DETAILED CORRESPONDENCE
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 .
This action is in response to the papers filed November 13, 2025. Currently, claims 1-9, 11-17, 19, 25, 27-28 are pending. Claims 11-17, 19, 25, 27-28 have been withdrawn as drawn to non-elected subject matter.
All arguments have been thoroughly reviewed but are deemed non-persuasive for the reasons which follow. This action is made FINAL.
Any objections and rejections not reiterated below are hereby withdrawn.
Election/Restrictions
Applicant's election without traverse of Group I, Claims 1-9 in the paper filed July 16, 2025 is acknowledged.
The requirement is still deemed proper and is therefore made FINAL.
Priority
This application claims priority to CHINA 202111029341.8, filed September 1, 2021.
It is noted that a translation of the foreign document has not been received.
Drawings
The drawings are acceptable.
Claim Rejections - 35 USC § 112
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.
Claim(s) 1-9 is/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.
The claims have been amended to require “using the obtained circulating tumor DNA reference sample as a reference for the cfDNA” however it is unclear how this step is performed. The step does not require any actual steps but merely provides an intended use for the circulating tumor DNA reference sample. The artisan would not know how to use the tumor DNA reference sample. It is unclear whether the claim requires a comparing step. It is unclear whether the tumor cells are the same subject as the cfDNA being used as a reference for. Even more the preamble of the claim is limited to preparing the reference sample and does not provide any guidance how the final step of the method is accomplished. The metes and bounds of the claimed invention are unclear.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claim(s) 1-5, 7-9 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Han et al. (BBA General Subjects, Vol. 1863, 1235-1242, 2019).
Han teaches culturing tumor cells MCF7 (mammary adenocarcinoma), SW480 and SW620 (colorectal adenocarcinoma cells) with CPT (camptothecin), an apoptosis inducer. The apoptosis inducer CPT was cultured with the tumor cells at 10M for 24 or 48 hours (limitations of Claims 8-9). Han teaches extracellular DNA released by cells can be detected in vitro cell culture medium (page 1237, col. 2). Han teaches
Han teaches patterns of DNA fragmentation resulting from cell death can also be identified in plasma cell-free DNA (page 1235, para 2). Han teaches induced cytoxicity is measured by time-course assays for total cell counts, viability and annexin V-positive cell percentage, with results then compared with the levels of fragmentation derived from dPCR analysis using both cellular and cell-free DNA templates (page 1236, col 1, para 2). Han teaches that both cellular and cell-free DNA from human cell lines are increasingly fragmented after anti-cancer drug treatment over time (page 1236, col. 1, para 2). Cell lines are derived from tumor cells. Therefore, inducing apoptosis in cell lines meets the limitations of the instant claims. Han teaches dPCR assays exhibited the capability to detect differential DNA fragmentation statuses of cfDNA compared to the results from cellular DNA (page 1240, col. 2).
Han also teaches cells were collected at three different time points (page 1236, col. 1). Supplementary Figure 1C illustrates cellular DNA for the different cells with CPT at the 5, 24 and 48 time points (limitations of Claim 4-5). Camptothecin is an apoptosis inducer that binds to topoisomerase-DNA complex and causes DN double strand break (limitations of Claims 2-3, 7).
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Response to Arguments
The response traverses the rejection. The response asserts Han does not teach using the obtained circulating tumor DNA reference sample as a reference for the cfDNA but instead tested RP fragmentation index which is a ration between short and long target copy numbers within the RNase P gene. This argument has been considered but is not convincing because the claim does not set forth the metes and bounds for using the circulating tumor DNA reference sample as a reference for the cfDNA. Han teaches detecting differential DNA fragmentation statuses of cfDNA compared to the results from cellular DNA. This comparison would be a use of the reference sample absent further limitations to the recitation.
The “technical purpose” referred to by the response is not relevant to a 102-anticipation rejection. The reference teaches each of the required steps and thus anticipates the claimed invention. Thus, for the reasons above and those already of record, the rejection is maintained.
