DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions. The preliminary amendments and arguments, filed with the application, have been entered.
Status of the Claims
Claim set received 14 January 2026 has been entered into the application.
Claims 1, 7 and 27-28 have been amended.
Claims 22 and 37 are cancelled.
Claims 2-6, 10-12, 14-17, 23-24, 26, 29-31, 33-36, 38-40, and 45-73 are previously cancelled.
Claims 74-75 are new.
Claim 25 is withdrawn.
Claims 1, 7-9, 13, 18-21, 27-28, 32, 41-44, and 74-75 are pending.
Election/Restrictions
Applicant’s election without traverse of Group 1, encompassing claims 1, 7-9, 22, 13, 18-22, 27-28, 41-44 in the reply filed on 4/25/2022, is acknowledged. The election of species was withdrawn.
Priority
Applicant’s claim to priority to provisional application 62/680,301 filed on 06/04/2018 is acknowledged.
Specification
The amendment to the specification received 14 January 2026 has been entered into the application.
Claim Rejections - 35 USC § 112
35 USC § 112(b)
It is noted the amendments received 14 January 2026 are necessitated by new ground(s) of rejection.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 7-9, 13, 18-21, 27-28, 32, 41-44, and 74-75 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 step (e) recites “comparing the subclonality score to at least one selected cutoff threshold value, wherein when the subclonality score is below the selected cutoff threshold value it indicates that the classification allele is from a reference cfNA fragment that originates from the target cell, wherein the at least one selected cutoff threshold value is set to indicate if the test sample comprises tumor DNA, thereby determining if the sample comprises tumor DNA.” The claimed step is rendered indefinite because the claim recites that if subclonality score is below the selected cutoff threshold value it indicates that the classification allele is from a reference cfNA fragment that originates from the target cell and wherein the at least one selected cutoff threshold value is set to indicate if the test sample comprises tumor DNA, thereby determining if the sample comprises tumor DNA, however, it is not clear if subclonality score and classification allele is being used in order to determine whether the sample comprises tumor DNA as compared to the subclonality score indicating the classification allele is from a reference sample fragment. For example, the step recites “wherein the at least one selected cutoff threshold value is set to indicate if the test sample comprises tumor DNA, thereby determining if the sample comprises tumor DNA” but the step does not require using the subclonality score/classification allele combination for distinguishing tumor DNA from non-tumor DNA (i.e., previous step (c)) for indicating/determining if the sample comprises tumor DNA. It is recommended to amend the claim to correct the disconnection of the analysis steps such that the subclonality score and classification allele can be utilized to distinguish tumor and non-tumor DNA as require by step (c) in order to determine if a sample comprises tumor DNA of subsequent step (e).
Claim 1 was amended to recite “wherein (a)-(e) are performed without foreknowledge of a genotype of a tumor associated with cancer.” However, the claimed step renders the claims indefinite. Here, step (c) requires mapping an allelic variant to a classification allele on a target or non-target nucleic acid variant filter list. …wherein the classification allele distinguishes tumor DNA from non-tumor DNA. As such, step (c) cannot be performed “without foreknowledge of a genotype of a tumor associated with cancer.” Distinguishing tumor DNA is foreknowledge of a cancer tumor genotype.
The claimed step is further indefinite because it is not clear how “…without foreknowledge of a genotype of a tumor associated with cancer” can limit test sequence information. It is not clear because performing sequencing to obtain sequence information is not related to whether or not knowledge is known about a specific genotype. Sequencing nucleic acids does not distinguish between what is known and what is unknown about nucleic acids but merely produces nucleic acid data from a sample that is subsequently analyzed. Here, it is recommended to amend the claim to recite the appropriate steps to which the analysis can be performed without foreknowledge of genes. For example, the steps that require comparing data or using the data are steps (c)-(e). As such, claim 1 wherein (a)-(e) step could be amended to recite “wherein (c)-(e) are performed without foreknowledge of a genotype of a tumor associated with cancer.”
