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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-15, in the reply filed on 12/08/2025 is acknowledged. Group II, claims 16-18, are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
A first office action on the merits of claims 1-15 is set forth herein and claims 16-18 are withdrawn from consideration.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825 because the "Sequence Listing" part of the disclosure submitted as a PDF file (37 CFR 1.821(c)(2)) or on physical sheets of paper (37 CFR 1.821(c)(3)) is not the same as the CRF of the "Sequence Listing" as required by 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii). The sequences of the instant specification, pg. 5, are not the same as the sequences CRF of the “Sequence Listing”.
Required response - Applicant must provide:
A replacement "Sequence Listing" as described above in items 1) c) or d) in accordance with 37 CFR 1.825(b)(1)(ii) or (iii); as well as
An amendment specifically directing its entry into the application as required by 37 CFR 1.825(b)(2)(ii);
A statement that identified the locations of any deletions, replacements or additions to the “Sequence Listing” as required by 37 CFR 1.825(b)(3);
A statement that the "Sequence Listing" added by amendment includes no new matter as required by 37 CFR 1.825(b)(5);
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4); and
A statement that the content of the previously-filed CRF is identical to the "Sequence Listing" part of the disclosure added by amendment as required by 37 CFR 1.825(b)(7), where provided under item 1) c) or d) (note that where a "Sequence Listing" part of the disclosure is provided under item 1) a) or b), the text file will also serve as the CRF, and the statement of identity is not required);
OR
A CRF as required by 37 CFR 1.821(e)(1) or 1.821(e)(2); and
A statement that the content of the CRF is identical to the "Sequence Listing" part of the disclosure previously submitted as a PDF file (37 CFR 1.821(c)(2)) or on physical sheets of paper (37 CFR 1.821(c)(3)), as required by 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii).
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.
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 1-15 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 1, the recitation of “comprising an adapter, wherein the adapter comprises nucleotide sequences of A01-T, A01-B, A02-T, A02-B, A03-T, A03-B, A04-T, A04-B, A05-T, A05-B, A06-T, and A06-B” in lines 1-3 of the claim is unclear. It is unclear what “A01-T, A01-B, A02-T, A02-B, A03-T, A03-B, A04-T, A04-B, A05-T, A05-B, A06-T, and A06-B” means? Are the “A01-T, A01-B, A02-T, A02-B, A03-T, A03-B, A04-T, A04-B, A05-T, A05-B, A06-T, and A06-B” referring to particular nucleic acid sequences? Further, it is unclear how these can be used to identify what adapters comprises nucleic acid sequences of “A01-T, A01-B, A02-T, A02-B, A03-T, A03-B, A04-T, A04-B, A05-T, A05-B, A06-T, and A06-B”. In addition, as the SEQ ID NOs listed in the specification of the instant application alongside the identifiers of “A01-T, A01-B, A02-T, A02-B, A03-T, A03-B, A04-T, A04-B, A05-T, A05-B, A06-T, and A06-B” are not the same as the SEQ ID NOs listed in the CRF, it is unclear which sequence listing identifies “A01-T, A01-B, A02-T, A02-B, A03-T, A03-B, A04-T, A04-B, A05-T, A05-B, A06-T, and A06-B”. In addition, it is unclear if the limitation requires an adapter that comprises all of the “A01-T, A01-B, A02-T, A02-B, A03-T, A03-B, A04-T, A04-B, A05-T, A05-B, A06-T, and A06-B” sequences or if the limitation requires multiple adapters each with its own nucleic acid sequence, i.e. an adapter comprising nucleic acid sequence of A01-T, an adapter comprising nucleic A01-B, etc. If the former is true, it is unclear what the composition of an adapter comprises nucleic acid sequences of “A01-T, A01-B, A02-T, A02-B, A03-T, A03-B, A04-T, A04-B, A05-T, A05-B, A06-T, and A06-B” would comprise and look like. Finally, the recitation of “the adapter comprises nucleotide sequences of A01-T…, and A06-B” in lines 1-3 of the claim is unclear if an adapter comprises nucleotide sequences “A01-T…, and A06-B” or also includes adapters comprising shorter sequences of “A01-T…, and A06-B”, i.e. an adapter comprising 2 nucleotides (shorter sequence) of A01-T nucleic acid sequence.
