DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. This action is in response to the amendment filed on 30 January 2026. Applicant's arguments and amendments to the claims have been fully considered but do not place the application in condition for allowance. All rejections not reiterated herein are hereby withdrawn.
Claim Status
3. Claims 1-5, 8-13, 16-17, 39-48 are pending.
Claims 39-46 are withdrawn from further consideration, there being no allowable generic or linking claim.
Claims 1-5, 8-13, 16, 17 and 47-48 read on the elected invention and have been examined herein. The claims have been examined to the extent that they read on the elected species of cg08141395. The claims encompass the non-elected species of CpG sites other than cg08141395. Prior to the allowance of the claims, any non-elected subject matter which has not been rejoined with the elected subject matter will be required to be removed from the claims.
In the reply of 30 January 2026, Applicant states “Since independent claims 1 and 10 should be allowable in view of the amendments and remarks herein, and since claims 39-46 have been amended similarly, Applicant respectfully requests that claims 39-46 be rejoined, the additional species searched, and all of the claims allowed pursuant to MPEP § 821.04.”
However, independent claims 1 and 10 are not allowable, particularly with respect to the elected species, for the reasons set forth below. When claims 1 and 10 become allowable with respect to the elected species, rejoinder of non-elected species will be considered, consistent with MPEP § 821.04.
Maintained / Modified Claim Rejections - 35 USC § 101
4. 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 1-5, 8-13, 16, 17 and 47-48 are rejected under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception of a law of nature / natural phenomenon, and/or an abstract idea without significantly more. The judicial exception is not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow.
Applicant' s attention is directed to MPEP 2106 “Patent Subject Matter Eligibility” which discusses the Alice/Mayo two-part test for evaluating subject matter eligibility.
Regarding Step 1 of the subject matter eligibility test set forth at MPEP 2106III, the claims are directed to the statutory category of a process.
Regarding Step 2A, prong one, the claims recite the judicial exception of a law of nature. The claims recite the correlation between the level of methylation at CpGs in differentially methylated regions (DMRs), and particularly the CpG site cg08141395” and the identity of a cell as being either a buccal cell or a white blood cell. As in Mayo Collaborative Services v. Prometheus, the recited relationship is a natural phenomenon that exists apart from any human action. See also Cleveland Clinic Foundation v. True Health Diagnostic, LLC, 2018-1218 (Fed Cir. 2019) which states that “The re-phrasing of the claims does not make them less directed to a natural law.”
The claims also recite the judicial exception of an abstract idea and particularly mental processes.
MPEP 2106.04(a) states that the enumerated groupings of abstract ideas include:
“1) Mathematical concepts – mathematical relationships, mathematical formulas or equations, mathematical calculations (see MPEP § 2106.04(a)(2), subsection I);…
3) Mental processes – concepts performed in the human mind (including an observation, evaluation, judgment, opinion) (see MPEP § 2106.04(a)(2), subsection III).”
The claims require applying or using a formula based on the methylation status of a CpG site to determine the amount of cellular heterogeneity in a sample. This step can be accomplished through critical thinking processes and thereby is an abstract step. Alternatively, the step can be accomplished using a generic computer or software program. The use of a generic computer or software program to implement an abstract idea does not itself impart patent eligibility.
As stated in MPEP 2106.04(a)(2) III “The courts do not distinguish between mental processes that are performed entirely in the human mind and mental processes that require a human to use a physical aid (e.g., pen and paper or a slide rule) to perform the claim limitation….Nor do the courts distinguish between claims that recite mental processes performed by humans and claims that recite mental processes performed on a computer.”
Herein, the use of a generic computer to apply a formula does not constitute something more than an abstract idea.
