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 .
Response to Amendment
Applicant’s reply of 01/21/2026 is acknowledged. Regarding the Office action mailed 07/21/2025:
The objections to the claims are withdrawn in view of the amendments.
The rejections under 35 USC 112(b) are withdrawn in view of the amendments.
The rejection under 35 USC 101 is withdrawn for claims 27, 30, and moot with regard to claims 52-71 (as these claims have been cancelled). The rejection is maintained for claims 2 and 3 as reiterated below. Applicant’s arguments will be addressed following the rejection.
Claim Rejections - 35 USC § 101
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 2 and 3 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more. Claim 2 recites “detecting death of a cell type or tissue…by detecting the methylation status” of certain nucleic acid sequences in cell-free DNA. This describes a natural correlation between a cell type or tissue and the methylation state of its DNA. Claim 3 recites “wherein the methylation status” of certain nucleic acids “is characteristic of a cell type or tissue”. This also describes a natural correlation between a cell type or tissue and the methylation state of its DNA. This judicial exception is not integrated into a practical application because the additional elements recited in the claim amount to “mere data gathering”; see MPEP 2106.05(g). The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements of obtaining a specimen of cell-free DNA from a subject, treating the cell-free DNA and determining methylation based on sequencing is not an inventive concept, but was well-known, routine and conventional; see Guo (Nature Genetics 49(4):635-642 (2017)), and discussion thereof in the Office action mailed 07/21/2025. Likewise, determining methylation by treating DNA with bisulfite, hybridizing methylation-dependent oligonucleotides to the treated DNA, and amplifying to determine methylation status was also well-known, routine and conventional; see Eads (Nucleic Acids Research 28(8):e32 (2000); figure 1).
Response to Arguments
Applicant’s arguments concerning the rejection under 35 USC 101 have been fully considered, but they are not persuasive. Applicant argues that claims 2 and 3 have been amended to depend from claim 1, which was not subject to the rejection. This argument is not persuasive. Claim 1 was not rejected because it is not directed to a judicial exception, whereas claims 2 and 3 are, as explained in the rejection above. Applicant also argues that the claims have been amended to remove the “determining step”. However, the claims still set forth a judicial exception, as noted in the rejection above1. Finally, Applicant argues the additional elements recited in the claim were not well-known routine and conventional because Guo did not use primers to hybridize to the sample DNA, but rather to adaptors ligated to the sample DNA. This argument is not persuasive because it was also known in the art to hybridize primers directly to the bisulfite-treated DNA, as evidenced by Eads. Therefore, the rejection of claims 2 and 3 are maintained.
Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter: the prior art does not teach or suggest determining the methylation status of cell-free DNA for at least two methylation sites (i.e., CpG dinucleotides) in each of at least two different sequences recited in claim 1, wherein the methylation status is determined by contacting the cell-free DNA with bisulfite, and hybridizing oligonucleotides to the resulting bisulfite-converted DNA, specifically to the single-stranded DNA molecules “corresponding to the forward strand of the double-stranded, cell-free DNA molecule” and “corresponding to the reverse strand of the double-stranded, cell-free DNA molecule”. The closest prior art would be some sort of whole-genome bisulfite sequencing approach using cell-free DNA, such as disclosed by Guo (Nature Genetics 49(4):635-642 (2017), previously cited in the Office action mailed 07/21/2025). However, in Guo, while there was hybridization of oligos to bisulfite-treated cell-free DNA, the oligonucleotides were not hybridized to DNA molecules “corresponding to the forward strand of the double-stranded, cell-free DNA molecule” and “corresponding to the reverse strand of the double-stranded, cell-free DNA molecule”. Rather, in Guo’s method, adaptors were ligated to the cell-free DNA. Following bisulfite treatment, oligonucleotide primers were hybridized to the adaptors and used to amplify the bisulfite-converted DNA for subsequent sequencing analysis. The claim is construed to require that the oligonucleotides are hybridized to DNA sequences corresponding to the original cell-free DNA, not to adaptors to which the cell-free DNA had been ligated.
While hybridizing primers directly to bisulfite-converted DNA (rather than adaptors) was known in the art (see Eads, Nucleic Acids Research 28(8):e32 (2000); figure 1), this approach involves designing primers based on specific sequences. There is no suggestion in the prior art to target two or more of the specific sequences recited in claim 1 in cell-free DNA, and determine the methylation status of two or more methylation sites within each of said specific sequences.
Conclusion
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 SAMUEL C WOOLWINE whose telephone number is (571)272-1144. The examiner can normally be reached 9am-5:30pm.
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, GARY BENZION can be reached at 571-272-0782. 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.
/SAMUEL C WOOLWINE/Primary Examiner, Art Unit 1681
1 It was also noted on page 5 of the Office action mailed 07/21/2025: “The claims also recite a natural law which is the association between the methylation patterns of certain DNA markers and their cell or tissue of origin.”