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 .
Interview Summary
The Examiner would like to note the inclusion of the Applicant’s interview summary regarding the video conference interview on November 25th, 2025. With the inclusion of this summary, the interview record is complete.
Response to Amendment
The amendment filed December 17th, 2025 is acknowledged. Regarding the Office Action mailed June 17th, 2025:
Maintained or modified rejections are set forth below, as necessitated by the amendments. Responses to arguments, if necessary, follow their respective rejection sections.
Claim Summary
Claims 28, 35, 53, 58, and 62 have been amended. Claims 1-27, 33-34, and 36-48 have been canceled. Claims 28-32, 35, and 49-62 are pending. Claims 28-32, 35, and 49-62 are under examination and discussed in this Office action.
Claim Objections
Claims 28, 53, and 62 are objected to because of the following informalities:
Claims 28, 53, and 62 all recite the limitation “obtaining an age of the test subject is reported to be within one age range of the plurality of age ranges that partitions age into decades”. This phrase is awkwardly worded. A suggestion would be to change it to read “obtaining an age of the test subject, wherein the age of the test subject is reported to be within one age range of the plurality of age ranges that partitions age into decades”.
Appropriate correction is required.
Claim Rejections - 35 USC § 101 – Modified – Necessitated by Amendment
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 28-32, 35, and 49-62 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract ideas without significantly more. While the claims are directed to a process, and therefore meet step 1 of the subject matter eligibility test (see MPEP 2106.03), the claim(s) recite the abstract ideas of validating that a cell-free deoxyribonucleic acid (cfDNA) sample is from a test subject and performing cancer prediction for the cfDNA sample.
Step 2A of the subject matter eligibility test requires a two-pronged analysis. Prong One asks: does the claim recite an abstract idea, law of nature or natural phenomenon? As discussed in MPEP 2106.04(II)(A)(1), the meaning of “recites” is “set forth” or “describes”. That is, a claim recites a judicial exception when the judicial exception is “set forth” or “described” in the claim. In the instant case, the claims describe abstract ideas: validating that a cfDNA sample is from a test subject and performing cancer prediction for the cfDNA sample.
Prong Two of the analysis under step 2A asks: does the claim recite additional elements that integrate the judicial exception into a practical application of the judicial exception? As discussed in MPEP 2106.04(II)(A)(2), “Because a judicial exception is not eligible subject matter, Bilski, 561 U.S. at 601, 95 USPQ2d at 1005-06 (quoting Chakrabarty, 447 U.S. at 309, 206 USPQ at 197 (1980)), if there are no additional claim elements besides the judicial exception, or if the additional claim elements merely recite another judicial exception, that is insufficient to integrate the judicial exception into a practical application. See, e.g., RecogniCorp, LLC v. Nintendo Co., 855 F.3d 1322, 1327, 122 USPQ2d 1377 (Fed. Cir. 2017) ("Adding one abstract idea (math) to another abstract idea (encoding and decoding) does not render the claim non-abstract"); Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016) (eligibility "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself."). For a claim reciting a judicial exception to be eligible, the additional elements (if any) in the claim must "transform the nature of the claim" into a patent-eligible application of the judicial exception, Alice Corp., 573 U.S. at 217, 110 USPQ2d at 1981, either at Prong Two or in Step 2B.” The considerations to be used for determining a meaningful integration of the judicial exception into a practical application are set forth at MPEP 2106.05(a) through (c) and (e) through (h). Turning to those sections of the MPEP:
MPEP 2106.05(a) has to do with improvements to the functioning of a computer or to any other technology or technical field. The claims at issue do not improve the functioning of a computer or other technology. While the instant claims recite steps of obtaining cfDNA samples from test subjects with a known age; sequencing the cfDNA via targeted whole genome bisulfite sequencing; determining a methylation density at a plurality of selected CpG sites based on the sequencing; predicting a sample age range with a trained regression model; validating the sample is from the reported subject; identifying pertinent CpG sites via regression models; performing cancer prediction for the cfDNA sample with the methylation sequence reads from that sample; excluding CpG sites related to cancer, sex, and ethnicity; using a non-transitory computer-readable storage medium with instructions to perform the previously listed steps; and a system for validation comprising a computer processor and the storage medium previously described, the claims do not improve upon whole genome bisulfite sequencing techniques, regression models, comparison techniques for validating a sample corresponds to the correct subject, computer storage, or a computer processor. The claims merely use existing methods for these steps. Note that MPEP 2106.05(a) indicates that “[g]athering and analyzing information using conventional techniques and displaying the result” is an example that the courts have indicated may not be sufficient to show an improvement to technology.
