CTNF 18/696,031 CTNF 100649 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Priority The instant application 18/696,031 filed on 3/27/24 is a 371 US national phase of PCT/KR2022/014662 filed on 9/29/22, and claims foreign priority to KR10-2021-0128751 filed on 09/29/2021 and KR10-2022-0124049 filed on 9/29/22. The priority date is determined to be 9/29/22 in the absence of a copy certified translation of KR10-2021-0128751 and/or KR10-2022-0124049. Receipt is acknowledged of KR10-2021-0128751 and KR10-2022-0124049 certified copies of papers required by 37 CFR 1.55. Priority Documents were electronically retrieved by USPTO from participating IP office on 3/27/24. 23-19 AIA Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e). Failure to provide a certified translation may result in no benefit being accorded for the non-English application. Claim Objections 07-29-01 AIA Claim 1 is objected to because of the following informalities: line 7 repeats “L1PA11_3end” already recited in line 6 . Appropriate correction is required. Claim Rejections - 35 USC § 112 – Indefiniteness 07-30-02 AIA 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. 07-34-01 Claims 1-7 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. Claim 1 preamble recites “A method for providing information for predicting a response to cancer therapy ”, however, only provides limitations for the obtaining of DNA methylation level. It is unclear how the obtained information is applied to the cancer therapy response prediction. Are increased DNA methylation levels of the at least one LINE-1 subfamily (relative to a control/reference?) indicative of a positive or negative response cancer therapy? Do methylation levels inform of possible resistance or susceptibility to cancer therapy? What are the specific LINE-1 DNA methylation level conditions associated with the possible outcomes of the prediction? The skilled artisan would not be able to discern the metes and bounds of this limitation based upon the claim as written. For purposes of compact prosecution, this claim is interpreted as requiring obtaining at least one LINE-1 subfamily DNA methylation level information towards the purpose of any cancer therapy response. Claims 2-7, which are either directly or indirectly dependent upon claim 1, do not provide clarification in regards to above claim 1 indefiniteness, and are similarly indefinite. Claim Rejections - 35 USC § 101 07-04-01 AIA 07-04 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 1-7 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims have been evaluated using the 2019 Revised Patent Subject Matter Eligibility Guidance (see Federal Register Vol. 84, No. 4 Monday, January 7, 2019). Step 1 : The claim is directed to the statutory category of a process. Step 2A, prong one : The claim recites a judicial exception. Claim 1 recitation of “ predicting a response”; and claims 2-3 recitations of “ calculating an estimate” are all abstract ideas. These limitations are abstract mental processes and/or mathematical concepts (see MPEP 2106.04(a)). The abstract mental processes of prediction and calculation are concepts performed in the human mind. The mathematical concepts of estimates, ratios, multiplication/summation, and scores require mathematical relationships, formulae, and calculations. Additionally, the claims are directed towards laws of nature and natural phenomena through the correlations of DNA methylation levels (genotype) and response to cancer therapy (phenotype) (see MPEP 2106.04(b)). Step 2A, prong two : The judicial exception is not integrated into a practical application. Claims 1-7 recite insignificant extra-solution activities directed towards mere data gathering at high levels of generality (see MPEP 2106.05(g)). It is further noted that the claims are not directed to a particular treatment or prophylaxis (see MPEP 2106.04(d)(2)). Claim 1 recites data gathering activities of “obtaining information on a DNA methylation level” of at least one LINE-1 subfamily; claim 2 recites additional data gathering activities and mental calculation of an estimate; claim 3 recites additional mental calculation; claim 4 recites a next generation sequencing method of data gathering; claim 5 recites a cancer immunotherapy at a high level of generality with no particular dosage, treatment regimen, or structural information; claim 6 specifies the isolated sample that the judicial exceptions are performed upon; and claim 7 recites the possible cancers for the judicial exceptions. Step 2B : The claim does not provide an inventive concept. MPEP 2106.05(d)): The courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity: i. Determining the level of a biomarker in blood by any means, Mayo , 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC , 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017); ii. Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. Ltd. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015); iii. Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017); iv. Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011); v. Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs. Ltd., 818 F.3d at 1377, 118 USPQ2d at 1546; vi. Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375; vii. Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics , 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014); and viii. Hybridizing a gene probe, Ambry Genetics , 774 F.3d at 764, 113 USPQ2d at 1247. The claims end with the judicial exceptions. Additionally, methods of predicting a response to cancer therapy comprising obtaining information on a DNA methylation level of a LINE-1 subfamily are not inventive ( Lizardi et al. ( 2012 ; US 2012/0147324 A1); and Sigalotti et al. ( 2013 ; US 2013/0316931 A1)). For the reasons set forth above, claims 1-7 are not directed to patent eligible subject matter. Claim Rejections - 35 USC § 103 07-20-aia AIA 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. 