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 .
Specification
The disclosure is objected to because of the following informalities: The specification refers to figures that do not properly match the discussion, see ¶0064 and following.
Appropriate correction is required.
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 13-15 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.
The claims are indefinite over the recitation of “cancer/tumor” because it is not clear if a tumor is a required element or an alternative.
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) 1-12, 17-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Nuzzo et al. (Nature Medicine Vol 26, July 2020 pages 1041-1043 AND additional online information; 11 pages total) in view of Zhu et al. (Mol Diagn Ther 24, 95–101 (2020)) and Gansauge et al. (Nature Protocols, 2013, Vol. 8, No. 4, pages 737-748).
Nuzzo teaches a method that comprises obtaining plasma and urine cfDNA, which are DNA samples that comprise single stranded DNA and double stranded DNA, inherently. See Methods, Sample processing and cfDNA isolation.
Nuzzo teaches carrying out cfDNA library prep, and then heat denaturing the library which produces single stranded DNA. See Methods, cfmeDIP-seq protocol.
Nuzzo teaches immunoprecipitating the ssDNA using one or more antibodies against 5mC.
Nuzzo teaches amplifying the immunoprecipitated DNA and sequencing the amplified DNA to detect the presence of 5mC, thereby detecting methylation in the cell-free polynucleotides. See Methods, Next-generation sequencing library construction.
Regarding claim 8, Nuzzo further teaches that the cell-free immunoprecipitation protocol is capable of detecting early-stage tumors and report accurate classification of patients across all stages of renal cell carcinoma in plasma and urine (abstract and throughout).
Nuzzo does not teach that the cfDNA library preparation includes the steps of (b), (c), and (d) as set forth in claim 1 and Claim 8.
Zhu teaches advantages of single-stranded DNA library preparation over double-stranded DNA library preparation for capturing cell-free tumor DNA. The reference teaches that the ctDNA content and plasma genomic abnormality scores were consistently higher in the ssDNA and pure-ssDNA libraries than in the matched dsDNA libraries. Zhu teaches that ssDNA libraries preserve more diversity and capture more ctDNA than dsDNA libraries and is preferred when performing genomic analysis of ctDNA. Abstract and throughout.
Zhu teaches that the ssDNA method included denaturing the DNA, adaptase, extension, adaptor ligation (p. 96, section 2.2). Zhu does not provide a detailed protocol, but Zhu cites to Gansauge2013 when discussing ssDNA library preparation (p. 96, 1st column).
Gansauge 2013 teaches a single stranded library preparation that includes steps of denaturing the DNA sample, ligating a single stranded adaptor to the 3’ endo of the ssDNA with a ssDNA ligase, converting the ssDNA into double stranded DNA with a DNA polymerase, and ligating a dsDNA adaptor to the dsDNA.
It would have been prima facie obvious to have modified the method taught by Nuzzo so as to have employed a single-stranded library preparation, as taught by Zhu and Gansauge. One would have been motivated to do so by the direct suggestion of Zhu who teaches the advantages of single-stranded DNA library preparation over double-stranded DNA library preparation for capturing cell-free tumor DNA.
With regard to claims 2 and 9, the sequencing prep taught by Gansauge includes an initial step of denaturing DNA.
With regard to claims 3, 4, 10, and 11 the bodily samples taught by Nuzzo include plasma and urine.
With regard to claims 5 and 12, Nuzzo teaches that the subjects are humans, which are mammals.
With regard to claims 6 and 18, the immunoprecipitation is performed with antibodies against 5mC. See Reporting Summary, section “Antibodies” which teaches the method uses 5-mC antibody provided in the MagMeDip kit.
With regard to claims 7 and 19, the amplifying is performed by PCR. See Nuzzo, Methods, Next-generation sequencing library construction.
With regard to claim 17, Nuzzo teaches that the methylation classifier can distinguish cancer types, namely RCC from UBC. See Figure 2(e) and p. 1043, 1st column.
Claim(s) 1-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over De Carvalho et al. (US 20200308651) in view of Zhu and Gansuange.
De Carvalho teaches a method that comprises obtaining plasma cfDNA, which is a DNA sample that comprises single stranded DNA and double stranded DNA, inherently. See abstract and examples, beginning at ¶0069.
De Carvalho teaches carrying out cfDNA library prep, and then heat denaturing the library which produces single stranded DNA. See ¶0076-0077.
De Carvalho teaches immunoprecipitating the ssDNA using one or more antibodies against 5mC, see ¶0077.
De Carvalho teaches amplifying the immunoprecipitated DNA and sequencing the amplified DNA to detect the presence of 5mC, thereby detecting methylation in the cell-free polynucleotides. See ¶0077-0079.
Regarding claim 8, De Carvalho further teaches that protocol is capable detecting tumors of a variety of types using cfDNA methylation profiles. See ¶0101 and following.
De Carvalho does not teach that the cfDNA library preparation includes the steps of (b), (c), and (d) as set forth in claim 1 and Claim 8.
Zhu teaches advantages of single-stranded DNA library preparation over double-stranded DNA library preparation for capturing cell-free tumor DNA. The reference teaches that the ctDNA content and plasma genomic abnormality scores were consistently higher in the ssDNA and pure-ssDNA libraries than in the matched dsDNA libraries. Zhu teaches that ssDNA libraries preserve more diversity and capture more ctDNA than dsDNA libraries and is preferred when performing genomic analysis of ctDNA. Abstract and throughout.
Zhu teaches that the ssDNA method included denaturing the DNA, adaptase, extension, adaptor ligation (p. 96, section 2.2). Zhu does not provide a detailed protocol, but Zhu cites to Gansauge2013 when discussing ssDNA library preparation (p. 96, 1st column).
Gansauge 2013 teaches a single stranded library preparation that includes steps of denaturing the DNA sample, ligating a single stranded adaptor to the 3’ endo of the ssDNA with a ssDNA ligase, converting the ssDNA into double stranded DNA with a DNA polymerase, and ligating a dsDNA adaptor to the dsDNA.
It would have been prima facie obvious to have modified the method taught by De Carvalho so as to have employed a single-stranded library preparation, as taught by Zhu and Gansauge. One would have been motivated to do so by the direct suggestion of Zhu who teaches the advantages of single-stranded DNA library preparation over double-stranded DNA library preparation for capturing cell-free tumor DNA.
With regard to claims 2 and 9, the sequencing prep taught by Gansauge includes an initial step of denaturing DNA.
With regard to claims 3, 4, 10, and 11 the bodily samples taught by De Carvalho were plasma, see ¶0072.
With regard to claims 5 and 12, De Carvalho teaches that the subjects are humans, which are mammals. ¶0072.
With regard to claims 6 and 18, the immunoprecipitation is performed with antibodies against 5mC. See ¶0077.
With regard to claims 7 and 19, the amplifying is performed by PCR. See ¶0077.
With regard to claims 13-15, De Carvalho teaches that the cancer is glioblastoma, see ¶0014, 0016, 0070, 0103 and Figure 4D.
With regard to claim 16, De Carvalho teaches classifying samples using a neural network, see ¶0032.
With regard to claim 17, De Carvalho teaches that the methylation classifier can discriminate GBM on the basis of the IDH gene mutational status. See Figure 4D and ¶0016.
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Juliet Switzer
Primary Examiner
Art Unit 1682
/JULIET C SWITZER/ Primary Examiner, Art Unit 1682
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