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 7/20/2026.
Applicant’s election without traverse of Group I in the reply filed on 3/17/2025 is acknowledged.
Claims 1, 4, 6-7 are pending. Claims 2-3, 5, 8-16 have been cancelled.
The following rejections are maintained. Response to arguments following.
This action is FINAL.
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, 4, 6-7 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.
Claims 1, 4, 6-7 are indefinite over the calculating step of claim 1. In particular the calculating step requires a global DNA methylation level by averaging methylation values of probe mapping, however, the step of measuring does not require probes used in the measurement.
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 now require microarray and DNA chip analysis and therefore are performed using a plurality of hybridization probes (p. 4). This arguments has been reviewed but have not been found persuasive. In particular it is not clear that the methylation measured “using microarray analysis or DNA chip analysis” require the “values of probes mapping at least 90%...”. In particular the measurement of methylation could be performed on microarray or chips that do not provide sufficient probes for calculation. Further there is no connection from the two 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 1, 4, 6-7 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception of a natural correlation and abstract idea without significantly more. The claim(s) recite(s) the judicial exception of the correlation of predicting response to cancer treatment and global DNA methylation level (law of nature) and abstract steps of “evaluating a response”. This judicial exception is not integrated into a practical application because the steps of the claims are considered abstract ideas. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because these steps are considered routine as discussed below.
The claims are drawn to steps of “evaluating a response”. As the phrases are not defined in the application, the terms are interpreted broadly. In particular, the terms can be interpreted as reading printouts and making mental analysis of the treatments. The dependent claims are limited to performing known biotechnical techniques for determination of methylation level of LINE-1 transposons.
The unpatentability of laws of nature was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., No. 10-1150 (March 20, 2012).
The unpatentability of abstract ideas was confirmed by the U.S. Supreme court in Bilski v. Kappos, No. 08-964, 2010 WL 2555192 (June 28, 2010) and in Alice Corp. v. CLS Bank Int'l, 134 S. Ct. 2347, 2354 (2014).
The following three inquiries are used to determine whether a claim is drawn to patent-eligible subject matter:
Step 1. Is the claim to a process, machine, manufacture, or composition of matter? Yes- the claims are clearly directed to a process.
Step 2A. Is the claim directed to a law of nature, a natural phenomenon, or an abstract idea (judicially recognized exceptions)? Yes- The claims are directed to a judicial exception. The judicial exception is the correlation of methylation level and predicting a response to cancer treatment and the abstract steps of “obtaining” and “evaluating”. These correlations are naturally occurring and exist apart from any human action.
Step 2B. Does the claim recite additional elements that amount to significantly more than the judicial exception? No-there are no elements or combination of elements in the claim that are sufficient to ensure that the claim as a whole amounts to significantly more than the judicial exception:
The claims are directed to judicial exceptions without significantly more. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims require general and routine steps that do not provide an "inventive step" as indicated above or abstract steps. The abstract steps are considered mental steps as it could encompass reading printouts and mental analysis.
Therefore the present claims do not require performing any steps that are not routine and conventional. For example, the claims do not require using a novel reagent to amplify.
The claims also do not require the use of a particular machine, wherein the particular machine implements one or more of the judicial exceptions or integrates the judicial exception(s) into a particular practical application.
Note that the Supreme Court in Mayo v. Prometheus has made clear that to transform an unpatentable law of nature into a patent-eligible application of such a law, one must do more than simply state the law of nature while adding the words "apply it." Essentially, appending conventional steps, specified at a high level of generality, to laws of nature, natural phenomena, and abstract ideas cannot make those laws, phenomena, and ideas patent-eligible.
In Prometheus, the Court found that "[i]f a law of nature is not patentable, then neither is a process reciting a law of nature, unless that process has additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself." Additionally, "conventional or obvious" "[pre]solution activity" is normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such a law". Flook, 437 U. S., at 590; see also Bilski, 561 U. S., at __ (slip op., at 14) ("[T]he prohibition against patenting abstract ideas 'cannot be circumvented by'.., adding 'insignificant post-solution activity'" (quoting Diehr, supra, at 191-192)).
The Court also summarized their holding by stating "[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately."
With regard to the dependent claims and the steps of extracting DNA and measuring methylation, the detection of levels for methylation uses known assays in the art. Lizardi et al. (US Patent Application 2012/0157324 June 21, 2012) teaches a method of measuring global DNA methylation level in a sample from a cancer patient (para 316). Although Lizardi et al. does not teach evaluating a response to immunotherapy, Lizardi et al. teaches that a calculation of an average value of methylation levels of LINE-1 provides global methylation levels between a sample with cancer and a sample that is normal (para 316). Lizardi et al. teaches that one can determine changes in a repetitive element family accuracy (para 316).
For these reasons the claims are rejected under section 101 as being directed to non-statutory subject matter.
