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 .
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 25 is new.
Claims 1-25 are under examination.
Claim Rejections - 35 USC § 101
The rejection is maintained from the previous Office Action of 9/22/2025 and modified in view of amendments filed 12/22/2025.
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 1-25 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 1-11 are drawn to a non-transitory computer readable medium, so a manufacture.
Claims 12-25 are drawn to a method, so a process.
Step 2A Prong One: Identification of an Abstract Idea
The claim(s) recite(s):
1. perform a first intra-individual analysis using a first biological sample to generate a first set of background-corrected methylation information representing a difference between methylation information from cell-free target nucleic acids from the first biological sample and methylation information 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 a second intra-individual analysis using a second biological sample to generate a second set of background-corrected methylation information representing a difference between methylation information from cell free target nucleic acids from the second biological sample and methylation information from genomic DNA from cells from the second biological sample wherein the second biological sample was obtained from the subject at a second timepoint subsequent to the first timepoint.
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. The step is therefore an abstract idea.
3. determine a change in signal between the first set of background-corrected methylation information from the first intra-individual analysis and the second set of background-corrected methylation information 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.
The step reads on analyzing signal data which can be performed by the human mind and is therefore an abstract idea.
Dependent claims 2-11 and 13-25 are further drawn to describing the information analyzed by the abstract idea steps, and therefore 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. The process results in determining information and can be performed by the human mind.
New claim 25 recites performing a second analysis comprising tracking tumor heterogeneity of a subject and further administering a guided therapy according to the tracked tumor heterogeneity. This limitation is general with respect to the analysis and does not recite any specific outcome so as to integrate the abstract idea into the additional element of administering therapy. Furthermore, a particular treatment is not recited. Administering “therapy” is not a particular treatment. The limitation is therefore a just “apply it,” step as described in MPEP 2106.05(f).
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 12/22/2025 have been fully considered but they are not persuasive.
Applicants argue (Remarks, page 6, par. 4) that the amended claims are limited in a meaningful way by reciting particular types of samples including cell-free target DNA and genomic DNA from cells, and a particular type of analysis. Applicants argue (Remarks, page 14, par. 1) that for these reasons the claims are directed to a patent eligible improvement.
In response, specificity in the recited judicial exception or any additional elements does not equate to an improvement to technology. Claims are analyzed using the Two Step analysis to determine if the recited judicial exception is integrated into an additional element that is a practical application under Step 2A Prong Two or if the recited judicial exception is integrated with additional element(s) that are not routine and conventional, under Step 2B.
Applicants argue that claim 1 recites at least the additional elements listed (page 14, par. 3). Applicants argue (Remarks, page 15) that these are wet lab steps that are recited in detail and are particular. Applicants argue that these steps are not incidental or tangential.
In response, claim 1 does not recite the argued limitations (bullet points). Claim 1 is entirely directed to an abstract idea of signal analysis. Instead, claim 18 recites physical steps of obtaining cell free DNA, performing bisulfite conversion and amplifying CpG sites of the bisulfite converted cell-free DNA.
Furthermore, the steps of obtaining cell free DNA, performing bisulfite conversion and amplifying CpG sites of the bisulfite converted cell-free DNA and genomic DNA recited in claim 18 are part of an initial data collection step and not a practical application. Categories of practical application are listed under Step 2A Prong Two. While the initial steps of performing bisulfite conversion and CpG site amplification of cell-free DNA and genomic DNA are additional elements, these steps do not apply the recited abstract ideas steps and therefore are not a practical application.
Applicants argue (Remarks, page 16) that the claims are an improvement to the technology of tracking tumor heterogeneity across different timepoints involving multiple intra-individual analyses. Applicants point to the steps of determining a first and second set of background corrected methylation information representing a difference between methylation information between the cell-free DNA and genomic DNA.
