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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 March 23rd, 2026 has been entered.
Response to Amendment
The amendment filed March 23rd, 2026 is acknowledged. Regarding the Office Action mailed January 7th, 2026:
The rejection set forth under 35 U.S.C. 101 is withdrawn in view of the amendments.
The rejection set forth under 35 U.S.C. 103 is withdrawn in view of the amendments.
New grounds of rejection are set forth below, as necessitated by the amendments and further considerations.
Claim Summary
Claims 1, 13, 36, 38, and 49 have been amended. Claims 5, 10, 12, 14-22, 24-35, 37, 40-48, and 50-51 have been canceled. Claims 1-4, 6-9, 11, 13, 23, 36, 38-39, 49 and 52 are pending. Claims 1-4, 6-9, 11, 13, 23, 36, 38-39, 49 and 52 are under examination and discussed in this Office action.
Claim Rejections - 35 USC § 112(b) - New - Necessitated by Amendment and Further Considerations
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 1-4, 6-9, 11, 13, 23, 36, 38-39, 49 and 52 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.
Claim 1 recites the limitation “comparing the subject's nucleosome peaks to nucleosome peaks of a control sample; detecting the presence of cancer in the subject based on the subject's nucleosome peaks compared to nucleosome peaks of the control sample”. It is unclear from this recitation what metric is required to determine that presence of cancer has been detected based on the comparison between a subject’s nucleosome peaks and nucleosome peaks of a control. This metric could include an adjustment of the peaks upstream from the control, an adjustment of the peaks downstream from the control, no peak where there is one in the control, a peak where there isn’t one in the control, and potentially many other options. Without a defined metric, it is unclear how it is possible to determine presence of cancer compared to a control. Therefore, the claim is found indefinite. Claims 2-4, 6-9, 11, 13, 23, and 36 are also rejected here for their dependence on claim 1 and not further clarifying the identified issue.
Claim 38 recites the limitation “administering a modified cancer treatment regimen to the subject when the subject's second cfDNA fragmentation profile shows a greater difference from the reference sample cfDNA fragmentation profile than the subject's first cfDNA fragmentation profile, and otherwise continuing to administer the cancer treatment”. First, it is unclear from this recitation what comprises a modified cancer treatment. This could include many different options (changing dose of current treatment, changing treatments, adding a treatment, etc.) depending on what difference is seen between the second profile and the reference profile, and it is unclear from the generic language of the difference how to determine what type of modification would be required. Second, it is unclear from this recitation what the timing requirements between obtaining first and second samples, and therefore determining the first and second profiles, are to determine the need for modified cancer treatment. For instance, a second sample can be collected as soon as a few minutes after administering cancer treatment, which can also be within a day of collecting the first sample prior to administering treatment. If the timing is as short as this, it is unclear how a second profile from this second sample could reasonably indicate that cancer treatment needs to be modified. Finally, the term “greater” in claim 38 is a relative term which renders the claim indefinite. The term “greater” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Claims 39, 49, and 52 are also rejected here for their dependence on claim 38 and not further clarifying the identified issues.
Claim Rejections - 35 USC § 112(a) - New - Necessitated by Amendment
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-4, 6-9, 11, 13, 23, 36, 38-39, 49, and 52 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
This is a new matter rejection.
Claim 1 recites the limitation “identifying positions of nucleosome peaks by determining midpoints between the start and end sites of the cfDNA from the sample”. As written, this limitation reads that nucleosomes peak positions can be determined from midpoint positions between start and end sites of cfDNA. This limitation is not described in the specification such that the Applicant has possession of the claimed invention. Turning to the specification, the description related to determining nucleosome peaks can be found on Page 22, lines 17-27, wherein it is stated that “[p]ublished scripts based on window protection scores were used to create nucleosome occupancy maps using plasma and urine data”. These scripts are published in Snyder ((Cell-free DNA Comprises an In Vivo Nucleosome Footprint that Informs Its Tissues-Of-Origin, Cell, 2016, 164, 57-68; cited previously), as indicated by the provided list of references and is incorporated by reference (see Page 20, lines 11-14 of the instant specification). However, it does not appear from a review of this reference that nucleosome peaks are determined by identifying positions of nucleosome peaks by determining midpoints between the start and end sites of the cfDNA from the sample. Other description related to nucleosome peaks does not discuss aspects of the limitation as cited. At Page 11, lines 19-31, there is description of cfDNA fragmentation pattern being used to generate a nucleosome map that identifies nucleosome positions, but no active steps by which to identify these positions. At Page 29, lines 19-22, there is description of peaks in coverage compared between plasma and urine samples, but no description related to if the position of these peaks are determined by cfDNA midpoints. Furthermore, there is no figure that provides a visual indication of determining nucleosome peak positions based on cfDNA midpoints. Given the lack of description related to identifying nucleosome peaks based on cfDNA midpoints, the currently claimed “identifying positions of nucleosome peaks by determining midpoints between the start and end sites of the cfDNA from the sample” is considered new matter that is not adequately described in the instant disclosure.
