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 .
REQUEST FOR CONTINUED EXAMINATION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 4/8/2026 has been entered.
Information Disclosure Statement
The IDS filed 12/22/2025 has been considered.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. Priority of US application 63/617989 filed 1/5/2024 is acknowledged.
Status of Claims
Amendments to the claims are acknowledged. Claim 26 is new.
Claims 2-5, 13-16 and 25 are cancelled.
Claims 1, 6-12, 17-24 and 26 are under examination.
Claim Rejections - 35 USC § 101
The rejection is maintained from the previous Office Action of 1/8/2026 and modified in view of amendments filed 4/8/2026.
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, 6-12, 17-24 and 26 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
Step 1: Process, Machine, Manufacture or Composition
Claims 1, 6-11 and 26 are drawn to a non-transitory computer readable medium, so a manufacture.
Claims 12 and 17-24 are drawn to a method, so a process.
Step 2A Prong One: Identification of an Abstract Idea
The claim(s) recite(s):
1. perform, at a baseline timpoint, a first intra-individual analysis using a first biological sample to generate a first set of background-corrected methylation information of a plurality of CpG sites representing a difference between methylation information of a plurality of CpG sites from cell-free target nucleic acids from the first biological sample and methylation information of a plurality of CpG sites from genomic DNA from cells from the first biological sample.
This step reads on subtracting or determining differences between signal data which can be performed by the human mind or with math. The step is therefore an abstract idea.
2. perform at a second time point, a second intra-individual analysis using a second biological sample to generate a second set of background-corrected methylation information of a plurality of CpG sites representing a difference between methylation information of a plurality of CpG sites from cell free target nucleic acids from the second biological sample and methylation information of a plurality of CpG sites from genomic DNA from cells from the second biological sample wherein between the baseline timepoint and second timepoint the subject is administered one or more tumor therapeutics.
This step reads on subtracting or determining differences between signal data obtained at a second time point, which can be performed by the human mind or with math. Claim 1 is drawn to instruction on computer readable media, therefore the limitation reciting that the subject is administered one or more tumor therapeutics between baseline and second timepoint is describing origins of the data which is analyzed. The step is therefore an abstract idea.
3. determine a change in signal between the first set of background-corrected methylation information of a plurality of CpG sites from the first intra-individual analysis and the second set of background-corrected methylation information of a plurality of CpG sites from the second intra-individual analysis.
The step reads on subtracting values determined in the previous two steps. This step can be performed by the human mind or with math. The step is therefore an abstract idea.
4. perform a second analysis comprising analyzing the determined change in signal between the first biological sample and the second biological sample and therefore track the tumor heterogeneity in the subject in response to the tumor therapeutic, the tracked tumor heterogeneity useful for guiding selection of a new tumor therapeutic when the tracked heterogeneity is stable or increasing or guiding continued administration of the tumor therapeutic when the tracked tumor heterogeneity is decreasing.
The step reads on analyzing signal data and tracking tumor heterogeneity can be performed by the human mind through mental analysis and is therefore an abstract idea. The limitation describing the usefulness of tracking tumor heterogeneity for guiding the selection of a therapeutic is an intended use and does not further limit the process step.
New claim 26 recites applying a machine learning model that analyzes the determined change in signal. The machine learning model is recited at a high degree of generality and reads on mathematics. Furthermore, the machine learning model is recited in a way equivalent to the words “apply it,” as described in MPEP 2106.05(f) and in the USPTO 2024 Guidance Update on Patent Subject Matter Eligibility, Including on Artificial Intelligence, Example 47, claim 2.
Dependent claims 1, 6-11, 17-24 and 26 are drawn to describing the information analyzed by the abstract idea steps and further abstract idea steps, and therefore are also judicial exceptions.
Step 2A Prong Two: Consideration of Practical Application
The claimed process results in a step of analyzing determined changes in signal from biological samples and tracking tumor heterogeneity. The process results in determining information and can be performed by the human mind.
The claimed process does not recite any additional elements that integrate the abstract idea into a practical application.
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.
Step 2B: 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 elements are drawn to:
1. obtaining sequence reads of cell free DNA from a first sample, as in claims 10 and 21.
2. obtaining long sequence reads at least 500 bases, from a second sample, as in claims 10 and 21.
3. obtaining target nucleic acid and reference nucleic acids from a first biological sample, as in claims 18 and 23.
4. performing bisulfite conversion of cell-free target nucleic acids and genomic DNA from cells, as in claims 18 and 23.
5. amplifying target regions of comprising CpG sites, as in claims 18 and 23.