In response, the argued limitations are drawn to data analysis by math performed on signal data or even a mental process of considering the difference between “information.” These steps do not reflect an improvement to technology because the claims do not recite any additional elements that reflect an improvement to technology. Data or information per se is abstract and while information may be improved, meaningful or useful, data/information resulting from an abstract idea is not in itself an “improvement to technology.”
In BuySafe, Inc. v. Google, Inc., the court put forth:
Such a claim falls outside section 101 if (a) it is “directed to” matter in one of the three excluded categories and (b) “the additional elements” do not supply an “inventive concept” in the physical realm of things and acts—a “new and useful application” of the ineligible matter in the physical realm—that ensures that the patent is on something “significantly more than” the ineligible matter itself. BuySafe, Inc. v. Google, Inc.
Instantly, the claims are directed to collecting a data set of information to be analyzed by initial steps of bisulfite conversion and CpG site amplification of cell-free DNA and genomic DNA are additional elements. The information is then analyzed by way of math or steps that can be performed by the human mind. The results of the analysis are not integrated into any “physical realm” additional elements that would reflect an improvement to technology.
Applicants argue (Remarks, page 16, par. 3) that the recited additional elements when considered in combination with the alleged judicial exception achieve the technical improvement.
In response, the recited additional elements are routine, conventional and well understood (as will be discussed herein) and the abstract idea steps merely analyze the difference between two samples, one of cell-free DNA and the other in genomic DNA to determine a change, i.e. profiling a spectra against a reference spectra. It is not clear where the technical improvement lies because bisulfite conversion and CpG site amplification to determine methylation status of cell free DNA and genomic DNA is routine. The subsequent comparison of the derived information is an abstract idea.
Applicants argue (Remarks, page 17, par. 1) that the intra-individual analysis corrects for the methylation information on a per-patient basis and therefore ensures that the background corrected methylation information is personalized for each patient.
In response, Applicants appear to argue an improvement in data analysis of background correcting methylation information against a second sample. The step can be performed with the human mind or with math and is therefore an abstract idea categorized under Step 2A Prong One.
Applicants argue (page 18) Step 2B and list additional elements as the limitations drawn to a first and second set of background corrected methylation information from cell-free target nucleic acids and genomic DNA from cells from a first and second sample, respectively. Applicants argue that the additional elements are not known in the art.
In response, the pointed to limitations are not drawn to physical processes or product parts in the real world realm, or necessitate computer technology on a physical computer, and therefore these limitations are not additional elements analyzed under Step 2B. The pointed to limitations are part of the abstract idea steps listed under Step 2A Prong One. The limitations describing that the methylation information is “from cell-free nucleic acids” and “genomic DNA” from a first and second sample only describes the origin of the information but do not change the nature of the information which is numerical data representing a difference in methylation signals. These limitations are therefore not analyzed with respect to whether they are routine, conventional and well understood under Step 2B.
Claim Rejections - 35 USC § 112-2nd paragraph
The rejections over claims 1 and 10 are withdrawn in view of Applicant’s amendments filed 12/22/2025. The instant rejection is maintained.
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 4 and 15 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 pre-AIA the applicant regards as the invention.
Claim 4 recites CpG islands or portions of one or more CpG islands shown in Tables 1-4. It is unclear which of the items listed in Tables 1-4 are “islands” and which are “portions” of islands. Claim 15 recites the same limitation which requires clarification.
Furthermore, claims 4 and 15 attempt to incorporate tables by reference. MPEP 2173.05(s) states that:
Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993).
According to USPTO guidance, MPEP 2173.05(s) must be adhered to else, the claim is found indefinite. Should Applicants intend to recite the subject matter listed in Tables 1-4, Applicants must incorporate the table(s) into the claim(s).
Response to Arguments
Applicant's arguments filed 12/22/2025 have been fully considered but they are not persuasive.
Applicants argue that Tables 1-4 makeup more than 70 pages and therefore incorporation is impractical.
In response, according to USPTO Guidance if the Table can be incorporated into the claims, it is therefore not impractical. This rejection must therefore be maintained.
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
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 extension fee 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 date of this final action.
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