cancer, let alone measuring the allele fractions of the same genetic variant in the plasma sample..." (p.10, ¶ 1).
The arguments are persuasive as the instant claims have been amended to require both a buffy coat specimen and a cfNA sample to be from a subject known to have cancer, (emphasis added). While Lanman teaches analyzing both leukocyte derived and tumor derived cfDNA (see Lanman, p. 11, fig.6), Lanman does not explicitly teach both a buffy coat specimen and a cfNA sample to be from a subject known to have cancer. Additionally, Lanman does not show administering a cancer therapeutic to the subject for treatment cancer. A new 103 rejection, necessitated by amendment, has been applied below.
Claim Rejections - 35 USC § 103
The rejection of claims 2, 4, 7, 17-19, and 21-22 under 35 U..S.C. 103 in the 04/22/2026 Office action is withdrawn in view of Applicant's amendment and remarks.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
103-1 (of 2):
Claims 1, 3, 5-14, 16, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Lanman, (PloS one, vol. 10(10):e0140712, pp.1-27 (Oct. 2015); cited on the 04/22/2026 form PTO-892) in view of Page (Clinical chemistry, vol. 63(2), pages 532-541 (published 02/01/2017); cited on the attached form PTO-892).
Regarding step (a) of claim 1, the recited providing both a genomic DNA and a cell-free nucleic acid (cfNA) sample from a subject with cancer reads on "2 micrograms of genomic DNA were isolated from leukocytes (WBCs) from 20 patient whole blood samples for whole exon sequencing... An aliquot of cfDNA extracted from the same matched blood sample was spiked (referred to as spike-in) into a normal control sample... A total of 10 ng cfDNA, including the spike-in and matrix underwent digital sequencing" (Lanman, p.20, ¶ 2); and "A 165 patient subset of the 510 samples from the five centers had matched plasma and tissue samples" (Lanman, p.11, ¶ 2).
Regarding step (b) of claim 1, the recited sequencing exons from genes in the cfNA to obtain a genetic variant plasma allele fraction measure comprising a confidence interval reads on "Isolated cfDNA fragments are subsequently converted to digital sequence libraries" (Lanman, p. 18, ¶ 2); "Germline SNPs are seen at frequencies (green dots) of either 50%... or 100%...somatic SNVs (red dots) are quantitated at much lower mutant allele frequencies" ( around 0.1 %) (Lanman, p.6, Figs.2A and 2B); "confidence intervals" (Lanman, p.21, ¶ 5), "95% confidence intervals" (Lanman, p.13, Fig.7; p.22, 15); and "confidence levels at 99.5%" (Lanman, p.19, 13); and "both germline and tumor-derived SNVs are analyzed and quantitated simultaneously" (Lanman, p.4, ¶ 3).
Regarding step (c) of claim 1, the recited performing germline sequencing of the genomic DNA to obtain a AF of the genetic variant reads on "2 micrograms of genomic DNA were isolated from leukocytes (WBCs) from 20 patient whole blood samples for whole exon sequencing" (Lanman, p.20, ¶ 2). "Germline SNPs are seen at frequencies (green dots) of either 50%... or 100%...somatic SNVs (red dots) are quantitated at much lower mutant allele frequencies ( around 0.1 %)" (Lanman, p.6, Figs.2A and 2B).
Regarding step (d) of claim 1, the recited identifying the variant as a cancer mutation of somatic origin by comparing the plasma AF to the buffy coat AF reads on "Germline SNPs are seen at frequencies (green dots) of either 50%... or 100%...somatic SNVs (red dots) are quantitated at much lower mutant allele frequencies ( around 0.1 %)" (Lanman, p.6, Figs.2A and 2B).
Regarding claim 3, the recited exome sequencing reads on "whole exome sequencing " (Lanman, p.4, ¶ 3).
Regarding claims 5-7, the recited read depths of at least 3,000 (claim 5); at least 8,000 (claim 6); and at 10,000 to about 5,000,000 (claim 7) reads per base reads on "each base was sequenced at average raw coverage depth of 8,000X" (Lanman, p.17, ¶ 4). Sequencing at a read depth of 10,000X is considered obvious when considering the possible range of read depths which would result in an average read depth of 8,000X.
