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 9/30/2025.
Claims 1, 3-6, 9, 14, 16, 26, 31-36, 40-42 are pending. Claims 2, 7-8, 10-13, 17-25, 27-30, 37-39 are cancelled.
The following rejections are newly applied necessitated by amendment (35 USC 103) or modified (35 USC 101) with response to arguments following.
This action is FINAL.
Withdrawn Rejections
The 35 USC 102 and 35 USC 103 rejections made in the previous office action is withdrawn based upon amendments to the claims. It is noted that the 35 USC 103(a) rejections are newly applied based upon the amendments to the claims as Markarov et al. suggests the required positive active steps.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 26,31,32,33,36 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more. The claim(s) recite(s) a judicial exception of correlation of methylation levels with indication of cell or tissue type or state, diagnosing pathology, monitoring treatment, detecting death of a cell or tissue. This judicial exception is not integrated into a practical application because the claims require steps of determining levels of CpG with well-known methylation methodologies. The detection does not provide a step to integrate the judicial exception. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims do not integrate the judicial exception to steps that are not considered routine and conventional steps.
These judicial exceptions are not integrated into a practical application because the claims only recite the natural correlation, wherein the step of determining does not integrate the judicial expectation. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the steps are considered general and routine knowledge as exemplified by the specification (as discussed below).
According to the 2019 Patent Eligibility Guidance an initial two step analysis is required for determining statutory eligibility.
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter? In the instant case the Step 1 requirement is satisfied as the claims are directed towards a process.
Step 2A Prong one. Does the claim recite a law of nature, a natural phenomenon or an abstract idea? Yes, a natural phenomenon.
The correlation of indication of cell or tissue type or state, diagnosing pathology, monitoring treatment, detecting death of a cell or tissue are considered a natural correlations. The step of detecting in the sample are considered a routine and conventional step as discussed below.
Step 2A prong two. Does the claim recite additional elements that integrate the judicial exception into a practical application? The answer is no as the steps require only routine and convention steps and does not integrate the judicial exception to a practical application.
Step 2B. Does the claim recite additional elements that are significantly more than the judicial exceptions? No as the claims do not require any elements that integrate the judicial exception.
These are considered routine methods of using well known methylation methodologies to detect levels in naturally occurring DNA (see p 6-7 of the specification). Makarov et al. (US Patent Application Publication 2005/0202490 September 15, 2005) teaches a method of treating DNA with bisulfite (para 77). Makarov et al. teaches amplifying by PCR (para 79). Makarov et al. teach labeling the sample with CPG sties to label DNA samples (para 30, 88). Makarov et al. teaches contacting to an array such that there is hybridization with probes and then detecting hybridization (para 54-55, 168). Makarov et al. teaches a method of treating DNA with bisulfite (para 77). Makarov et al. teaches amplifying by PCR (para 79). Makarov et al. teaches that the PCR uses adaptor ligation (para 37-38). Makarov et al. teach labeling the sample with CPG sties to label DNA samples (para 30, 88). Makarov et al. teaches contacting to an array such that there is hybridization with probes and then detecting hybridization (para 54-55, 168). Makarov et al. teaches that adaptors do not have CpG but rather are attached to molecules that are CpG rich (para 122 and 144). Although Makarov et al. does not specifically teach methyltransferase, Makarov et al. does suggest that methyltransferase can be used in methods of CpG methylation status (para 3 and 52).
Therefore the steps do not integrate the judicial exception.
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 the claims have been amended to require positive action steps (p. 7). The reply asserts that the these are specific and distinct steps more than mere observations or interpretation (p. 7). These arguments have been reviewed but have not been found persuasive. Although the claims have been amended, the steps of the claims still encompass routine methods of using well known methylation methodologies to detect levels in naturally occurring DNA (see p 6-7 of the specification). Further Markov et al. suggests these steps.
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) 1,3-6,9,14,16,26,31,34-35,40-42 is/are rejected under 35 U.S.C. 103 as being unpatentable over Makarov et al. (US Patent Application Publication 2005/0202490 September 15, 2005).
With regard to Claim 1, Makarov et al. teaches a method of treating DNA with bisulfite (para 77). Makarov et al. teaches amplifying by PCR (para 79). Makarov et al. teach labeling the sample with CPG sties to label DNA samples (para 30, 88). Makarov et al. teaches contacting to an array such that there is hybridization with probes and then detecting hybridization (para 54-55, 168). Makarov et al. teaches that adaptors do not have CpG but rather are attached to molecules that are CpG rich (para 122 and 144). Although Makarov et al. does not specifically teach methyltransferase, Makarov et al. does suggest that methyltransferase can be used in methods of CpG methylation status (para 3 and 52).
With regard to claims 3-4, Makarov et al. teaches fragmenting DNA before amplification (para 71-72).
With regard to claim 5, Makarov et al. teaches that the DNA fragments can be 200 bp (para 93).
With regard to claim 6, Makarov et al. teaches that the DNA is 50pg (para 280) which would encompass >0.01 pg.
