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.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 07 August 2026 has been entered.
Status of the Claims
Claim set received 07 August 2026 has been entered into the application.
Claims 1 and 74 have been amended.
Claims 2-6, 10-12, 14-17, 22-24, 26, 29-31, 33-36, 37-40, and 45-73 cancelled.
Claim 25 is withdrawn.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 The election of species was withdrawn.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.
Claim Rejections - 35 USC § 112
SC § 112(b)
It is noted the amendments received 07 August 2026 are necessitated by new ground(s) of rejection.
The rejection of claim 1 wherein (a)-(e) under 35 U.S.C §112(b) in the Office Action mailed 07 April 2026 is withdrawn in view of the amendments received 07 August 2026.
The rejection of claim 1 step (e) under 35 U.S.C §112(b) in the Office Action mailed 07 April 2026 is withdrawn in view of the amendments received 07 August 2026.
The rejection of claim 1 without foreknowledge of a genotype under 35 U.S.C §112(b) in the Office Action mailed 07 April 2026 is withdrawn in view of the amendments received 07 August 2026.
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 was amended to recite “wherein (a)-(e) are performed without requiring a tumor tissue sample obtained from the subject.” The amended claim step renders the claim indefinite because the previous steps do not require a tumor tissue sample from a subject. Claim 1 step (a) recites “obtained by sequencing cell-free nucleic acid (cfNA) fragments or amplicons thereof from a test sample obtained from the subject” which does not provide a tumor tissue sample that is to be not required. Thus, it is not clear how the limitation “without requiring a tumor tissue sample obtained from the subject” is to limit the claim when no tumor tissue sample is required.
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 07 April 2026 and modified in view of the amendments filed 07 January 2026. It is noted the amendments received 07 August 2026 are necessitated by new ground(s) of rejection.
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 that the test sample comprises tumor DNA
This step can be performed in the human mind by observing, evaluating, and setting the threshold value to indicate 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 requiring a tumor sample obtained from the subject
This step describes that step (a)-(e) of claim 1 are performed without requiring a tumor sample obtained from the subject.
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., 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. Although claim 74 was amended to recite that said DNA is associated with colorectal cancer, there are no data analysis steps associating colorectal cancer and the DNA of a subjects’ test sample so that said subject can subsequently be administered an immunotherapy based on said nucleic acid data analysis.
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. Here, the relationships between the nucleic acid data (i.e., colorectal tumor DNA) analysis steps and administrating immunotherapy merely provides a nominal/insignificant relationship to the exception and does not recite a particular treatment or prophylaxis. See MPEP 2106.04(d)(2)(b).
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 07 August 2026, have been fully considered but the rejection is maintained.
The Applicant states the claims recite a specific sequencing and computational workflow that improves the technological process of detecting tumor-derived cell-free nucleic acids in a liquid biopsy sample [remarks, page 8]. The Applicant states the claimed solution employs experimentally generated classification alleles associated with subclonality scores to distinguish tumor-derived nucleic acid fragments from non-tumor-derived nucleic acid fragments without requiring conventional tumor tissue-based analysis. The Applicant states the claims are directed to a specific improvement in sequencing based diagnostic technology rather than an abstract idea [remarks, page 8].
In response, as noted in Step 2A Prong II of the 101 analyses above, claim 1 does not provide an improvement because claim 1 is drawn to abstract ideas, and the additional elements, individually and in combination, of claim 1, are drawn to mere extra-solution activities (i.e., receiving data) and tangential computer elements (i.e., computer) which is insufficient to construct a practical application/improvement to technology. Thus, as noted in Step 2A Prong II above, the received test sequence information, identified allelic variant, mapped allelic variant, identify subclonality score, and compared subclonality score is insufficient to construct a practical application such as treating a subject, transformation of matter, or improving upon an existing technology.
The Applicant points to the specification background for guidance. The Applicant states that cell-free DNA obtained from blood originates from multiple cellular sources, including hematopoietic stem cells exhibiting clonal hematopoiesis of indeterminate potential (CHIP), whose mutations may occur in genomic regions associated with cancer despite not originating from tumor cells. The Applicant states conventional sequencing approaches may incorrectly identify CHIP-derived mutations as tumor-derived mutations, thereby reducing diagnostic specificity [remarks, page 8].
In response, because the applicant is arguing limitations not recited in the claims “hematopoiesis of indeterminate potential (CHIP) which any incorrectly identified CHIP-derived mutations as tumor-derived mutations that can correctly be identified.”, the argument is not persuasive. Here, the claims only utilize hematopoietic stem cells as non-target (claim 27) and are not analyzed for any CHIP mutations, for example. Additionally, the additional element of a CHIP to reflect any potential improvement to technology is not recited in the claim. Each of the steps (b) to (e) are drawn to data analysis and step (a) is an extra solution step of receiving data.
The Applicant states the present disclosure addresses this technological problem by generating experimentally derived classification alleles and associated subclonality scores that enable the cellular origin of cfNA fragments to be determined with improved specificity and sensitivity. The Applicant states the specification further explains that these techniques facilitate detection of tumor-derived nucleic acids present at very low abundance in cfNA samples and thereby improve early disease detection [remarks, page 8].
In response, as noted in Step 2A Prong II of the 101 analyses above, the claims do not provide an improvement because the claims are drawn to abstract ideas, and the additional elements, individually and in combination, of claim 1, are drawn to mere extra-solution activities (i.e., receiving data) and tangential computer elements (i.e., computer) which is insufficient to construct a practical application/improvement to technology. Additionally, generating quantitative with more efficient data analysis steps do not integrate the recited judicial exception into a practical application because the data analysis steps of the claims read on abstract ideas. See MPEP 2106.04(a)(2)(III)(C)(1-3).