MPEP 2106.05(b) has to do with whether the claims involve the use of a particular machine. In this case, the claims do not involve the use of a particular machine. While the instant claims recite steps of obtaining cfDNA samples from test subjects with a known age; sequencing the cfDNA via targeted whole genome bisulfite sequencing; determining a methylation density at a plurality of selected CpG sites based on the sequencing; predicting a sample age range with a trained regression model; validating the sample is from the reported subject; identifying pertinent CpG sites via regression models; performing cancer prediction for the cfDNA sample with the methylation sequence reads from that sample; excluding CpG sites related to cancer, sex, and ethnicity; using a non-transitory computer-readable storage medium with instructions to perform the previously listed steps; and a system for validation comprising a computer processor and the storage medium previously described and involve the use of machines (e.g. a computer), no particular computer is required by the claims. Furthermore, no machine is required for obtaining the sequencing data, and certainly no particular machine. Further considerations such as the particularity or generality of the recited machine must be taken into account, as well as whether the involvement of the machine is merely instructions to apply an exception or extra-solution activity. MPEP 2106.05(f) describes “mere instructions to apply an exception”, noting that “[r]equiring the use of software to tailor information and provide it to the user on a generic computer” is an example of “the claim invokes computers…merely as a tool to perform an existing process” which the courts have found to be merely instructions to apply. MPEP 2106.05(g) describes “extra-solution activity”, noting that “[d]etermining the level of a biomarker in blood” is an example of “mere data gathering” which the courts have found to be insignificant extra-solution activity.
MPEP 2106.05(c) has to do with whether the claims involve a particular transformation. Here, none of the limitations of the claims involve a particular transformation. For example, targeted whole genome bisulfite sequencing does not transform the sequenced DNA into something else during the sequencing process, it is still DNA after sequencing.
MPEP 2106.05(e) has to do with “other meaningful limitations”. The additional limitations imposed upon the abstract idea of validating that a cfDNA sample is from a test subject in the instant case have to do with obtaining cfDNA samples from test subjects with a known age; sequencing the cfDNA via targeted whole genome bisulfite sequencing; determining a methylation density at a plurality of selected CpG sites based on the sequencing; predicting a sample age range with a trained regression model; validating the sample is from the reported subject; identifying pertinent CpG sites via regression models; performing cancer prediction for the cfDNA sample with the methylation sequence reads from that sample; excluding CpG sites related to cancer, sex, and ethnicity; using a non-transitory computer-readable storage medium with instructions to perform the previously listed steps; and a system for validation comprising a computer processor and the storage medium previously described. These limitations are not considered “meaningful limitations”. MPEP 2106.05(e) states: “The phrase "meaningful limitations" has been used by the courts even before Alice and Mayo in various contexts to describe additional elements that provide an inventive concept to the claim as a whole.” Ultimately, there is no information output, there is simply the validation of information and a prediction. Furthermore, even though the system is described as “trained”, there is no further detail that could meaningfully provide integration of the judicial exception. These limitations do not arrive at an inventive concept. In addition, as has been discussed, they represent insignificant extra-solution activity, i.e. “data gathering”.
MPEP 2106.05(f) raises the question as to whether the additional elements recited in the claim represent “mere instructions to apply an exception”. Here, the judicial exception is the abstract idea of validating that a cell-free deoxyribonucleic acid (cfDNA) sample is from a test subject. The additional elements recited in the claims (i.e. obtaining cfDNA samples from test subjects with a known age; sequencing the cfDNA via targeted whole genome bisulfite sequencing; determining a methylation density at a plurality of selected CpG sites based on the sequencing; predicting a sample age range with a trained regression model; validating the sample is from the reported subject; identifying pertinent CpG sites via regression models; performing cancer prediction for the cfDNA sample with the methylation sequence reads from that sample; excluding CpG sites related to cancer, sex, and ethnicity; using a non-transitory computer-readable storage medium with instructions to perform the previously listed steps; and a system for validation comprising a computer processor and the storage medium previously described) do amount to mere instructions to apply the abstract idea, since the collection of cfDNA samples from subjects, sequencing those samples, and analyzing the resulting sequencing data with a trained regression model serve as mere conventional steps taken for the purpose of gathering data about the DNA methylation state in a subject, which any practical use of the abstract idea would require. Furthermore, the generic use of a computer amounts to mere instructions to apply an exception. As previously noted, “[r]equiring the use of software to tailor information and provide it to the user on a generic computer” is an example of “the claim invokes computers…merely as a tool to perform an existing process” which the courts have found to be merely instructions to apply an exception.