The step is further unclear because claim 1 requires sequencing data, however, the claim recites “wherein (a)-(e) are performed without foreknowledge of a genotype of a tumor associated with cancer.” It is indefinite because the previous and subsequent steps and claims do not provide any genotyping methods/technique that produces genotype data that can be used to associate sequence data to a tumor associated with cancer. Thus, is it not clear how this limitation is intended to limit the above steps. These above steps, (a)-(e), do not require genotyping, however, they do require “the classification allele” to be able to distinguish tumor from non-tumor DNA. Thus, if the method requires knowledge of the sequence in the classification allele, then, there seems to be knowledge of a tumor genotype, otherwise, distinguishing tumor DNA and non-tumor DNA would not be possible. Here, the claims do not recite any steps for comparing sequencing data to genotyping data and does not recite any steps for genotyping the cfDNA of the test sample such that genotyping can be used to associate a tumor to a cancerous tumor. It is known that sequencing methods determines the precise order of nucleotides (A, T, C, G) in a DNA molecule while genotyping methods detects only specific, predefined genetic variants (like SNPs) in a sample. Thus, it is recommended, for clarity, to amend the claim to match nucleic acid data gathering methods utilized (i.e., sequencing or genotyping) such that only sequencing or genotyping data is used to determine between tumor and non-tumor DNA for determining if a sample comprises tumor DNA.
Claims 7-9, 13, 18-21, 27-28, 32, 41-44, and 74-75 are rejected because they fail to provide limitations to overcome the deficiencies of the base claim(s).
Claim Rejections - 35 USC § 101
The instant rejection is maintained for reason for record in the Office Action mailed 17 July 2025 and modified in view of the amendments filed 14 January 2026. It is noted the amendments received 14 January 2026 are necessitated by new ground(s) of rejection.
The rejection of claim 22 and 37 under 35 U.S.C §112(b) in the Office Action mailed 17 July 2025 is withdrawn in view of the amendments received 14 January 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 1, 7-9, 11, 13, 18-21, 27-28, 32, 41-44, and 74-75 are rejected under 35 U.S.C. §101 because the claimed invention is directed to non-statutory subject matter.
Following the flowchart of MPEP 2106
Step 1 - Process, Machine, Manufacture or Composition
Claims 1, 7-9, 11, 13, 18-21, 27-28, 32, 41-44, and 74-75 are drawn towards a method, so a process.
2A Prong I - Identification of an Abstract Idea
Claim 1 recites:
(b) identifying at least one allelic variant in the test sequence information
This step can be performed in the human mind by observing and evaluating the test sequence information to identify at least one allelic variant and is therefore an abstract idea.
(c) mapping the allelic variant to at least one classification allele on a target nucleic acid variant filter list or to a non-target nucleic acid variant filter list, a using a computer
This step can be performed in the human mind by organizing data (i.e., allelic variants) to a classification allele(s) on a variant filter list to determine locations of genes (i.e., mapping) and is therefore an abstract idea. This step encompasses performing mathematical concepts (i.e., algebra, statistics/probabilities) for mapping variants to a classification allele which reads on abstract ideas.
wherein the classification allele has an associated subclonality score and the classification allele distinguishes tumor DNA from non-tumor DNA
This step merely describes the classification allele that is processed by the abstract idea as having an associated subclonality score and distinguishes tumor DNA from non-tumor.
(d) identifying the subclonality score of the classification allele using a computer
This step can be performed in the human mind by observing, comparing, and evaluating classification allele(s) to identify the subclonality score and is therefore an abstract idea.
(e) comparing the subclonality score to at least one selected cutoff threshold value
This step can be performed in the human mind by observing and comparing the subclonality score to at least one selected cutoff threshold value and is therefore an abstract idea.
wherein when the subclonality score is below the selected cutoff threshold value it indicates that the classification allele is from a reference cfNA fragment that originates from the target cell
This step can be performed in the human mind by observing and evaluating whether the subclonality score is below a selected threshold in order to indicate if the classification allele is from a reference cfDNA fragment and is therefore an abstract idea.
wherein the threshold value is set to indicate if the test sample comprises tumor DNA, thereby determining if the sample comprise tumor DNA.
This step can be performed in the human mind by observing, evaluating, and setting the threshold value to indicate if the test sample comprises tumor DNA for determining if the sample comprises tumor DNA and is therefore an abstract idea.
wherein (a)-(e) are performed without foreknowledge of a genotype of a tumor associated with cancer.
