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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 8/08/2025 has been entered.
Claims 1-2, 5, 8-12, 14-15, 31-33 are pending. Claims 3-4, 6-7, 13, 16-30 are cancelled.
The following rejections modified or newly applied (35 USC 112b). Response to arguetmsn following.
This action is NONFINAL.
Withdrawn Rejections
The obviousness double patenting rejection made in the previous office action is withdrawn based upon amendments.
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.
Claim 2 is 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 2 contains the trademark/trade names of the fluorophores. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe fluorophores and, accordingly, the identification/description is indefinite.
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) 1-2, 5, 8-12, 14, 31-33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Song et al. (US Patent Application Publication 2017/0298422 October 19, 2017 cited on IDS) In view of Tsai et al. (WO2016/028887 February 2016 cited on IDS).
With regard to claim 1, Song et al. teaches a method for localizing epigenetic modifications of DNA (para 3). Song et al. teaches providing a target with an epigenetic modification annealed to a non-target strand with a first fluorophore at a 3’ end (para 7). Song et al. taches that the fluorophores can be Cy3 and Cy5 and they can be optically distinguished (para 18). Song et al. teaches that a second fluorophore can be used to label an epigenetic modification, denature, annealing, immobilizing on a support and detection of the fluorophores (paragraphs 7-11, 43-55, 60). Song et al. teaches a capture tag (biotin) captured by a surface tethered neutravidin (para 7). Song et al. teaches that the modifications can be 5mC and 5hmC (para 12).
However, Song et al. does not teach a ratio of first probe to target DNA strand is at least 10:1, but teaches probes (fragments) (figure 1). Furthermore, Song et al. does not specifically teach incubation with an exonuclease.
With regard to claim 2, Song et la. teaches use of CY3 and Cy5 (para 18).
With regard to claim 8, Song et al. teaches that the support is a polymer coated quartz slide (surface) (para 109).
With regard to claim 9, Song et al. teaches that the DNA is cfDNA (para 49).
With regard to claim 10, Song et al. teaches imagining with TIRF microscopy).
With regard to claim 11-12, Song et al. teaches specific localization of at least one 5hmC epigenetic marker which would be strand specific as it detects a particular modification in a particular strand (para 115 and 119).
With regard to claims 31-33, Song et al. teaches fragmenting wherein the fragments are 50bp to 500 bp (para 52) and as such encompass the mearing fragment size of about 165-250 bp.
However, Song et al. does not teach a ratio of first probe to target DNA strand is at least 10:1 or exonuclease.
With regard to claim 1, Tsai et al. teaches determination of base modification by annealing a first target probe to a target DNA and annealing a second probe to a non-target DNA strand (para 87). Therefore Tsai et al. teaches that targets can be immobilized such that only the region of interest is isolated. Although Tsai et al. does not explicitly teach that the ratio of probe to target is at least 10 to 1, example 1, teaches such a ratio. Furthermore it would be obvious that if the sample is being enriched that there is a small amount of the target as compared to the probe such that the reactions solution can enrich the target using the larger amount of probe starting material. Song et al. teaches that the support comprise surface tethered moiety selected from avidin, streptavidin and neutravidin, such that the DNA is captured and imagined (para 7). As Tsai teaches that the first and second probe are labeled with biotin (paragraph 101) it would be obvious that the probes are capable of probes with an avidin biotin pairing with the probes. Tsai et al. teaches a method of using E. coli exonuclease to digest non-annealed single stranded DNA (p. 39).
With regard to claim 5, Tsai teaches a first and second probe that are single stranded and complementary (para 6, 45, 24, and 87).
With regard to claims 14, Tsai et al. teaches a method of using E. coli exonuclease to digest non-annealed single stranded DNA (p. 39).
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 Song et al. with the teachings of Tsai et al. in order to isolate sample target regions that has epigenetic modification by determining the location using probes and then detecting the modifications (para 101 of Tsai). The ordinary artisan would have a reasonable expectation of success as Tsai et al. teaches that these probes can be used to isolate and detect modifications. Song et al. teaches that the support comprise surface tethered moiety selected from avidin, streptavidin and neutravidin, such that the DNA is captured and imagined (para 7). As Tsai teaches that the first and second probe are labeled with biotin (paragraph 101) it would be obvious that the probes are capable of probes with an avidin biotin pairing with the probes.
Response to arguments
The reply traverses the rejection. A summary of the arguments is provided below with response to arguments following.