With regard to claim 9, Makarov et al. teaches the use of cell free DNA (para 413-416).
With regard to claims 14-16, Makarov et al teaches adaptors that comprise methylated cytosine (para 99) and adaptors that are not methylated (para 99 and 122).
With regard to claim 26, Makarov et al. teaches that CpG methylation is indicative of cell or tissue type (para 18-21).
With regard to claim 31, Makarov et al. teaches identifying DNA methylation pattern of a state based upon predetermined threshold (para 200 and 364).
With regard to claim 34-35, Makarov et al. teaches a method of using DNA from urine or blood (para 60).
With regard to claims 40 and 41, the claims are drawn to the labeling binding “effected” prior to contacting or following contacting. However, the specification has not defined this term. The term is being interpreted with the broadest reasonable interpretation of “bring about or cause to happen”. As such the claims are interpreted as labeling that brings about or cause to happen anything prior to contacting and following contacting. As such these steps would encompass any use of labeling including the labeling of Makarov et al.
With regard to claim 42, the claim is drawn to the ligation “is effected” prior to subjecting. As such the claim is interrupted as any binging of the adaptors prior to subjecting, which would include the use of the adaptors in Makarov.
Claim(s) 32 is/are rejected under 35 U.S.C. 103 as being unpatentable over Makarov et al. (US Patent Application Publication 2005/0202490 September 15, 2005).
Makarov et al. teaches a method of treating DNA with bisulfite (para 77). Makarov et al. teaches amplifying by PCR (para 79). Makarov et al. teaches that the PCR uses adaptor ligation (para 37-38). Makarov et al. teach labeling the sample with CPG sties to label DNA samples (para 30, 88). Makarov et al. teaches contacting to an array such that there is hybridization with probes and then detecting hybridization (para 54-55, 168). However, Makarov et al. does not explicitly teaches diagnosing and treating.
However, with regard to claim 32, Makarov et al. suggests that methylation levels can be used in diagnosis and treatment (para 3, 7). Makarov et al. teaches that the method can be used for diagnosis and treatment (para 83).
Therefore it would be prima facie to one of ordinary skill in the art at the time of the effective filing date to modify the method of Makarov et al. to perform the steps of diagnosing and treating as Makarov et al. suggests one can use the methylation methods for diagnose and treatment. The ordinary artisan would have a reasonable expectation of success as Makarov et al. teaches that cancer is associated with methylation levels.
Claim(s) 33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Makarov et al. (US Patent Application Publication 2005/0202490 September 15, 2005) in view of Zhang et al. (US Patent Application Publication 2018/0274039 Sept 27, 2018).
Makarov et al. teaches a method of treating DNA with bisulfite (para 77). Makarov et al. teaches amplifying by PCR (para 79). Makarov et al. teaches that the PCR uses adaptor ligation (para 37-38). Makarov et al. teach labeling the sample with CPG sties to label DNA samples (para 30, 88). Makarov et al. teaches contacting to an array such that there is hybridization with probes and then detecting hybridization (para 54-55, 168). However, Makarov et al. does not explicitly teaches diagnosing and treating.
However, with regard to claim 33, Makarov et al. does not teach monitoring treatment.
With regard to claim 33, Zhang et al. teaches that one can use CpG levels in order to monitor treatment responses in a patient (para 308).
Therefore it would be prima facie to one of ordinary skill in the art at the time of the effective filing date to modify the method of Makarov et al. to perform the steps of diagnosing and treating as Makarov et al. suggests one can use the methylation methods for monitoring treatment as taught by Zhang et al. . The ordinary artisan would have a reasonable expectation of success as Zhang et al. teaches that treatment monitoring of cancer is associated with methylation levels.
Claim(s) 36 is/are rejected under 35 U.S.C. 103 as being unpatentable over Makarov et al. (US Patent Application Publication 2005/0202490 September 15, 2005) in view of Dor et al. (US Patent Application Publication 2017/0121767 May 4, 2017).
Makarov et al. teaches a method of treating DNA with bisulfite (para 77). Makarov et al. teaches amplifying by PCR (para 79). Makarov et al. teaches that the PCR uses adaptor ligation (para 37-38). Makarov et al. teach labeling the sample with CPG sties to label DNA samples (para 30, 88). Makarov et al. teaches contacting to an array such that there is hybridization with probes and then detecting hybridization (para 54-55, 168). However, Makarov et al. does not explicitly teaches diagnosing and treating.
However, with regard to claim 36, Makarov et al. does not teach detecting cell or tissue death based upon methylation pattern.
With regard to claim 36, Dor et al. teaches that one can determine cell death from CpG in cfDNA based upon comparison to a threshold (para 372, 377).
Therefore it would be prima facie to one of ordinary skill in the art at the time of the effective filing date to modify the method of Makarov et al. to perform the steps of determining cell death as taught by Dor et al. . The ordinary artisan would have a reasonable expectation of success as Dor et al. teaches that determining cell death based upon methylation patterns (para 372).
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