Claim 1 also recites the limitation “responsive to detecting the presence of cancer, performing an invasive cancer diagnostic on the subject if nucleosome peaks indicating cancer are identified in the urine sample”. As written, this limitation reads that that claimed method can be used to indicate presence of cancer and further indicate performing an invasive cancer diagnostic. This limitation is not described in the specification such that the Applicant has possession of the claimed invention. Turning to the specification, there is no description related to performing an invasive diagnostic following comparison of subject nucleosome peaks with control nucleosome peaks to determine the presence of cancer. Instead, there is description related to the use of urine cfDNA as a non-invasive diagnostic (see Page 2, lines 13-15; Page 9, lines 22-25; Page 10, lines 1-7 of the instant specification). In other words, it appears the description in the instant specification is directed to non-invasive samples and techniques. There is no further indication in the specification that an invasive diagnostic should follow detecting presence of cancer via nucleosome peaks in urine cfDNA. Given the lack of description related to invasive diagnostics, the currently claimed “responsive to detecting the presence of cancer, performing an invasive cancer diagnostic on the subject if nucleosome peaks indicating cancer are identified in the urine sample” is considered new matter that is not adequately described in the instant disclosure.
Claims 2-4 and 6-9, 11, 13, 23, and 36 are also rejected here for their dependence on claim 1, and therefore also encompassing the identified new matter.
Claim 38 recites the limitation “administering a modified cancer treatment regimen to the subject when the subject's second cfDNA fragmentation profile shows a greater difference from the reference sample cfDNA fragmentation profile than the subject's first cfDNA fragmentation profile, and otherwise continuing to administer the cancer treatment”. As written, this limitation reads that the claimed method can be used to change treatment course when the second fragmentation profile has a greater difference from a reference than the first fragmentation profile, or not if there is no greater difference. This limitation is not described in the specification such that the Applicant has possession of the claimed invention. Turning to the specification, there is description related to determining a first and second fragmentation profile and determining a response to treatment based on the similarity or difference in the first and second fragmentation profiles as compared to a reference (see Page 3, lines 12-24 of the instant specification), which is also presented earlier in the claim. There is also description related to monitoring over time and making appropriate adjustments in treatment (see Page 19, lines 18-25 of the instant specification), as well as description for adjusting course of treatment based on subsequent measurement of cfDNA fragment frequency ranges (see Page 20, lines 5-10 of the instant specification). However, there is no description related to a second fragmentation profile with a greater difference from the reference sample cfDNA fragmentation profile than the subject's first cfDNA fragmentation profile being indicative of modifying a cancer treatment regimen, or not if there is no greater difference. Given this lack of description, the currently claimed “administering a modified cancer treatment regimen to the subject when the subject's second cfDNA fragmentation profile shows a greater difference from the reference sample cfDNA fragmentation profile than the subject's first cfDNA fragmentation profile, and otherwise continuing to administer the cancer treatment” is considered new matter that is not adequately described in the instant disclosure.
Claims 39, 49, and 52 are also rejected here for their dependence on claim 1, and therefore also encompassing the identified new matter.
Prior Art
The prior art made of record below and not relied upon is considered pertinent to applicant's disclosure, in addition to what has been cited in previous Office Actions.
Otandault (Recent advances in circulating nucleic acids in oncology, Annals of Oncology, February 2019, 30, 374-384) cites Markus et al showing “in contrast to plasma where cfDNA fragments of mononucleosome length are predominant, the length of the most abundant fragments in urine is short (80–81bp), which is consistent with DNA wrapped in a subnucleosomal structure and undergoing DNA digestion.” (Page 376, column 1, paragraph 1). However, Otandault does not teach on other aspects as claimed, such as determining nucleosome peaks from these fragments or detecting presence of cancer based on differences in nucleosome peaks determined from 80-81 bp fragments in cancer patients and controls.
Conclusion
All claims stand rejected.
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.
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/ALLISON E SCHLOOP/Examiner, Art Unit 1683
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683
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