This step describes that step (a)-(e) of claim 1 are performed without foreknowledge of a genotype associated with cancer.
Claims 7-9, 13, 18-21, 27-28, 32, and 41-44 are further drawn to limitations that describe the abstract ideas of claim 1 and are therefore also abstract ideas.
2A Prong II - Consideration of Practical Application
Claim 1 does not recite any additional element which integrates the recited judicial exception into a practical application. Here, in the instant case, the claims merely set forth a method of data analysis for analyzing nucleic acid sequence data for detecting if the nucleic acid originates from a target cell. As such, practicing the claims merely results in a subclonality score associated with a classification allele that is compared to a threshold to determine if the classification allele is from a reference cfDNA fragment or if the sample comprises tumor DNA. Such a result only produces information (i.e., and classification allele and associated subclonality score) and does not provide for a practical application in the physical-realm of physical things and acts, i.e., the claims do not utilize the data generated by the judicial exception to affect any type of change. See MPEP 2106.04(a)(2)(A)(iv). Therefore, the received test sequence information, identified allelic variant, mapped allelic variant, identify subclonality score, and compared subclonality score and the abstract ideas do not construct a practical application such as treating a subject, transformation of matter, or improving upon an existing technology.
Claim 74 recites administering one or more immunotherapies while 75 recites further anti-PD-I antibody, anti-CTLA-4 antibody, and anito-PDL1 antibody immunotherapies. Here, the administrating and immunotherapies steps do not integrate the recited judicial exception into a practical application because the claims do not provide any diseases (i.e., specific cancers) to which the immunotherapies are to treat. Furthermore, neither claim 1 nor the dependent claims recite any specific genes related to any specific cancers/diseases. Additionally, steps (a)-(e) of claim 1 are generic because the claimed steps recite a nucleic acid sequence analysis that targets any cell and any gene for determining if a sample(s) comprises any “tumor” DNA for administering one or more immunotherapies. This step therefore does not apply or use the exception in any meaningful way (i.e., identifying a disease using nucleic acid analysis to determine genes related to a cancer to determine a cancer in order to administer a treatment (i.e., immunotherapies)) because the administration of the immunotherapies of claim 74-75 is not correlated and/or associated to treating and/or targeting any specific disease/cancer. See MPEP 2106.05(f).
This judicial exception is not integrated into a practical application because the claims do not meet any of the following criteria:
an additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field;
an additional element that applies or uses a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
an additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
an additional element effects a transformation or reduction of a particular article to a different state or thing; and
an additional element applies or uses 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.
2B analysis - Consideration of Additional Elements and Significantly More
The claimed method also recites "additional elements" that are not limitations drawn to an abstract idea.
The recited additional element of using computer of claim 1 does not add significantly more than the recited judicial exception because using a computer to process and analyze the abstract idea is well-known and conventional. See MPEP 2106.05(b) and 2106.05(d).
The recited additional element of receiving data of claim 1 step (a) does not add significantly more than the recited judicial exception because receiving sequenced nucleic acid data that is subsequently processed and analyzed by the abstract ideas is a deemed a well-known and conventional extra-solution activity. See MPEP 2106.05(d)(II)(vii) and 2106.05(g).
The recited additional element of sequencing nucleic acids and amplicons of claim 1 step (a) does not add significantly more than the recited judicial exception because sequencing nucleic to gathering nucleic acid data that is subsequently processed and analyzed by the abstract ideas is deemed a well-known and conventional. See MPEP 2106.05(d) (II) (iii, v, vii).
The recited additional element of using amplifying segment of cfNA fragments of claims 41 and 44 does not add significantly more than the recited judicial exception because amplifying nucleic acids to obtain nucleic acid data that is subsequently processes and analyzed by the abstract ideas is well-known and conventional. See MPEP 2106.05(d)(II)(vii).
The recited additional element of using enriching segments of cfNA fragments of claim 43 does not add significantly more than the recited judicial exception because enriching nucleic acids to obtain nucleic acid data that is subsequently processes and analyzed by the abstract ideas is well-known and conventional. See MPEP 2106.05(d)(II) (ii and vii).
