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 .
This action is in response to papers filed 12/12/2025.
Claims 1, 5, 7-8, 10-13, 15, 17-18, 25, 31-37, 39, 41-43, 54, 62 are pending.
Claims 2-4, 6, 9, 14, 16, 19-24, 26-30, 38, 40, 44-53, 55-61, 63-68 are cancelled.
The following rejections are newly applied necessitated by amendment.
This action is FINAL.
Withdrawn Rejections
The 35 USC 112b and 35 USC 102 and 35 USC 103 rejections made in the previous office action are withdrawn based upon amendments to the claims.
Specification
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required: although the term “primer” is recited in the specification the term “exogenous primers” is not recited in the specification.
Claim Rejections - 35 USC § 112
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, 5, 7-8, 10-13, 15, 17-18, 25, 31-37, 39, 41-43 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.
Although the specification recites the term “primers” the specification does not teach “exogenous primers”. In particular it is not clear based upon the recitation if the term “exogenous primers” is intended to be different from the recitation of “primers” in the specificaoin. As such this recitation is considered new matter.
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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.
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) 1,5,7,8,10,12,15,25,37,39 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ji et al. (Clinical Chemical Acta 2004 Vol 342 p. 145-153) in view of in view of Lofton-Day et al. (US Patent 2003/0180779 Sept 25, 2003 previously cited).
With regard to claim 1, Ji et al. teaches a method of providing a sample of nucleic acid fragments that have one or more methylated cytosines (p. 146-147). Ji et al. teaches converting to yield converted fragments (p. 149 1st column). Ji et al. teaches using primers and a mixture of dNTPs (p. 149 2nd column). Ji et al. teaches different concentrations of biotinylated dCTP (p. 150). As such Ji et al. teaches the biotin of moiety modified dCTPs and the binding of lacking dCTPs and dGTPs using a linker based PCR.
With regard to claim 5, Ji et al. taches that bound fragments are separated from unbound (p 150 and figure 5).
With regard to claim 7, Ji et al. teaches that the DNA is amplified and therefore it is enriched (p. 146 2nd column).
With regard to claim 8, Ji et al. teaches use of targets from cancer (p. 146 1st column last paragraph).
With regard to claim 10 and 12, Ji et al. taches the use of fragmented genomic DNA and blood samples (p. 146 1st column last paragraph).
With regard to claim 15, Ji et al. teaches the use of biotin (p 150 and figure 5).
With regard to claim 25, Ji et al. teaches that the target has at least one CpG site (para 146 2nd column 1st paragraph).
With regard to claim 37 and 39, Ji et al. taches that bound fragments are separated from unbound with multiple methylated cytosines (p 150 and figure 5).
With regard to claims 1, Lofton-Day et al. teaches a method of using biotin labeled dCTP and unlabeled dCTP (para 42 and 145) for methaytlion analysis and high throughput comparisons. Although Lofton Day et al. does not provide the specific percentages, Lofton Day teaches that the ratio of label to unlabeled should be optimized to maximize label information and detection (para 145).
Therefore it would be prima facie obvious to one of ordinary skill in the art at the time of the effective filing date to modify the method of Ji et al to perform routine optimization of the percentage of labeling of the dCTP and dGTP as Lofton Day teaches that determination of the ratio is routine optimization performed such that the label is incorporated and detected. Absence secondary considerations the amount of a known label to perform a known detection would be considered routine experimentation in order to provide sufficient biotin for detection of the methaytlion.
Claim(s) 11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ji et al. (Clinical Chemical Acta 2004 Vol 342 p. 145-153) and Lofton-Day et al. (US Patent 2003/0180779 Sept 25, 2003 previously cited) as applied to claims 1,5,7,8,10,12,15,25,37,39 in view of Barany et al. (US Patent Application Publication 2018/0265917 September 20, 2018 previously cited).
Ji et al. teaches a method of providing a sample of nucleic acid fragments that have one or more methylated cytosines (p. 146-147). Ji et al. teaches converting to yield converted fragments (p. 149 1st column). Ji et al. teaches using primers and a mixture of dNTPs (p. 149 2nd column). Ji et al. teaches different concentrations of biotinylated dCTP (p. 150). As such Ji et al. teaches the biotin of moiety modified dCTPs and the binding of lacking dCTPs and dGTPs using a linker based PCR. Lofton-Day et al. teaches a method of using biotin labeled dCTP and unlabeled dCTP (para 42 and 145) for methaytlion analysis and high throughput comparisons. Although Lofton Day et al. does not provide the specific percentages, Lofton Day teaches that the ratio of label to unlabeled should be optimized to maximize label information and detection (para 145).