The reply asserts that Song permit single molecular epigenetic imaging but not loci specific and strand specific localization (p. 6). Th reply asserts that Song teaches ends of DNA molecules and not the claimed probes (p. 7). The reply asserts that one would not digest non-annealed ssDNA because it would digest ssgenomic DNA (p. 7).
The reply asserts that the proposed modification would change the principal of operation as the operation would be modified with replacing DNA terminal capture tags of Song with probes comprising capture tags (p. 7).
The reply asserts that there is an unexpected results in example 3 (p. 8). The applicant asserts that the claims have been amended to recite that the specific affinity tag pair is biotin-neutravidin and the modification is 5hmC (p. 8). The reply asserts that there is no a particular step of localizing modification (p. 8). The reply asserts that example 3 discloses that after treating the probe annealed target DNA sample with an exonucleases there was an improvement by 10000 fold (p. 8).
These arguetmsn have been reviewed but have not been found persuasive.
Song et al. teaches labeling such that the imaging can detect 5hmC modifications and as such would be considered loci specific. Further it is noted that the combination of Song et al and Tsai teaches the sample imaging method as is claimed. The reply asserts that one would not used the probes of Tsai with the exonuclease as it would change the operation of Song. However, the operation would be the same as in each method DNA is hybridized to supports and epigenetic modifications are detected. The use of probes versus direct attachment to target DNA appears to be an obvious modification that would have the same intended outcome of detection (see rejection above).
Example 3 states that to overcome the problem of the surface being occupied by SP (ssDNA probe) that the TS (target) sample is incubated to digest ssDNA (p. 24). However the claims do not require incubating the target sample, but rather incubating the product of the annealed first probe to the DNA strand and annealing a second probe to the non-target strand. As such it is confusing if the specification is performed to the target sample or to a first probe to the target DNA. Furthermore, although the specification teaches adding exonuclease increases the method by 10000 fold, the arguments have not presented evidence that this would be unexpected by the ordinary artisan. Tsai et al. teaches a method of using E. coli exonuclease to digest non-annealed single stranded DNA (p. 39). As such it would be well known in the art of record that adding exonuclease would remove non-anneal strands.
Claim(s) 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Song et al. (US Patent Application Publication 2017/0298422 October 19, 2017 cited on IDS) and Tsai et al. (WO2016/028887 February 2016 cited on IDS) as applied to claims 1-2, 5, 8-12, 14-15, 31-33 and in view of Williams et al. (US Patent Application 20110065597 March 17, 2011).
Song et al. teaches a method for localizing epigenetic modifications of DNA (para 3). Song et al. teaches providing a target with an epigenetic modification annealed to a non-target strand with a first fluorophore at a 3’ end (para 7). Song et al. teaches that a second fluorophore can be used to label an epigenetic modification, denature, annealing, immobilizing on a support and detection of the fluorophores (paragraphs 7-11, 43-55, 60). Tsai et al. teaches determination of base modification by annealing a first target probe to a target DNA and annealing a second probe to a non-target DNA strand (para 87). Therefore Tsai et al. teaches that targets can be immobilized such that only the region of interest is isolated. Although Tsai et al. does not explicitly teach that the ratio of probe to target is at least 10 to 1, example 1, teaches such a ratio. Furthermore it would be obvious that if the sample is being enriched that there is a small amount of the target as compared to the probe such that the reactions solution can enrich the target using the larger amount of probe starting material.
However, Song et al and Tsai et al. do not teach an attomolar detection limit.
With regard to claim 15, Williams et al. teaches that 10 attomolar solutions can be used in TIRF microscope detection (para 23 and 37).
Therefore it would be prima facie obvious to one of ordinary skill in the art at the effective filing date to use a known detection amount (attomolar) in the detection of Song and Tsai et al. which use TIRF microscope detection. The ordinary artisan would be motivated to use a known solution amount such as the one taught by Williams in the fluorescent detection assay of TIRF in order to use an amount of solution that can detect targets.
Response to arguments
The reply traverses the rejection. The reply asserts that Williams does not provide attomolar detection limit as described in the specification (p. 9). These arguments have been reviewed but have not been found persuasive. Williams et a. teaches limits for TIRF microscope detection (para 23 and 37). The claim only requires an attomolar detection limit and as such the combination of references suggests the required step.
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Conclusion
No claims are allowed.
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
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