The claims also recite the judicial exception of a mathematical concept of the formula that is used to correct for cellular heterogeneity, including the particular formula recited in claims 8 and 16 See MPEP 2106.04(a)(2):
“A claim that recites a mathematical calculation, when the claim is given its broadest reasonable interpretation in light of the specification, will be considered as falling within the “mathematical concepts” grouping. A mathematical calculation is a mathematical operation (such as multiplication) or an act of calculating using mathematical methods to determine a variable or number, e.g., performing an arithmetic operation such as exponentiation. There is no particular word or set of words that indicates a claim recites a mathematical calculation. That is, a claim does not have to recite the word “calculating” in order to be considered a mathematical calculation. For example, a step of “determining” a variable or number using mathematical methods or “performing” a mathematical operation may also be considered mathematical calculations when the broadest reasonable interpretation of the claim in light of the specification encompasses a mathematical calculation.”
Regarding Step 2A, prong two, having determined that the claims recite a judicial exception, it is then determined whether the claims recite additional elements that integrate the judicial exception into a practical application.
Herein, the claims do not recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). The additionally recited steps of providing a biological sample, and determining methylation of a CpG site (and a target nucleic acid sequence in claims 47 and 48) are part of the data gathering process necessary to observe the judicial exception. These steps do not practically apply the judicial exception.
Regarding Step 2B, the next question is whether the remaining elements/steps – i.e., the non-patent-ineligible elements/steps - either in isolation or combination, amount to significantly more than the judicial exception.
Herein, the claims as a whole are not considered to recite any additional steps or elements that amount to significantly more than routine and conventional activity and do not add something “significantly more” so as to render the claims patent-eligible. The additionally recited steps of providing a biological sample, and determining methylation status of a CpG site (and a target nucleic acid in claims 47 and 48), including determining methylation by contacting nucleic acids in the biological sample with bisulfite under alkaline conditions and performing methylation-sensitive PCR on the bisulfite treated nucleic acids were well-known, routine and conventional in the prior art. This finding is evidenced by the teachings in the specification. For example, the specification (para [0059]; paragraph numbering herein is with respect to the published application) states:
“Methods of determining the methylation status of a target nucleic acid sequence and/or a DMR loci (e.g., one or more CpG dinucleotides or of a CpG island within a target sequence or a DMR loci) are known in the art. It would be appreciated that the most common method for evaluating the methylation status of DNA begins with a bisulfite-based reaction on the DNA (see, for example, Frommer et al., 1992, PNAS USA, 89(5):1827-31). Commercial kits are available for bisulfite-modifying DNA. See, for example, EpiTect Bisulfite or EpiTect Plus Bisulfite Kits (Qiagen).”
See also para [0061] of the specification.
Further, see:
Guetg, D. (U.S. 20040248120, para [0049]) and Chen, B. (U.S. Patent No. 6180344; col. 11, lines 1-15) which each teach methods of methylation-sensitive PCR of DNA that has been modified by treatment with bisulfite (e.g., para [0049]); and Herman et al (EP0954608; published 2006) which teaches methods of methylation-specific PCR of DNA that has been modified by treatment with bisulfite under alkaline conditions (e.g., para [0011] and [0021]).
See also Eipel (Aging. May 2016. 8(5): 1034; cited in the IDS) which teaches methods for determining the relative level of buccal cells and leukocytes / white blood cells in a buccal swab sample by assaying for the methylation status of two cell-type specific CpGs - i.e., cg07380416 and cg20837735 (p. 1038, col. 2).
Additionally MPEP 2106.05(d) II states:
The courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
i. Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
ii. Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
iii. Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017); …
vii. Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014); and
viii. Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247.
Note that while the claims recite detecting the methylation status at a particular CpG site - i.e., cg08141395 - the identity of the CpG is part of the judicial exception and not something in addition to the recited judicial exceptions.
Further, to the extent that the claims encompass the use of a computer to apply the formula and calculate a correction for cellular heterogeneity, MPEP 2106.05(a) states that ”Limitations that the courts have found not to be enough to qualify as “significantly more” when recited in a claim with a judicial exception include: i. Adding the words “apply it” (or an equivalent) with the judicial exception, or mere instructions to implement an abstract idea on a computer, e.g., a limitation indicating that a particular function such as creating and maintaining electronic records is performed by a computer, as discussed in Alice Corp., 134 S. Ct. at 2360, 110 USPQ2d at 1984 (see MPEP § 2106.05(f))”
In Mayo v. Prometheus, the Supreme Court stated: "[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately."