However, Ji et al. and Lofton Day does not teach that the sample is cfDNA.
With regard to claim 11, Barany et al. teaches methods of measuring methaytlion from cfDNA samples using biotin labels (para 297-310).
Therefore it would be prima facie obvious to one of ordinary skill in the art at the time of the effective filing date to modify the method of Ji et al. and Lofton Day to use known samples that methylation can be measured including cfDNA from Barany et al. The ordinary artisan would be motivated to detect cfDNA methylation in order to measure cell free changes in methylation. Furhtermore the ordinary artisan would have a reasonable expectation of success as Barany et al. teaches detection of methaytlion in cfDNA.
Claim(s) 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ji et al. (Clinical Chemical Acta 2004 Vol 342 p. 145-153) and Lofton-Day et al. (US Patent 2003/0180779 Sept 25, 2003 previously cited) as applied to claims 1,5,7,8,10,12,15,25,37,39 in view of Carroll et al. (US Patent Application Publication 2018/0325461 November 15, 2018 cited previously)..
Ji et al. teaches a method of providing a sample of nucleic acid fragments that have one or more methylated cytosines (p. 146-147). Ji et al. teaches converting to yield converted fragments (p. 149 1st column). Ji et al. teaches using primers and a mixture of dNTPs (p. 149 2nd column). Ji et al. teaches different concentrations of biotinylated dCTP (p. 150). As such Ji et al. teaches the biotin of moiety modified dCTPs and the binding of lacking dCTPs and dGTPs using a linker based PCR. Lofton-Day et al. teaches a method of using biotin labeled dCTP and unlabeled dCTP (para 42 and 145) for methaytlion analysis and high throughput comparisons. Although Lofton Day et al. does not provide the specific percentages, Lofton Day teaches that the ratio of label to unlabeled should be optimized to maximize label information and detection (para 145).
Ji et al. teaches use of bisulfite treatment (p. figure 7). However, Ji and Lofton Day do not teach that selectively deaminating the unmethylated cytosines.
With regard to claim 13, Carroll et al. teaches that bisulfite can be used to deaminate unmethylated cytosine residues (para 42).
Therefore it would be prima facie obvious to the ordinary artisan at the time of the effective filing date to modify the method of JI et al. to use the bisulfite used in Ji et al. such that the unmethylated cytosine residues are deaminated. The ordinary artisan would have a reasonable expectation of using bisulfite in a known method of deamination in the methylation process of Ji and Lofton Day.
Claim(s) 17-18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ji et al. (Clinical Chemical Acta 2004 Vol 342 p. 145-153) and Lofton-Day et al. (US Patent 2003/0180779 Sept 25, 2003 previously cited) as applied to claims 1,5,7,8,10,12,15,25,37,39 in view of Koshinsky et al. (US Patent Application Publication 2006/0147958 July 6, 2006 previously cited).
Ji et al. teaches a method of providing a sample of nucleic acid fragments that have one or more methylated cytosines (p. 146-147). Ji et al. teaches converting to yield converted fragments (p. 149 1st column). Ji et al. teaches using primers and a mixture of dNTPs (p. 149 2nd column). Ji et al. teaches different concentrations of biotinylated dCTP (p. 150). As such Ji et al. teaches the biotin of moiety modified dCTPs and the binding of lacking dCTPs and dGTPs using a linker based PCR. Lofton-Day et al. teaches a method of using biotin labeled dCTP and unlabeled dCTP (para 42 and 145) for methaytlion analysis and high throughput comparisons. Although Lofton Day et al. does not provide the specific percentages, Lofton Day teaches that the ratio of label to unlabeled should be optimized to maximize label information and detection (para 145). Ji et al. teaches a substrate (microarray), however, Ji and Lofton Day does not teach that the substrate has wells.
With regard to claim 17-18, Koshinsky et al. teaches that biotin labeled nucleic acid can be attached to a streptavidin coated surface such as a bead or well (para 159).