Regarding claim 8, the recited AF confidence interval is obtained with a confidence level of 95% reads on "95% confidence intervals" (Lanman, Fig.7, p.13; and p.22, ¶ 5); and "at 99.5% confidence level" (Lanman, p.19, ¶ 3).
Regarding claims 9-12, the recited AFs in the plasma sample of 5-20% (claim 9); of 0.1-5% (claim 10); of at least 0.1 %, 0.25%, 0.5%, or 1.0% (claim 11 ); and of 0.1 % or lower (claim 12) reads on the mutation allele frequencies (MAF) around 0.1 % of cell-free DNA samples (seen in Lanman, Figs. 2A and 2B, p.6), and MAF ranges including ranges from 0.25% up to > 10% (seen in Lanman, Table 2, p.8).
Regarding claim 13, the recited genetic variant is selected from the group consisting of a single nucleotide variation (SNV), an indel, a copy number variation (CNV), a fusion, a rearrangement, a repeat, and an aneuploidy reads on "SNVs" (Lanman, p.4, ¶ 3-4); "CNVs for three genes, and the three gene amplifications" (Lanman, p.9, ¶ 1-2); and indels (Lanman, p.15, ¶ 1).
Regarding claim 14, the recited genetic variant is selected from the group consisting of an insertion, a deletion, a copy number amplification (CNA), a copy number loss (CNL), a transversion, a translocation, and an inversion. reads on "SNVs" (Lanman, p.4, ¶ 3-4); "CNVs for three genes, and the three gene amplifications" (Lanman, p.9, ¶ 1-2); and indels (Lanman, p.15, ¶ 1).
Regarding claim 16, the recited types of cancer reads on "A 165 patient subset...tumor cancer histologies included 57 colorectal cancers (CRC), 22 other GI (non-CRC), 18 melanoma, 18 lung cancer, 15 breast cancer, 8 genitourinary cancer, and 27 other cancer types of lesser frequency" (Lanman, p.11, ¶ 2).
Regarding claim 20, the recited filtering reads obtained from sequencing reads on "removal of low quality reads" (Lanman, p.4, ¶ 3).
While Lanman shows genomic DNA samples matched with cfDNA samples from cancer patients (Lanman, p.4, ¶ 4), Lanman does not explicitly show a buffy coat sample comprising genomic DNA and a cfNA sample, both from a subject with cancer of step (a) of claim 1 (shown by Page).
Lanman does not specifically show administering a cancer therapeutic to the subject for treatment cancer of step (e) of claim 1 (shown by Page).
While Lanman shows performing germline sequencing of genomic DNA to obtain an AF measure, Lanman does not show performing germline sequencing of buffy coat genomic DNA of step (c) of claim 1 (shown by Page).
Regarding step (a) of claim 1, the recited providing both a buffy coat sample comprising genomic DNA and a cell-free nucleic acid (cfNA) from the subject having cancer reads on "We recruited 42 patients with radiologically-confirmed MBC (metastatic breast cancer)... Twenty milliliters of venous blood was collected...and 3 mL of the obtained plasma processed using the Circulating Nucleic Acids kit (Qiagen)... DNA was isolated from 200-uL buffy coat (for germ line DNA)" (Page, p.533, col.1, ¶ 2).
Regarding step (c) of claim 1, the recited performing germline sequencing of the buffy coat genomic DNA reads on "DNA was isolated from 200-uL buffy coat (for germ line DNA)" (Page, p.533, col.1, ¶ 2); and "A minimum of ...5 ng lymphocyte DNA...was used to generate libraries" (Page, p.533, col.1, ¶ 3).