This is similar to the present situation wherein the additional steps and elements are recited at a high degree of generality and are all routine, well understood and conventional in the prior art. The recited steps and elements do not provide the inventive concept necessary to render the claims patent eligible. See also Genetic Technologies Ltd. v. Merial L.L.C. 818 F.3d at 1377, 1379 (Fed. Cir. 2016).
For the reasons set forth above, when the claims are considered as a whole, the claims are not considered to recite something significantly more than a judicial exception and thereby are not directed to patent eligible subject matter.Response to Remarks:
In the response of 30 January 2026, Applicant resubmitted the arguments provided in the reply of 01 October 2025. The response states that the prior reply points out numerous benefits and improvements of the claimed methods. Applicant concludes “Thus, it is clear that the claimed methods significantly improve upon conventional technology or technological processes, which falls squarely within the Desjardins guidelines issued by the Director. The claimed methods clearly include "significantly more" and Applicant respectfully requests that the rejection of the pending claims under 35 U.S.C. § 101 be withdrawn.”
These arguments and the prior arguments have been fully considered but are not persuasive. In citing the Guidelines regarding Subject Matter Eligibility Declarations published December 4, 2025, Applicant noted that in the Guidelines Director Squires wrote: “On November 4, 2025, I designated the Desjardins decision as precedential to 1) ensure the case reasoning binds all examination and appeals activity, and 2)
underscore that improvements in computational performance, learning,
storage, data sets and structures, for example, can constitute patent-eligible
technological advancements under the Alice framework.” (Emphasis added). The guidance provided therein was focused on improvements in the software related arts and particularly identified changes to the MPEP in view of the Ex parte Desjardins decision.
However, the fact pattern of the present claims is not similar to that in Ex parte Desjardins. As discussed in MPEP 2106.04(d) (I), the claims in Ex Parte Desjardins were considered to recite an improvement in the machine learning technology itself and “additionally included data structure elements reciting adjustments in values to plurality of performance parameters while preserving prior values.”
The present claims do not recite limitations that improve the performance of the technology of machine learning models or limitations that improve another technology or technical field. The cited guidance and the changes to the MPEP do not state that any method which is asserted to provide an improvement over another method will be considered to be an improvement to the functioning of a computer, or an improvement to a technology or a technical field.
Herein, Applicant asserts that the claimed method of determining the amount of cellular heterogeneity in a oropharyngeal sample by determining the number of white blood cells and buccal cells in the sample is less expensive and less complex and can be performed more rapidly than other methylation methods. It is further asserted that the method is more accurate than the method of Houseman.
However, these are not improvements to the functioning of a computer or to a technology or technical field. Rather, these are improvements to the judicial exception itself of the correlation between methylation levels and the identity of a cell as being a buccal cell or white blood cell. The response does not point to a particular technology or technical field that is improved upon by the claimed methods.
A claim is not considered to be patent eligibility under 35 U.S.C. 101 based on a general finding that an invention is an improvement over a prior art reference. Rather, there is a requirement to establish that the claimed method results in an improvement in the functioning of a computer or an improvement to another technology or technical field (see MPEP 2106.04(d)(1) and 2106.05(a)). Herein, Applicant has not established that they have improved any particular methylation assay per se. Applicant has argued that the method improves the judicial exception of determining the relative amount of buccal and white blood cells in a sample based on the correlation between the methylation level at particular CpGs and the identity of a cell as a buccal cell or white blood cell. An improvement to a judicial exception does not constitute an improvement that provides a practical application of a judicial exception.