6. administer guided therapy, as in claim 25.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because obtaining cfDNA and reference nucleic acids, performing amplification on sample nucleic acids including regions with CpG sites is routine, conventional and well understood. Evidence is provided in at least Lo et al. (US 2021/0265007). Yi et al. (BMC Molecular Biol, vol. 18 (2017) pgs. 1-8) also evidences bisulfite conversion (Abstract) and teach CpG site amplification (page 2, col. 2, par. 2 and Figure 1) Administering guided therapy in response to tumor analysis by cell free DNA analysis is also routine, conventional and well-understood.
Other elements of the method include the non-transitory computer readable medium which is a recitation of generic computer structure that serves to perform generic computer functions that are well-understood, routine, and conventional activities previously known to the pertinent industry. 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 4/8/2026 have been fully considered but they are not persuasive.
Applicants argue (Remarks, page 11, par. 4) that the claims are directed to a specific method for tracking tumor heterogeneity requiring specific types of nucleic acid information. Applicants further argue that the claims are directed to analyzing a change in signal between which a subject is administered one or more tumor therapeutics.
In response, specificity is not a criteria for determining subject matter eligibility. Under Step 2A Prong One, process steps are evaluated using Broadest Reasonable Interpretation (BRI) to determine if the step, as recited, can be performed by the human mind or with math. With respect to the limitation reciting “wherein between the baseline timepoint and second timepoint the subject is administered one or more tumor therapeutics,” this limitation can not be performed by instructions on a computer readable medium and is therefore interpreted as a description of the data analyzed at the second timepoint.
Applicants argue (Remarks, page 12, par. 3) that it is not clear how one can mentally generate methylation information from nucleic acids of a first biological sample, such as cell free target nucleic acids and genomic DNA from cells.
In response, analyzing a physical sample to generate methylation information would be a physical process and therefore considered an “additional element,” however, the claims do not recite such a step. Instead, the claims are broadly directed to performing an analysis “using a first biological sample,” and “using a second biological sample.” Moreover, the steps are carried out by a processor. Neither the characteristics of the sample or how it is used are recited. Therefore, the “biological sample” is interpreted as data and the step as a whole is interpreted as information analysis which can be performed by the human mind or with math.
Applicants argue that the claims recite “generate…background-corrected methylation representing a difference between methylation information” and it is not clear how one can mentally generate methylation information from nucleic acids of a second biological sample.
In response, methylation information can be generated from sequence data of methylated DNA. Once generated, signal or sequence data can be analyzed by the human mind or with mathematical algorithms. The claims do not recite any physical steps for gathering methylation information. Therefor under BRI, the analysis steps are interpreted as data analysis carried out by instructions on a processor.
Applicants argue (Remarks, page 12, par. 3) that methylation information of nucleic acids represents large-scale data that can not readily be processed and combined simply in the human mind.
In response, embodiments of changes in methylation include analysis with alignment and methylation calling or differential analysis which all broadly read on abstract ideas because these techniques are drawn to math. The claims are not specific to any data analysis techniques which may be considered as an “additional element” under Step 2B. Furthermore, a step that can be performed by the human mind but is performed over vast amounts of data could still constitute an abstract idea. The amount of data upon which a calculation is performed does not alter the nature of the calculation away from one that is math or is able to be performed by the human. While specific data or quantities are not recited, for the record, it is important to explain that analyzing a lot of data does not augment the steps being performed to analyze the data, which are abstract ideas. Computations on a lot of data performed mentally, or with paper and pencil, would take considerable time and effort, but that is, of course, the singular purpose of computers and computer networks, to perform large numbers of calculations, via algorithms, rapidly, and without error (assuming no error in user input). Although a general purpose computer can perform calculations at a rate and accuracy that can far outstrip the mental performance of a skilled artisan, the nature of the activity is essentially the same, and constitutes an abstract idea. See Bancorp Serves., L.L. C. v. Sun Life Assur. Co. of Canada (U.S.), 687 F.3d 1266,1278 (Fed. Cir. 2012) (holding that “the fact that the required calculations could be performed more efficiently via a computer does not materially alter the patent eligibility of the claimed subject matter”); see also See SiRF Tech., Inc. v. Int’l Trade Comm ’n, 601 F.3d 1319,1333 (Fed. Cir. 2010) (holding that: In order for the addition of a machine to impose a meaningful limit on the scope of a claim, it must play a significant part in permitting the claimed method to be performed, rather than function solely as an obvious mechanism for permitting a solution to be achieved more quickly, i.e., through the utilization of a computer for performing calculations).