MPEP 2106.05(g) has to do with whether the additional elements of the claim amount to insignificant extra-solution activity. MPEP 2106.05(g) notes that “[d]etermining the level of a biomarker in blood” is an example of “mere data gathering” which the courts have found to be insignificant extra - solution activity. Likewise, MPEP 2106.05(g) notes that “[p]erforming clinical tests on individuals to obtain input for an equation” also represents insignificant extra-solution activity. This aligns closely with the instant claims, where the additional elements of the claims amount to obtaining cfDNA samples from test subjects with a known age; sequencing the cfDNA via targeted whole genome bisulfite sequencing; determining a methylation density at a plurality of selected CpG sites based on the sequencing; predicting a sample age range with a trained regression model; validating the sample is from the reported subject; identifying pertinent CpG sites via regression models; performing cancer prediction for the cfDNA sample with the methylation sequence reads from that sample; excluding CpG sites related to cancer, sex, and ethnicity; using a non-transitory computer-readable storage medium with instructions to perform the previously listed steps; and a system for validation comprising a computer processor and the storage medium previously described. It should be noted that the abstract idea of validating the sample is from the reported subject amounts to insignificant extra-solution activity because it only requires physically looking at the predicted age and comparing it to the reported age of the subject. The same is true of performing cancer prediction for the cfDNA sample, it only requires physically looking at results and saying whether there is cancer or not.
MPEP 2106.05(h) has to do with whether the additional elements amount to more than generally linking the use of a judicial exception to a particular technological environment or field of use. Here, the recitation of the method being used to validate that a cfDNA sample is from a test subject is considered a “field of use”. However, as MPEP 2106.05(h) indications, such limiting to a particular “field of use” does not confer patentability on otherwise ineligible subject matter.
Having considered the factors discussed in MPEP 2106.05 (a)-(c) and (e)-(h), it is clear that the additional elements recited in the claims, whether considered individually or as a combination, do not integrate the judicial exception (e.g. the abstract idea of validating that a cfDNA sample is from a test subject) into a practical application of that exception in such a way as to provide meaningful limits on the use of the judicial exception.
Response to Arguments
Applicant's arguments filed December 17th, 2025 have been fully considered but they are not persuasive.
The Applicant first summarizes subject matter eligibility as outlined in the MPEP (Pages 10-11 of the Remarks filed December 17th, 2025). The Applicant argues that, based on the eligibility requirements, “(1) under Step 2A, Prong Two, the additional elements integrate any alleged judicial exception into a practical application, and (2) under Step 2B, the additional elements are non-routine and unconventional activity that amount to an inventive concept.” (Page 11 of the Remarks filed December 17th, 2025).
The Applicant identifies a number of aspects of claim 28 that are considered to be additional elements beyond the alleged abstract idea judicial exception (Page 6 of the Remarks filed December 17th, 2025). The Applicant also states that the additionally amended limitation regarding response to validating cannot be characterized as part of the alleged abstract idea (Page 11 of the Remarks filed December 17th, 2025).
In response to this these arguments, as it has been analyzed above, while the aspects of claim 28 may be additional elements beyond the alleged abstract idea, they do not represent additional elements that amount to more than the judicial exception itself given that these elements are insignificant extra-solution activity, i.e. “data gathering”. Furthermore, the additionally amended limitation regarding response to validating is itself an abstract idea as it can amount to a mental step performed in the human mind (e.g. looking at results and saying a test subject has cancer or not). A judicial exception cannot serve to integrate a judicial exception into a practical application (see MPEP 2106.04(II)(A)(2)). Therefore, these aspects of the Applicant’s arguments are not found persuasive.
The Applicant next argues that the additional limitations sufficiently integrate any alleged judicial exceptions into a practical application under Step 2A, Prong Two (Page 11 of the Remarks filed December 17th, 2025). The Applicant provides relevant aspects of the MPEP, namely “limitations the courts have found indicative that an additional element (or combination of elements) may have integrated the exception into a practical application include: an improvement in the functioning of a computer, or an improvement to other technology or technical field...." MPEP § 2106.04(d)” (Page 12 of the Remarks filed December 17th, 2025). The Applicant argues that the steps claimed relate to a concrete technical improvement to bioinformatics-based cancer prediction from cfDNA fragments, following by aspects of the invention (Page 12 of the Remarks filed December 17th, 2025). The Applicant argues that the recited technological solution thereby integrates the alleged judicial exception into a practical application, supporting eligibility under Step 2A, Prong Two (Page 12 of the Remarks filed December 17th, 2025).