As discussed in the prior Office action, MPEP 2016.04 II states that when evaluating whether the claim as a whole integrates the exception into a practical application of that exception, “if the additional claim elements merely recite another judicial exception, that is insufficient to integrate the judicial exception into a practical application.” Herein, the additional element of applying a formula to obtain an absolute value is the judicial exception of an abstract idea and the judicial exception of a mathematical formula. The step of determining the amount of cellular heterogeneity in the sample (based on the results of using the formula) is the judicial exception of an abstract idea. Thus, these steps are not steps in addition to the judicial exception since they themselves are a judicial exception. Further, the identity of the particular CpG sites within a DMR locus which are assayed to determine the methylation status and provide the asserted accurate results is part of the judicial exception itself - i.e., the natural law of the correlation between the methylation status at the CpG sites and the occurrence of a buccal cell versus a white blood cell in a oropharyngeal biological sample. Therefore, these limitations in the claims are not an application of the law of nature, but rather are part of the law of nature. Thus, these elements are also not something in addition to the recited judicial exceptions.
Regarding Applicant’s argument that the present invention is an improvement over the prior art method of Houseman because the presently claimed methods do not involve genome wide analysis of methylation levels, these arguments are not persuasive because they are directed to a limitation that is not recited in the claims. The present claims do not exclude the use of a genome wide analysis of methylation levels. Claim 1 broadly recites “determining the methylation status of at least one locus in the biological sample.” Thereby, claim 1 includes any method for determining the methylation status of CpG sites, including genome wide methylation analysis. Claim 10 recites “performing methylation-sensitive PCR on the bisulfite-converted nucleic acid with a pair of primers that amplifies at least one locus.” The claim does not require any particular primers for performing the amplification reaction and thereby includes whole genome amplification and analysis of methylation sites. Thus, even if the asserted improvement was to a technology or technical field, the claims do not recite each of the limitations that result in the asserted improvement.
Applicant has asserted that the claimed method is an improvement over the Houseman because that method “- requires obtaining genome wide methylation data, which is expensive; - is inherently inaccurate because of the amount of noise in the array-based measurements as well as the normalization process used in data preprocessing… - the normalization process used in data preprocessing is required because array methylation "M values" are reference-dependent ratios that are non-normally distributed prior to normalization; and - results in values that are not absolute.”
However, Houseman is not the closest prior art to the claimed invention and thus a comparison to Houseman also does not establish that the claimed method provides an improvement per se. Rather, the prior art of Eipel (Aging. May 2016. 8(5): 1034; cited in the IDS) was cited in the 101 rejection of 30 October 2025 to further establish the conventionality of methods of assaying for methylation status at individual CpG sites. Eipel teaches methods for determining the relative level of buccal cells and leukocytes / white blood cells in a buccal swab sample by assaying for the methylation status of two cell-type specific CpGs - i.e., cg07380416 and cg20837735 (p. 1038, col. 2). Eipel (p. 1038) states “We reasoned that epigenetic characteristics of buccal epithelial cells and leukocytes might be utilized to determine the cellular composition in buccal swabs.” Accordingly, methylation analysis of individual CpG sites, rather than whole genome methylation analysis of CpG sites as taught by Houseman, was already a methodology known in the prior art and was a methodology used to determine the amount of buccal and white blood cells in a saliva sample.
In summary, it is maintained that Applicant has not established that the claimed method provides an improvement to the functioning of a computer or an improvement to another technology or technical field so as to establish that the claims recite additional elements or steps that integrate the recited judicial exception into a practical application of that exception.
New Claim Rejections - 35 USC § 112(b) - Indefiniteness
5. 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 1-5, 8-9 and 47 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.
Claims 1-5, 8-9 and 47 are indefinite over the recitation of “methylation status of the at least one DMR locus” because “the at least one DMR locus” lacks proper antecedent basis in view of the amendment to claim 1 to omit the prior recitation of “differentially methylated region (DMR) locus.” This rejection may be obviated by amendment of claim 1 to recite “methylation status of the at least one locus.”
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CARLA J MYERS whose telephone number is (571)272-0747. The examiner can normally be reached M-Th 6:30-5:00 EST.
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/CARLA J MYERS/Primary Examiner, Art Unit 1682