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 are not directed to a correlation in abstract or mental evaluation but rather provides specific steps of analysis and transformation (p. 5-6). The reply asserts that the claims are not well understood or conventional as the claimed global DNA methylation metric succeeds in prediction of immunotherapy response whereas standards markers do not (p. 6-7). These arguetmsn have been reviewed but have not been found persuasive.
These arguments have been considered but are not found persuasive.
The reply asserts that the claims have been amended to include steps that are more than the judicial exception. However, the steps of obtaining a sample and measuring methylation are general and routine methods of isolating samples and measuring methylation levels. These steps use known and conventual assays such as PCR. As such the steps do not appear to encompass something more than the judicial exception. With regard to the calculating step, this step does not require any particular steps more than obtaining data from the methylation measurement. As such this “calculating” step can include data collection. Finally the evaluation of response is considered the judicial exception itself. Furthermore, with regard to the use of the methylation levels being used for immunotherapy response, this an correlation which is taking data of nature and applying it to treatment decisions. This would encompass an judicial exception which is not integrated int the claims to a particular step that is not considered routine and conventional.
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) 1,4,6-7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lizardi et al. (US Patent Application 2012/0157324 June 21, 2012) in view of Sigalotti et al. (US Patent Application Publication 2013/0316931 November 28, 2013 previously cited).
With regard to Claim 1, Lizardi et al. teaches obtaining a cancer sample (para 44 and 54). Lizardi et al. teaches a method of measuring global DNA methylation level in a sample from a cancer patient using PCR (para 39 and 316). Although Lizardi et al. does not teach evaluating a response to immunotherapy, Lizardi et al. teaches that a calculation of an average value of methylation levels of LINE-1 provides global methylation levels between a sample with cancer and a sample that is normal (para 316). Lizardi et al. teaches that one can determine changes in a repetitive element family accuracy (para 316). Lizardi et al. teaches using probes of the transposons to determine average methylation levels of the subsets (para 48).
However, Lizardi et al. does not teach evaluating response to immunotherapy or the use of LIHS.
With regard to claim 1, Sigalotti et al. teaches obtaining DNA methylation level from a sample of a cancer subject (para 10). Sigalotti et al. calculating an average methylation level of the genes (para 139).
Sigalotti et al. evaluating response to cancer treatment based upon global DNA methylation level (para 10-15). Sigalotti et al. teaches immunotherapy (para 28). Sigalotti et al. teaches that LINE-1 transposons is L1HS (table 4).
With regard to claim 4, Sigalotti et al. suggests a method of evaluating response to treatment with the global level of LINE 1 methylation is increased compared to a reference (para 27-28).
With regard to Claim 6, Sigalotti et al. teaches a sample can include blood, serum, cerebrospinal fluid, sputum and urine (para 25).
With regard to Claim 7, Sigalotti et al. teaches that the cancer is melanoma (para 93).
Therefore it would be prima facie obvious to modify the method of Lizardi et al. to determine the average as taught by Lizardi in global DNA methylation from the LiHS of Sigalotti (e.g. LINE 1 transposon type) to evaluate immunotherapy. The ordinary artisan would be motivated to evaluate immunotherapy as Sigalotti et al. suggests that methylation of LIHS differs based on rather the patient is responding.
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 Lizardi et al. does not identify LIHS or LIPA as targets, a probe selection methodology, or averaging probe derived methylation values (p. 8). The reply asserts that Lizardi does not provide LIHS or LIPA but rather just L1P (p. 8).
The reply asserts that the teaching uses third party reports and not the microarray based method (p. 9). The reply asserts that that the table of Sigalotti does not teach global methylation but rather is based upon bisulfite pyrosequencing (p. 9). The reply asserts that neither provides immunotherapy response (p 10). The reply asserts that further Sigalotti teaches the opposite relationship (p 10).
These arguments have been reviewed but have not been found persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). It is noted that the combination of the two references suggests the steps of the claims. It is further noted for the wherein clause, as noted int eh 35 USC 112b, the claims have not provided a clear recitation of the steps required. Lizardi et al. teaches the calculation of an average value of methylation levels using probes. Furthermore Sigalotti et al. suggests a method of evaluating response to treatment with the global level of LINE 1 methylation is increased compared to a reference (para 27-28).
The reply appears to be asserting that both the references do not teach immunotherapy and that the references provide opposite results. However, Sigalotti et al. suggests a method of evaluating response to treatment with the global level of LINE 1 methylation is increased compared to a reference (para 27-28). Therefore it would be prima facie obvious to modify the method of Lizardi et al. to determine the average as taught by Lizardi in global DNA methylation from the LiHS of Sigalotti (e.g. LINE 1 transposon type) to evaluate immunotherapy. The requirement of a particular correlation of low or high is within the wherein clause and does not alter the required steps. Furthermore the wherein clause is based upon a median vale comparison which could encompass numerous different comparisons.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu Cheng (Winston) Shen can be reached on 5712723157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KATHERINE D SALMON/Primary Examiner, Art Unit 1682