Regarding claim 2, the recitation of “further comprising PCR amplification primers and a PCR amplification reagent, wherein the PCR amplification primers comprise nucleotide sequences of R01-F, R01-R, R02-F, and R02-R” in lines 1-3 of the claim is unclear. It is unclear what “R01-F, R01-R, R02-F, and R02-R” means? Are the “R01-F, R01-R, R02-F, and R02-R” referring to particular nucleic acid sequences? Further, it is unclear how these can be used to identify what primers comprises nucleic acid sequences of “R01-F, R01-R, R02-F, and R02-R”. In addition, as the SEQ ID NOs listed in the specification of the instant application alongside the identifiers of “R01-F, R01-R, R02-F, and R02-R” are not the same as the SEQ ID NOs listed in the CRF, it is unclear which sequence listing identifies “R01-F, R01-R, R02-F, and R02-R”. In addition, it is unclear if the limitation requires a primer that comprises all of the “R01-F, R01-R, R02-F, and R02-R” sequences or if the limitation requires multiple primers each with its own nucleic acid sequence, i.e. a primer comprising nucleic acid sequence of R01-F, a primer comprising nucleic R01-R, etc. If the former is true, it is unclear what the composition of a primer comprises nucleic acid sequences of “R01-F, R01-R, R02-F, and R02-R” would comprise and look like. Finally, the recitation of “the primers comprises nucleotide sequences of R01-F, R01-R, R02-F, and R02-R” in lines 1-3 of the claim is unclear if a primer comprises nucleotide sequences “R01-F, R01-R, R02-F, and R02-R” or also includes primers comprising shorter sequences of “R01-F, R01-R, R02-F, and R02-R”, i.e. a primer comprising 2 nucleotides (shorter sequence) of R01-F nucleic acid sequence.
Regarding claim 3, the recitation of “further comprising a PCR amplification reagent, wherein the PCR amplification reagent comprises a polymerase, dNTP, MgCl2, and Tris-HCl” in lines 1-3 of the claim is unclear. It is unclear if a singular PCR amplification reagent (i.e. “a PCR amplification reagent”) is required from the list of a polymerase, dNTP, MgCl2, and Tris-HCl, or if multiple PCR amplification reagents are required.
Claims 4-6, 9-11, 14, & 15 are rejected due to their dependence on claim 1, claims 7 & 12 are rejected due to their dependence on claim 2, and claims 8 & 13 are rejected due to their dependence on claim 3.
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.
Claim(s) 1-10 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hongcang (CN 113604540 A, November 2021), as cited in the IDS dated 06/06/2024.
Regarding claim 1, it is noted as discussed above that the recitation of “comprising an adapter, wherein the adapter comprises nucleotide sequences of A01-T, A01-B, A02-T, A02-B, A03-T, A03-B, A04-T, A04-B, A05-T, A05-B, A06-T, and A06-B” in lines 1-3 of the claim is unclear. In addition, it is unclear if the limitation requires an adapter that comprises all of the “A01-T, A01-B, A02-T, A02-B, A03-T, A03-B, A04-T, A04-B, A05-T, A05-B, A06-T, and A06-B” sequences or if the limitation requires multiple adapters each with its own nucleic acid sequence. Finally, the recitation of “the adapter comprises nucleotide sequences of A01-T…, and A06-B” in lines 1-3 of the claim is unclear if an adapter comprises nucleotide sequences “A01-T…, and A06-B” or also includes adapters comprising shorter sequences of “A01-T…, and A06-B”, i.e. an adapter comprising 2 nucleotides (shorter sequence) of A01-T nucleic acid sequence. Therefore, for the purposes of this rejection, the claim is given its broadest reasonable interpretation to comprise an adapter comprising shorter sequences of A01-T, A01-B, etc.
Hongcang teaches a reduced representation bisulfite sequencing (RRBS) library using circulating tumor DNA using methylated adapter sequences RRBS-1 through RRBS-12 with upstream and downstream sequences as shown in SEQ ID NO. 1 through SEQ ID NO. 24 where SEQ ID NO. 1 of Hongcang comprises a short sequence of A01-T nucleic acid sequence of the instant application, SEQ ID NO. 2 of Hongcang comprises a short sequence of A01-B nucleic acid sequence of the instant application, SEQ ID NO. 3 of Hongcang comprises a short sequence of A02-T nucleic acid sequence of the instant application, SEQ ID NO. 4 of Hongcang comprises a short sequence of A02-B nucleic acid sequence of the instant application, SEQ ID NO. 5 of Hongcang comprises a short sequence of A03-T nucleic acid sequence of the instant application, SEQ ID NO. 6 of Hongcang comprises a short sequence of A03-B nucleic acid sequence of the instant application, SEQ ID NO. 7 of Hongcang comprises a short sequence of A04-T nucleic acid sequence of the instant application, SEQ ID NO. 8 of Hongcang comprises a short sequence of A04-B nucleic acid sequence of the instant application, SEQ ID NO. 9 of Hongcang comprises a short sequence of A05-T nucleic acid sequence of the instant application, SEQ ID NO. 10 of Hongcang comprises a short sequence of A05-B nucleic acid sequence of the instant application, SEQ ID NO. 11 of Hongcang comprises a short sequence of A06-T nucleic acid sequence of the instant application, and SEQ ID NO. 12 of Hongcang comprises a short sequence of A06-B nucleic acid sequence of the instant application (adapter comprises nucleic acid sequences of A01-T…A06-B) (paragraph [0010] lines 1-20; claim 4 lines 1-9; claim 5 lines 1-22; sequence listing).