Regarding step (e) of claim 1, the recited administering a cancer therapeutic to the subject reads on the patient specific cancer therapeutic "treatment details," (see, e.g., capecitabine, lapatinib, paclitaxel, etc.) shown above each graph in figures 2A-2G (Page, Fig. 2, p. 538). Also see section "Dynamic changes in cfDNA in longitudinal follow-up" (Page, p. 534, col.2, starting at ¶ 4), which discusses the monitoring and treatment of the 9 patients shown in fig.2, p.538.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method for determining somatic or germline origin of a genetic variant using genomic and cfDNA samples of Lanman to include sequencing of genomic DNA obtained from buffy coat specimens, and administering a cancer therapeutic to a subject with cancer, of Page, because Page shows buffy coat specimens can be used to obtain DNA for germline analysis (Page, p.533, col.1, ¶ 2), and Page shows results of serial monitoring in 9 patients demonstrate that cfDNA profiling of mutations and amplifications could provide useful data in terms of tumor heterogeneity. One of ordinary skill in the art would have understood how to and been motivated to modify Lanman with Page to result in strategies for determining origin of genetic variants and applying that knowledge to tumor landscape analysis to improve patient care. One would have had a reasonable expectation of success in doing so because Lanman and Page are generally drawn to related teaching of analyzing variants in cell free nucleic acids, especially with regard to cancer, and one of ordinary skill in the art would have understood how to and would have been motivated to modify the teachings of Lanman with and as such, the combination would have been obvious.
103-2 (of 2):
Claims 2, 4, 17-19, and 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Lanman in view of Page as applied to claims 1, 3, 5-14, 16, and 20 above, and further in view of Siravegna, (Nature reviews Clinical oncology, vol. 14(9), pp.531-548 (March 2017); cited on the 04/22/2026 form PTO-892).
Lanman in view of Page does not show the cfNA comprises cfRNA of claim 2 (shown by Siravegna).
Lanman in view of Page does not show whole transcriptome sequencing of claim 4 (shown by Siravegna).
Lanman in view of Page does not show determining a tissue of origin of the genetic variant of claim 17 (shown by Siravegna).
Lanman in view of Page does not show detecting a presence or absence of residual cancer of claim 18 (shown by Siravegna).
Lanman in view of Page does not show determining methylation profiles of claim 19 (shown by Siravegna).
Lanman in view of Page does not show determining tumor mutation burden (TMB) of claim 21 (shown by Siravegna).
Lanman in view of Page does not show identifying the genetic variant as antigenic somatic variant and using somatic mutations to calculate the TMB of claim 22 (shown by Siravegna).
Regarding claim 2, the recited cfNA comprises cfRNA reads on "mRNA originating from a highly expressed gene...might be shed into the circulation (...as cfRNA) (Siravegna, p.534, col.1, ¶ 1), and the section titled "circulating RNAs" which includes "identification of tumour-specific gene-expression profiles" (Siravegna, p.534, col.1, ¶ 2).
Regarding claim 4, the recited whole transcriptome sequencing reads on "Harvesting of exosomes from biological fluids enables the isolation and subsequent analysis of mRNA, and thus the detection of mutations, splice variants, as well as gene-expression profiling" (Siravegna, bridging p.533-534).
Regarding claim 17, the recited determining a tissue of origin of the genetic variant reads on "miRNAs are the most abundant cfRNA molecules in the blood ... The landscape of miRNAs in blood seems to correlate with that of the solid tumors from which they originate" (Siravegna, p.534, col.1, ¶ 3); and "tumor DNA was found in 100% of patients with oral cancers ... saliva is enriched for tumor DNA originating from the oral cavity" (Siravegna, bridging pp.536-537).
Regarding claim 18, the recited detecting a presence or absence of residual cancer in the subject reads on "ctDNA levels can be used to monitor MRD (minimal residual disease) following surgery or other curative treatments" (Siravegna, p.540, col.1, ¶ 2).
Regarding claim 19, the recited determining methylation profiles of the cfNA reads on the section titled "Methylation profiles in ctDNA - predicting response to chemotherapy" (Siravegna, p.539, col.2 through p.540, col.1).