07-21-aia AIA Claims 1- 4 and 6-7 are re jected under 35 U.S.C. 103 as being unpatentable over Li zardi et al. ( 2012 ; US 2012/0147324 A1). Re levant to claim 1 , Lizardi et al. Abstract teaches “methods and compositions of identifying status biomarkers associated with a status of a subject .” Lizardi et al. paragraph 0006 teaches “In some forms of the methods and compositions of identifying status biomarkers associated with a status of a subject, the method can comprise, for example, determining the methylation state of one or more status biomarkers in one or more DNA samples ”. Further relevant to claim 1 , Lizardi et al. paragraph 0030 teaches that the statuses include various cancers “and/or response to treatment.” Further relevant to claim 1 , Lizardi et al. Tables 11A and 11B and associated paragraph 0334 teach instantly claimed LINE-1 subfamilies. Relevant to claim 2 , Lizardi et al. paragraph 0163 teaches detection of methylated and unmethylated DNAs and estimation of methylation. Relevant to claim 3 , Lizardi et al. paragraphs 0039 and 0272 teach calculation of methylation level. Relevant to claim 4 , Lizardi et al. paragraph 0350 teaches detection via Nanopore DNA sequencing ( performing next generation sequencing ). Relevant to claim 6 , Lizardi et al. paragraph 0260 teaches detection of circulating DNA and that “the detection of circulating DNA is facilitated by the fact that each dying cell releases thousands of molecules of LINE-1 DNA , and therefore the limit of detection of these assays corresponds to a relatively small number of cells of interest.” Lizardi et al. paragraph 0020 teaches that the source of the subject DNA samples can be of cell-free origin (e.g., blood). Relevant to claim 7 , Lizardi et al. paragraph 0030 teaches instantly claimed cancers. Lizardi et al. does not teach a specific embodiment having all the claimed elements. That being said, however, it must be remembered that "[w]hen a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious." KSR v. Teleflex , 127 S.Ct. 1727, 1740 (2007) (quoting Sakraida v. AG. Pro , 425 U.S. 273, 282 (1976)). "[W]hen the question is whether a patent claiming the combination of elements of prior art is obvious," the relevant question is "whether the improvement is more than the predictable use of prior art elements according to their established functions." ( Id. ). Addressing the issue of obviousness, the Supreme Court noted that the analysis under 35 USC 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR at 1741. The Court emphasized that "[a] person of ordinary skill is... a person of ordinary creativity, not an automaton." Id. At 1742. Consistent with this reasoning, it would have been prima facie obvious to have selected various combinations of various disclosed elements — including LINE-1 subfamilies, calculations, sequencing methods, sample sources, and cancers — for a method of providing information for predicting a response to cancer therapy, to arrive at compositions "yielding no more than one would expect from such an arrangement." 07-22-aia AIA Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Lizardi et al. ( 2012 ; US 2012/0147324 A1) , as applied to claim s 1-4 and 6-7 above, and further in view of Sigalotti et al. ( 2013 ; US 2013/0316931 A1) . The teachings of Lizardi et al. are applied to instantly rejected claim 5 as they were previously applied to claims 1-4 and 6-7 as rendering obvious a method. Lizardi et al. is silent to specifics regarding cancer immunotherapy . However, these limitations were known in the prior art and taught by Sigalotti et al. Relevant to claim 5, Sigalotti et al. paragraphs 0027-0028 teach that the level of LINE-1 methylation is associated with the patient’s likelihood of response to immunotherapy. Although Lizardi et al. is silent to the Sigalotti et al. cancer immunotherapy , it would have been prima facie obvious to the skilled artisan. Lizardi et al. and Sigalotti et al. are analogous disclosures to the instant LINE-1 methylation level and association with cancer therapies. The skilled artisan would have been motivated to combine the analogous art. Lizardi et al. paragraph 0247 teaches that the treatment is “the medical management of a subject with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder” and includes further specification of intended treatment. Sigalotti et al. paragraph 0028 explicitly teaches that immunotherapy response (among other therapies and treatments) prediction is associated with LINE-1 methylation. Thus, the skilled artisan would have been motivated to include the Sigalotti et al. cancer immunotherapy within the Lizardi et al. treatment response prediction methodology because Sigalotti et al. teaches that LINE-1 methylation has informed cancer immunotherapy predictions previously and Lizardi et al. provides for treatment response predictions for a wide range of possible treatments. The skilled artisan would have a reasonable expectation of success based on the disclosures of Lizardi et al., and further in view of Sigalotti et al., as discussed in the preceding paragraphs. Conclusion Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sarah J Kennedy whose telephone number is (571)272-1816. The examiner can normally be reached Monday - Friday 8a - 5p. 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For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /SARAH JANE KENNEDY/Examiner, Art Unit 1682 /WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682 Application/Control Number: 18/696,031 Page 2 Art Unit: 1682
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