Applicants argue that the claims now recite that the subject is administered therapy between the baseline timepoint and second time point.
In response, claim 1 is drawn to instruction on computer readable media, therefore the limitation reciting that the subject is administered one or more tumor therapeutics between baseline and second timepoint is describing origins of the data which is analyzed. The step of administering is not recited as an active process step, and the “wherein” clause is interpreted as a description of where the data analyzed originated (i.e. from a sample collected after a subject received therapy).
Applicants argue (Remarks, page 15, par. 2) that the claims recite a combination of additional elements that integrate the alleged judicial exception into a practical application. Applicants argue (Remarks, page 15, par. 2) that the claims achieve an improvement to technology which is tracking tumor heterogeneity.
In response, under Step 2A Prong Two, the claims do not recite any additional elements that reflect an improvement to technology. The claims result in analyzing determined change in signal between samples which is an abstract idea and not an improvement to technology, i.e. data is abstract and does not constitute technology. Furthermore, tracking tumor heterogeneity is also information analysis that can be performed by the human mind and therefore an abstract idea because this step reads on mental analysis of a tumor state.
Applicants argue (Remarks, page 15, par. 3) that additional elements should be considered in combination. Applicants point to limitations reciting that the subject is administered one or more tumor therapeutics between baseline and second timepoint and tracking tumor heterogeneity.
In response, the claims have been amended such that the step “the subject is administered one or more tumor therapeutics,” merely describes the data that is analyzed. The limitation is recited within the instructions stored on the computer readable medium of claim 1. Therefore the “wherein” clause is interpreted as a description of how the data was determined, to thereby characterize the data and not an actual physical step performed within the context of the claimed process. Furthermore, the step of tracking tumor heterogeneity broadly reads on a mental process of information analysis and is not an “additional element.”
Suggestions for Amendments
As discussed in the interview (summary filed 4/1/2026), to overcome the rejection under 35 USC 101 the claims could be amended to include an additional element (i.e. physical step) that integrates the process into a practical application. The method claims could be amended to recite a definitive step of administering specific guided therapy consistent with the specification (par. 0209). Specific treatments for administration, resulting from tracking tumor heterogeneity, are disclosed as chemotherapy, gene therapy, gene editing, ration therapy. The administering step should integrate the previous steps (i) to (iv) such that the administration is carried out rather than be an conditional limitation.
Claim Rejections - 35 USC § 112-2nd paragraph
The rejection of claims 4 and 15 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in view of Applicant’s amendments on 4/8/2026 cancelling the claims.
Claim Rejections - 35 USC § 103
The rejection of claims 1-9, 12-20, and 23-24 under 35 U.S.C. 103(a) as being unpatentable over Bjornsson et al. (Jama vol. 299 (2008) pages 2877-2883) in view of Friedlander et al. (US 2014/0006365) is withdrawn in view of Applicant’s amendments are arguments.
The rejection of claim 10, 11, 21 and 22 under 35 U.S.C. 103(a) as being unpatentable over Bjornsson et al. in view of Friedlander et al. as applied to claims 1-9, 12-20, 23-24 above, and further in view of Lo et al.(US 2021/0265007) is withdrawn in view of Applicant’s amendments and arguments.
E-mail communication Authorization
Per updated USPTO Internet usage policies, Applicant and/or applicant’s representative is encouraged to authorize the USPTO examiner to discuss any subject matter concerning the above application via Internet e-mail communications. See MPEP 502.03. To approve such communications, Applicant must provide written authorization for e-mail communication by submitting the following statement via EFS Web (using PTO/SB/439) or Central Fax (571-273-8300):
Recognizing that Internet communications are not secure, I hereby authorize the USPTO to communicate with the undersigned and practitioners in accordance with 37 CFR 1.33 and 37 CFR 1.34 concerning any subject matter of this application by video conferencing, instant messaging, or electronic mail. I understand that a copy of these communications will be made of record in the application file.
Written authorizations submitted to the Examiner via e-mail are NOT proper. Written authorizations must be submitted via EFS-Web (using PTO/SB/439) or Central Fax (571-273-8300). A paper copy of e-mail correspondence will be placed in the patent application when appropriate. E-mails from the USPTO are for the sole use of the intended recipient, and may contain information subject to the confidentiality requirement set forth in 35 USC § 122. See also MPEP 502.03.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Anna Skibinsky whose telephone number is (571) 272-4373. The examiner can normally be reached on 12 pm - 8:30 pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Ram Shukla can be reached on (571) 272-7035. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Anna Skibinsky/
Primary Examiner, AU 1635
Prosecution Insights