Therefore it would be prima facie obvious to one of ordinary skill in the art at the time of the effective filing date to modify the method of Ji and Lofton Day to use streptavidin coated wells instead of the microarray of Ji. The ordinary artisan would have a reasonable expectation of success as Koshinsky et al. teaches that both can attach biotin labeled nucleic acid.
Claim(s) 31-36 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ji et al. (Clinical Chemical Acta 2004 Vol 342 p. 145-153) and Lofton-Day et al. (US Patent 2003/0180779 Sept 25, 2003 previously cited) as applied to claims 1,5,7,8,10,12,15,25,37,39 in view of Shanghai (CN111454926 Translation 05/11/2020).
Ji et al. teaches a method of providing a sample of nucleic acid fragments that have one or more methylated cytosines (p. 146-147). Ji et al. teaches converting to yield converted fragments (p. 149 1st column). Ji et al. teaches using primers and a mixture of dNTPs (p. 149 2nd column). Ji et al. teaches different concentrations of biotinylated dCTP (p. 150). As such Ji et al. teaches the biotin of moiety modified dCTPs and the binding of lacking dCTPs and dGTPs using a linker based PCR. Lofton-Day et al. teaches a method of using biotin labeled dCTP and unlabeled dCTP (para 42 and 145) for methaytlion analysis and high throughput comparisons. Although Lofton Day et al. does not provide the specific percentages, Lofton Day teaches that the ratio of label to unlabeled should be optimized to maximize label information and detection (para 145). Ji et al. teaches a mixture, however, Ji and Lofton Day do not teaches the percents of binding moiety to non-binding moiety.
With regard to claims 31-36 and 54 and 62, Shanghai teaches methods and products of both biotin and non-biotin labeled dNTPs including 10% and 20% (example 2).
Therefore it would be prima facie obvious at the time of the effective filing date to use the recited percentages for labeling dNTPs of Ji and Lofton Day as taught by Shanghai. The ordinary artisan would be motived to use these recited percentages as Shanghai teaches that these can be used in ratios for target detection.
Claim(s) 41-43 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ji et al. (Clinical Chemical Acta 2004 Vol 342 p. 145-153) and Lofton-Day et al. (US Patent 2003/0180779 Sept 25, 2003 previously cited) as applied to claims 1,5,7,8,10,12,15,25,37,39 in view of Molloy et al (WO2011/057354 May 19, 2011 cited on IDS)
Ji et al. teaches a method of providing a sample of nucleic acid fragments that have one or more methylated cytosines (p. 146-147). Ji et al. teaches converting to yield converted fragments (p. 149 1st column). Ji et al. teaches using primers and a mixture of dNTPs (p. 149 2nd column). Ji et al. teaches different concentrations of biotinylated dCTP (p. 150). As such Ji et al. teaches the biotin of moiety modified dCTPs and the binding of lacking dCTPs and dGTPs using a linker based PCR. Lofton-Day et al. teaches a method of using biotin labeled dCTP and unlabeled dCTP (para 42 and 145) for methaytlion analysis and high throughput comparisons. Although Lofton Day et al. does not provide the specific percentages, Lofton Day teaches that the ratio of label to unlabeled should be optimized to maximize label information and detection (para 145). Ji et al. teaches a mixture, however, Ji and Lofton Day do not teaches sequencing a library from the sequenced fragments provided in Ji et al (figure 5).
With regard to claims 41-43, Molloy et al. teaches performing high throughput sequencing on the methylated fragments of the library (example 1). High throughput sequencing encompass the 20 million reads.
Therefore it would be prima facie obvious at the time of the effective filing date to use the sequencing method of Molloy et al in the method of Ji and Lofton Day in order to obtain a large number of sequences from the methylated fragments obtained by Ji and Lofton Day. The ordinary artisan would have a reasonable expectation of success as Ji et al. teaches that the PCR fragments should be sequenced (figure 5) and Molloy et al. teaches a method of such sequencing.
Conclusion
No claims are allowed.
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 KATHERINE D SALMON whose telephone number is (571)272-3316. The examiner can normally be reached 9-530.
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/KATHERINE D SALMON/Primary Examiner, Art Unit 1682