The recited additional element of administering medications and medication of claim 74-75 does not add more significantly than the recited judicial exception because administering medication(s) is well-known and conventional. See MPEP 2106.05(d)(II). To provide evidence of conventionality of administering immunotherapies for treating cancer, Lehman et al. (Lehman) reviews using checkpoint inhibitors PD-L1, PD-1, and CTLA for treating cancer (Curr Oncol Rep. 2017 Jul;19(7):49, doi:10.1007/s11912-017-0609-2).
In conclusion and when viewed as a whole, these additional claim element(s) do not provide meaningful limitation(s) to transform the abstract idea recited in the instantly presented claims into a patent eligible application of the abstract idea such that the claim(s) amounts to significantly more than the abstract idea itself. Therefore, the claim(s) are rejected under 35 U.S.C. 101 as being directed to non-statutory subject matter.
Response to Arguments
Applicant’s arguments, filed 14 January 2026, have been fully considered but the rejection is maintained.
The Applicant states incorporating “subclonality filtering” provides an improvement in sequencing and diagnosing technology the eliminate false positives in a liquid biopsy sample without prior knowledge of the samples. The Applicant points to the specification [0223] for guidance. The Applicant reiterates that using "subclonality filtering" provides an enhanced output over other methods to characterize a liquid biopsy sample [remarks, page 9].
In response, and as noted in Step 2A Prong I of the 101 analysis above, filtering data by subclonality scores reads on abstract ideas. For example, claim 1 step (e) encompasses observing, comparing, and evaluating subclonality scores (i.e., quantitative/numerical data) to cutoff thresholds for determining whether data (i.e., subclonality score) is indicative of a classification allele from a reference cfDNA fragment or is indicative of sample comprises tumor DNA. For further example, filtering quantitative/numerical data (i.e., subclonality score) also reads on mathematical concepts because filtering data using threshold(s) requires using equalities and inequalities for determining whether information is below or above a value. Therefore, filtering data is not an improvement to technology because filtering data is an abstract idea.
The Applicant states the claims as a whole recites specific and defined sequencing processing workflow results in real-world diagnostic outcome that is not well-understood, routine, or conventional. The Applicant states the claims take cell-free nucleic acid fragments and transform raw sequencing information into subclonality scores based on the use of classification alleles rather than using simple thresholding mitigates false positives from being called. The Applicant states this mitigation is further achieved without the need for prior knowledge of the tumor (such as the need for sequencing a tumor tissue sample for genotyping). The Applicant asserts that the elements of the method, when viewed as a whole, produce an improved diagnostic capability not achieved by conventional methods [remarks, pages 9-10].
In response, and as described above, the claims are drawn to merely gathering and analyzing information (i.e., nucleic acid sequence data) using conventional methods (i.e., computers, sequencing, medications, cells) and displaying the results (i.e., determination if classification allele is from a reference cfDNA fragment or indicates the test sample is comprises tumor DNA). See MPEP 2106.05(a)(II). Furthermore, the claims utilize conventional and well-known additional elements (i.e., computers, sequencing, medication, cells) for processing nucleic acid data to obtain input for equations (i.e., subclonality score) for determining whether cfDNA is from a reference cfDNA fragment or for determining if a sample comprises tumor DNA. See MPEP 2106.05(d)(II) (i, iii, v, viii) and MPEP 2106.05(g)(i). Here, the claims, under Step 2B of the 101 analyses, do not provide further additional elements that can evaluated for conventionality and routineness. Thus, when viewed as a whole, these additional claim element(s) do not provide meaningful limitation(s) to transform the abstract idea recited in the instantly presented claims into a patent eligible application of the abstract idea such that the claim(s) amounts to significantly more than the abstract idea itself. Therefore, the claim(s) are rejected under 35 U.S.C. 101 as being directed to non-statutory subject matter.
Conclusion
Claims 1, 7-9, 13, 18-21, 27-28, 32, 41-44, and 74-75 are rejected.
No claims are allowed.
Finality
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.
Inquiries
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH C PULLIAM whose telephone number is (571)272-8696. The examiner can normally be reached 0730-1700 M-F.
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/J.C.P./Examiner, Art Unit 1687
/Anna Skibinsky/
Primary Examiner, AU 1635
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