Additionally, regarding the analysis steps, a judicial exception alone is not eligible subject matter and is insufficient to integrate the judicial exception into a practical application. Here, claim 1 is drawn to mere abstract idea without utilizing any additional elements outside data gathering and tangential computer elements. See MPEP 2106.04(d)(II).
The argument is not further persuasive because the Applicant is arguing the specification further explains that these techniques facilitate detection of tumor-derived nucleic acids present at very low abundance in cfNA samples, but the claims do not recite or require analyzing tumor-derived nucleic acids present at very low abundance in cfNA samples. Therefore, in addition to the claims being drawn to abstract data analysis steps, the argument is not persuasive because the applicant is arguing limitations not recited in the claims (i.e., detection of tumor-derived nucleic acids present at very low abundance in cfNA samples).
The Applicant states the claims provide a concrete improvement over conventional techniques. The Applicant points to the specification [para 0223] for guidance. The Applicant states the specification further explains that simple allele-frequency thresholding excludes clinically relevant mutations, while filtering based upon tumor tissue is clinically impractical because of its complexity and cost. The Applicant states in contrast, the specification demonstrates that the disclosed classifier eliminates false positives while maintaining clinically acceptable sensitivity and enables clinically feasible ctDNA diagnostics without requiring prior tumor genotype information. The Applicant states the claimed process therefore improves the functioning of sequencing-based diagnostic technology itself and is analogous to other patent-eligible improvements in laboratory and computer-assisted diagnostic techniques recognized by the Office's subject matter eligibility guidance [remarks, page 9].
In response, as noted in Step 2A Prong II of the 101 analyses above, the claims do not provide an improvement because the claims are drawn to abstract ideas, and the additional elements, individually and in combination, of claim 1, are drawn to mere extra-solution activities (i.e., receiving data) and tangential computer elements (i.e., computer) which is insufficient to construct a practical application/improvement to technology. It is noted that filtering data reads on abstract ideas and does not provide an improvement to technology or a practical application. It is further noted that the claims do not recite or require a classifier that eliminates false positives while maintaining clinically acceptable sensitivity and enables clinically feasible ctDNA diagnostics without requiring prior tumor genotype information. Thus, the argument is not persuasive because the Applicant is arguing limitations not presented/recited in the claim set.
The Applicant states that the claims do not merely compare numbers but the comparison is performed only after sequencing cfNA fragments, identifying allelic variants, mapping those variants to experimentally generated classification alleles, and retrieving associated subclonality scores from biologically derived reference data and forms one step within a specific sequencing-based workflow directed to improving interpretation of liquid biopsy sequencing results [remarks, page 10].
In response, although claim 1 step (e) recites comparing the subclonality scores of the classification allele compares data after claim 1 steps (a-d), comparing data reads on abstract. Therefore, the comparing step of claim 1 step (e) the argument is not persuasive because the comparing is drawn to abstract ideas.
The Applicant states that the pending claims amount to significantly more than any alleged abstract idea. The Applicant states that the claims require receipt of sequence information generated from sequencing cfNA fragments, mapping allelic variants to classification alleles contained within biologically derived reference datasets, utilizing experimentally generated subclonality scores associated with those classification alleles, and comparing those scores against selected cutoff threshold values to classify the cellular origin of the detected nucleic acid fragments. The Applicant states that these limitations define a particular technological implementation directed to solving a specific problem unique to liquid biopsy sequencing, rather than merely automating a mental process or mathematical calculation. The Applicant states when considered as an ordered combination, the claimed elements improve the technological capability of sequencing-based liquid biopsy assays by reducing false positive tumor calls arising from CHIP-derived mutations while maintaining clinically acceptable sensitivity, as demonstrated in the specification [remarks, page 10].
In response, as noted in Step 2B of the 101 analyses above, there are no additional elements (features/limitations/steps), individually and in combination, recited in the claim(s) beyond the judicial exception(s) so that to contribute to an inventive concept (i.e., amount to significantly more than the judicial exception(s)). Here, the claimed limitations (i.e., using computer of claim 1, receiving data of claim 1 step (a), using sequencing nucleic acids and amplicons of claim 1 step (a), using amplifying segment of cfNA fragments of claims 41 and 44, using enriching segments of cfNA fragments of claim 43, and administering medications and medication of claim 74-75) individually and as a whole, do not add more significantly than the recited judicial exception as they are conventional and routine elements. Here, the claimed limitations/elements (individually and as whole) are drawn to merely gathering and analyzing information (i.e., nucleic acid sequence data) for obtaining input for equations for detecting nucleic acid mutations in a sample using conventional methods (i.e., computers, sequencing, medications, cells) and displaying the results (i.e., determining a classification allele is from a reference cfDNA fragment or an indication the test sample 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 that a sample comprises tumor DNA. See MPEP 2106.05(d)(II) (i, iii, v, viii) and MPEP 2106.05(g)(i).
Additionally, and with respect to the ordered combination, the argument is not persuasive because the ordered combination of additional elements of the claims does not recite limitations for reducing false positive tumor calls arising from CHIP-derived mutations while maintaining clinically acceptable sensitivity, but for comparing and classifying nucleic acid based on a subclonality score. Moreover, claim 1 recites data gathering elements to obtain data (i.e., nucleic acid data) that is subsequently processed and evaluated utilizing a computer for comparing and classifying data based on a value (i.e., subclonality score) which does not provide an unconventional order of additional elements.
Thus, the claims, under Step 2B of the 101 analyses, do not provide further additional elements that can be evaluated for conventionality and routineness. Therefore, 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
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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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