Regarding claim 2, it is noted as discussed above that the recitation of “further comprising PCR amplification primers and a PCR amplification reagent, wherein the PCR amplification primers comprise nucleotide sequences of R01-F, R01-R, R02-F, and R02-R” in lines 1-3 of the claim is unclear. In addition, it is unclear if the limitation requires a primer that comprises all of the “R01-F, R01-R, R02-F, and R02-R” sequences or if the limitation requires multiple primers each with its own nucleic acid sequence. Finally, the recitation of “the primers comprises nucleotide sequences of R01-F, R01-R, R02-F, and R02-R” in lines 1-3 of the claim is unclear if a primer comprises nucleotide sequences “R01-F, R01-R, R02-F, and R02-R” or also includes primers comprising shorter sequences of “R01-F, R01-R, R02-F, and R02-R”, i.e. a primer comprising 2 nucleotides (shorter sequence) of R01-F nucleic acid sequence. Therefore, for the purposes of this rejection, the claim is given its broadest reasonable interpretation to comprise a primer comprising shorter sequences of R01-F, R01-R, R02-F, and R02-R.
Hongcang teaches the use of amplification primers for PCR enrichment of the methylated library with primer sequences SEQ ID NO. 25 through SEQ ID NO. 31 where SEQ ID NO. 26 of Hongcang comprises a short sequence of R01-F of the instant application, SEQ ID NO. 27 of Hongcang comprises a short sequence of R01-R of the instant application, SEQ ID NO. 28 of Hongcang comprises a short sequence of R02-F of the instant application, and SEQ ID NO. 29 of Hongcang comprises a short sequence of R02-R of the instant application (primer comprises nucleic acid sequences of R01-F, R01-R, R02-F, and R02-R) (paragraph [0013] lines 1-4; claim 8 lines 1-6; sequence listing).
Regarding claim 3, Hongcang teaches the use of PCR amplification reagents of 2x KAPA HiFi HotStart Uracil + Ready Mix which contains the PCR amplification reagents of polymerase, dNTP, MgCl2, and Tris-HCl (Table 14).
Regarding claim 4, Hongcang teaches the use of a terminal-modifying enzyme (dephosphorylase) and the use of a 10X CutSmart buffer containing Kac, Tris-Ac, and Mg(Ac)2 (paragraph [0027] lines 1-5; Table 10).
Regarding claim 5, Hongcang teaches the use of dNTP mixture containing dATP, dCTP, and dGTP (Table 8).
Regarding claims 6-10, Hongcang teaches the use of an end repair enzyme, a DNA ligase, and dATP (end repair enzyme, ligase, and ATP) (paragraph [0013] lines 1-3; paragraph [0014] lines 1-2).
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(s) 11-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hongcang (CN 113604540 A, November 2021), as cited in the IDS dated 06/06/2024, in view of Shen (Shen et al.; Nature Letter, Vol. 563, pages 579-599, November 2018).
The teachings of Hongcang with respect to claims 1-5 are discussed above and incorporated herein.
Regarding claims 11-15, Hongcang teaches reduced representation bisulfite sequencing (RRBS) library using circulating tumor DNA in the postiiv3e control sample of blood tissue samples from lung cancer patients (positive control is a cancer tissue sample) (paragraph [0061] lines 1-6).
Hongcang does not teach that the negative control is healthy human blood DNA.
Shen teaches RRBS in circulating tumor DNA samples compared to blood samples of healthy controls (negative control is healthy human blood sample) (abstract lines 1-19; pg. 580 column 2 1st full paragraph lines 1-9). In addition, Shen teaches that RRBS in circulating tumor DNA samples compared to negative control samples from healthy human blood samples identified thousands of differentially modified regions enabling ability to establish biomarkers for minimally invasive detection (abstract lines 16-19; pg. 580 column 2 1st full paragraph lines 9-13).
Hongcang and Shen are considered to be analogous to the claimed invention because they are all in the same field of using RRBS in tumor samples. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the use of a positive control of a cancer tissue sample in Hongcang to incorporate the use of a negative control of healthy human blood samples as taught in Shen because Shen teaches that doing so would provide the ability to identify differentially methylated regions and biomarkers in cancer versus healthy control samples to enable minimally invasive detection.
Conclusion
Claims 1-15 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BAILEY C BUCHANAN whose telephone number is (703)756-1315. The examiner can normally be reached Monday-Friday 8:00am-5:00pm ET.
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, 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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/BAILEY BUCHANAN/Examiner, Art Unit 1682
/JEHANNE S SITTON/Primary Examiner, Art Unit 1682