In response to this these arguments, again, while the aspects of claim 28 may be additional elements beyond the alleged abstract idea, they do not represent additional elements that amount to more than the judicial exception itself given that these elements are insignificant extra-solution activity, i.e. “data gathering”. Also, as has been noted above, MPEP 2106.05(a) indicates that “[g]athering and analyzing information using conventional techniques and displaying the result” is an example that the courts have indicated may not be sufficient to show an improvement to technology. The Applicant has not indicated a novel way of collecting information on cfDNA methylation, nor a different analysis technique other than conventional regression models for prediction. Therefore, the additional elements do not serve to integrate the judicial exceptions into a practical application, and these aspects of the Applicant’s argument are not found persuasive.
The Applicant next argues that the additional limitations are non-routine, unconventional, and not well understood activity in the technological field, thereby amount to an inventive concept supporting eligibility under Step 2B (Page 12 of the Remarks filed December 17th, 2025). The Applicant provides aspects of the MPEP, namely “an examiner should determine that an element (or combination of elements) is well-understood, routine, conventional activity only when the examiner can readily conclude, based on their expertise in the art, that the element is widely prevalent or in common use in the relevant industry" (italics for emphasis). MPEP § 2106.05(d).” (Page 12 of the Remarks filed December 17th, 2025). The Applicant argues that the additional elements are not so widely prevalent because this requires a high degree of understanding among artisans in the field such that it doesn’t need to be described in detail (Page 13 of the Remarks filed December 17th, 2025). The Applicant states that the additional elements are not so widely prevalent as to render them conventional, routine, or well understood, and also that the prior art does not teach or suggest the additional elements given the lack of art rejections (Page 13 of the Remarks filed December 17th, 2025). The Applicant argues that because of this, the additional elements further support finding of eligibility under Step 2B, in addition to Step 2A, Prong Two (Page 13 of the Remarks filed December 17th, 2025).
In response to these arguments, it is noted that the aspects of claim 1 that the Applicant has identified as additional elements do represent well-understood, routine, and conventional activity. Obtaining demographic data about a test subject, methylations sequencing of cfDNA, determining methylation density, and using trained regression models to determine a predicted value are routine in the relevant field. Also, a lack of art rejection does not then immediately convey that additional elements are not routine as a determination can be made based on general knowledge and court recognized routine elements. Furthermore, the Applicant has not clearly argued which aspects may represent an additional element that is not so widely prevalent as to be well-understood, routine, and conventional. Therefore, these aspects of the Applicant’s argument are not found persuasive.
While the Applicant has directed arguments towards claim 28, the Applicant makes clear that claims 53 and 62 recite analogous limitations, and that these claims and their dependent claims are directed to patentable subject matter (Page 13 of the Remarks filed December 17th, 2025). However, given the arguments presented above, the rejection under 35 U.S.C. 101 is modified as necessitated by amendment and maintained.
Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure:
Horvath (DNA methylation age of human tissues and cell types, Genome Biology, December 2013, 14, 1-19; previously cited) obtained a large DNA methylation dataset through the combination of publicly available sequencing data (Page 2, column 1, Description of the (non-cancer) DNA methylation data sets), trained regression models on the data to develop an age predictor (Page 2, column 1, The multi-tissue age predictor used for defining DNAm age), and confirmed the accuracy of the predictor across a number of tissues and cells (Page 2, column 2, Predictive accuracy across different tissues). This modeling was performed on a computer using the software package R (Page 13, column 1 and 2, Definition of DNAm age using a penalized regression model). This prior art is pertinent to the disclosure as it describes developing an age predictor using DNA methylation data. However, it does not describe the limitation of validating that a sample is from a test subject based on a predicted age of the sample and the reported age of the test subject, nor does it specifically detail using methylation data from cfDNA.
Huang and Wang (Cell-Free DNA Methylation Profiling Analysis—Technologies and Bioinformatics, Cancers, November 2019, 11, 1-22; previously cited) review methods of DNA methylation profiling in cfDNA in regards to cancer detection. They detail a number of different techniques for detecting methylation (starting Page 2, section 2, Technologies for DNA Methylation Detection), as well as how analysis of cfDNA methylation has developed (Page 11, section 3.4, Identification of Tumor-Specific Methylation Profile). This prior art is pertinent to the disclosure as it describes detection of methylation changes in cfDNA as it relates to cancer. However, it does not describe how to use methylation changes in cfDNA to determine age of a test subject, nor does it describe validating that a sample is from a test subject based on a predicted age of the sample and the reported age of the test subject.
Conclusion
All claims stand rejected.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Allison E Schloop whose telephone number is (703)756-4597. The examiner can normally be reached Monday-Friday 8:30-5 ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Anne Gussow can be reached at (571) 272-6047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ALLISON E SCHLOOP/
Examiner, Art Unit 1683
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683