Regarding claims 21 and 22, the recited determining tumor mutation burden (TMB) (claim 21) and identifying the genetic variant as antigenic somatic variant and using somatic mutations to calculate the TMB (claim 22) reads on "Quantitative analysis of cfDNA can be used to assess tumor burden ... the absolute levels of cfDNA in the circulation provide limited information; however, when levels of cfDNA are coupled with identification of somatic mutations (that is, focusing on ctDNA), they provide valuable diagnostic information" (Siravegna, p.539, col.1, ¶ 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the method for determining somatic or germline origin of a genetic variant using buffy coat genomic and cfDNA samples, and administering a cancer therapeutic to a subject with cancer, of Lanman and Page with the approaches of Siravegna for detecting tissue of origin, detecting residual disease, determining methylation profiles, determining TMB, as well as analyzing cfRNA in transcriptome profiling, because Siravegna teaches exploiting liquid biopsy approaches in patient screening could provide a more comprehensive view of tumor characteristics, including aggressiveness and the overall molecular landscape (p.545, ¶ 3). One of ordinary skill in the art would have understood how to and been motivated to combine Lanman and Page with Siravegna to result in strategies for determining origin of genetic variants and applying that knowledge to tumor landscape analysis to improve patient care. One would have had a reasonable expectation of success in doing so because Lanman, Page, and Siravegna are generally drawn to related teaching of analyzing variants in cell free nucleic acids, especially with regard to cancer, and one of ordinary skill in the art would have understood how to and would have been motivated to combine the teachings of Lanman and the related teachings of Siravegna, and as such, the combination would have been obvious.
Response to Applicant Arguments - 35 USC § 103
Applicant's arguments filed 07/17/2026 have been fully considered but they are not persuasive.
Applicant asserts:
• "The cited disclosures still do not teach or suggest sequencing cell-free nucleic acid from a plasma sample and sequencing genomic DNA from a buffy coat specimen
from the same subject known to have a cancer" (Remarks, p. 13, ¶ 3).
The arguments are not persuasive because new 103 rejections necessitated by amendment have been applied above in which Page (Clinical chemistry, vol. 63(2), pages 532-541 (published 02/01/2017); cited on the attached form PTO-892) shows sequencing cell-free nucleic acid from a plasma sample and sequencing genomic DNA from a buffy coat specimen, both from the same subject known to have a cancer (see Page, p.533, col.1, ¶ 2); and shows patient specific cancer therapeutic(s) administration (see Page, Fig. 2, p. 538).
Double Patenting
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.
Instant claims 1-14 and 16-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over one or more claims in reference applications: 16/678,060, 19/098,448, 19/170,971, 19/170,982, 19/170,988, and 19/636,271 in view of Lanman, (PloS one, vol. 10(10):e0140712, pp.1-27 (Oct. 2015); cited on the 04/22/2026 form PTO-892) and Page (Clinical chemistry, vol. 63(2), pages 532-541 (published 02/01/2017); cited on the attached form PTO-892).
Although the reference claims are not identical to the instant claims, in a BRI they also are not patentably distinct from the instant claims: either (i) because the instant claims recite obviously equivalent or broader limitations in comparison to the reference claims or (ii) because the instant claims recite limitations which are obvious over the cited art.
Each reference application recites method and/or system claims for classifying or identifying a genetic variant or locus as somatic or germline in cell-free DNA. Although the instant application recites limitations for a buffy coat (shown by Page, p.533, col.1, ¶ 2), administering a cancer therapeutic (shown by Page, Fig. 2, p. 538), confidence intervals and confidence levels (shown by Lanman, Fig.7, p.13; p.19, ¶ 3; p.22, ¶ 5), this narrowing versus the reference claims is interpreted as obvious, such that the instant invention would have been prima facie obvious in view of the cited art.
This is a provisional nonstatutory double patenting rejection.
Response to Applicant Arguments - Double Patenting
Applicant's arguments filed 07/17/2026 have been fully considered but they are not persuasive.
Applicant asserts "the Office relies on Lanman for the alleged teaching of 'a buffy coat,' among other things. Office Action at Page 19, Paragraph 68." (Remarks, p..16, ¶ 2.)
The arguments are not persuasive because Page (p.533, col.1, ¶ 2) is relied on for teaching providing and sequencing both a buffy coat sample comprising genomic DNA and a cell-free nucleic acid (cfNA) from a subject having cancer, and administering a cancer therapeutic to a subject with cancer. Therefore the nonstatutory double patenting rejection is maintained.
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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/M.A.V./Examiner, Art Unit 1687
/Karlheinz R. Skowronek/Supervisory Patent Examiner, Art Unit 1687
Prosecution Insights