Claim(s) 1-3, 8-9 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Marques et al. (European J. of Cancer, Vol. 127, pages 130-138, January 31, 2020).
Marques teaches induction of apoptosis increased sensitivity to detect cancer mutations in plasma. Specifically, Marques teaches doxetaxel was cultured with lung cancer cells and xenografted mice (abstract). Marques teaches performing ctDNA analysis following the treatment. Increasing docetaxel concentrations were used, including 10uM (page 131, col. 2). Marques teaches ctDNA was assessed both in vitro and in vivo (page 132, col. 1).
Response to Arguments
The response traverses the rejection. The response asserts Marques does not teach using the obtained circulating tumor DNA reference sample as a reference for the cfDNA. The response further argues Marques fails to describe any fragmentation characteristics of cfDNA derived from cells or in plasma. This argument has been considered but is not convincing because the claim does not require fragmentation characteristics are analyzed or described. Thus, the response is arguing a limitation not in the claim.
Further, tumor tissue and blood were collected to evaluate the levels of apoptosis DNA release levels (abstract). Further, Marques teaches size distribution of cfDNA present in plasma was analyzed to establish a correlation between cfDNA and apoptosis (section 3.3).
Thus, for the reasons above and those already of record, the rejection is maintained.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Han et al. (BBA General Subjects, Vol. 1863, 1235-1242, 2019) in view of Yang et al. (J. of Cellular and molecular Medicine, Vol. 25, pages 801-812, December 1, 2020).
Han teaches culturing tumor cells MCF7 (mammary adenocarcinoma), SW480 and SW620 (colorectal adenocarcinoma cells) with CPT (camptothecin), an apoptosis inducer. The apoptosis inducer CPT was cultured with the tumor cells at 10M for 24 or 48 hours (limitations of Claims 8-9). Han teaches extracellular DNA released by cells can be detected in vitro cell culture medium (page 1237, col. 2). Han teaches Han also teaches cells were collected at three different time points (page 1236, col. 1). Supplementary Figure 1C illustrates cellular DNA for the different cells with CPT at the 5, 24 and 48 time points (limitations of Claim 4-5). Camptothecin is an apoptosis inducer that binds to topoisomerase-DNA complex and causes DN double strand break (limitations of Claims 2-3, 7).
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Han does not teach the apoptosis inducer is gracillin.
However, Yang teaches gracillian shows potent efficacy against colorectal cancer and stimulates apoptosis in human CRC cells. Gracillin significantly reduces viability and migration and stimulates apoptosis in human CRC cells (abstract). Yang teaches SW480 cells were used and apoptosis was induced by gracillian. Yang teaches 10uM of gracillian induces apoptosis of SW480 cells (Figure 1 c).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention to have substituted the apoptosis inducer CPT in the method of Han with the apoptosis inducer gracillin. The ordinary artisan would have appreciated gracillian and CPT were both apoptosis inhibitors and could have been substituted one for another and the results of the substitution would have been predictable. Thus, it would have been obvious to one of ordinary skill in the art to replace the CPT apoptosis inducer with another apoptosis inducer, namely gracillian, because one of ordinary skill in the art would have been able to carry out such a substitution, and the results were reasonably predictable.
Response to Arguments
The response traverses the rejection. The response asserts Claim 6 depends from claim 1 and requires the limitations of claim and Yan fails to cure the deficiencies of Han. This argument has been considered but is not convincing for the reasons argued above. Thus, for the reasons above and those already of record, the rejection is maintained.
Conclusion
No claims allowable over the art.
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 JEANINE ANNE GOLDBERG whose telephone number is (571)272-0743. The examiner can normally be reached Monday-Friday 6am-3:30pm.
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, Wu-Cheng (Winston) Shen can be reached on (571) 272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JEANINE A GOLDBERG/Primary Examiner, Art Unit 1682
December 17, 2025
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