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 .
Claims 18-24, 29-33, and 35-36 are pending and under examination. Claims 1-17, 25-28, 34, and 37 are canceled. Claims 18-24, 29-33, and 35-36 are amended.
Response to Amendment
The Amendment filed 2/17/26 has been entered. Claims 18-24, 29-33, and 35-36 are pending. Applicant’s amendments to claims 20-22 and 33 have overcome the objections previously set forth in the Non-Final Office Action mailed 11/17/25.
The 2/17/26 submission of the certified English translation of foreign priority document CN202010361690.9 is acknowledged. The priority date is determined to be 4/30/20.
Response to Arguments
Applicant’s arguments, see pages 8-12, filed 2/17/26, with respect to the rejections of claims 18-24, 29-33, and 35-36 under 35 USC 101, 102, and 103 have been fully considered and are found persuasive. Therefore, the rejections documented in the Non-Final mailed 11/17/25 have been withdrawn. However, upon further consideration, new grounds of rejections necessitated by claim amendments are made in this Final Office Action.
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 18-24, 29-33, and 35-36 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).
This new 101 rejection is necessitated by claim amendments filed 2/17/26.
Step 1: The claims are directed to the statutory category of a process.
Step 2A, prong one: The claims recite a judicial exception.
Claim 18 recites a correlation of methylation levels and tumor status. This phenotype-genotype correlation is a law of nature and natural phenomena (see MPEP 2106.04(b)).
Step 2A, prong two: The judicial exception is not integrated into a practical application.
None of the claims provide any additional elements in addition to the judicial exceptions already claimed that would prevent the claims from having a pre-emptive effect on the use of the judicial exception. Claims 18-24, 29-33, and 35-36 recite extra-solution and data-gathering limitations for the judicial exception. These limitations generate the input data of the judicial exceptions, with no specification of a particular treatment or prophylaxis (see MPEP 2106.04(d)(2)). The non-particular/non-specific nature of the treatment is emphasized by the Specification page 9 recitation of “Optionally, the treatment is administration of surgery, chemotherapy, radiotherapy, chemoradiotherapy, immunotherapy, oncolytic virus therapy, any other kind of tumor treatment method used in the art, or a combination of these treatment methods.”
Step 2B: The claims do 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 are directed to well-understood, routine, and conventional activities in the life science arts recited at a high-level of generality. The claimed SEQ ID NO for the primers and probes have 100% nucleotide similarities to previously identified methylation investigation regions, allowing the skilled artisan to design primers and probes through routine primer and probe optimization (see Olek et al. 2017 (US 9,719,131 B2; USPat citation A in PTO-892 filed 11/17/25); ABSS sequence search results against the Issued Patents Database (NPL citation U in PTO-892 filed 11/17/25 for SEQ ID NO: 4 and 43-45, and NPL citation U in associated PTO-892 for SEQ ID NO: 34-36 and 46-48; and below 103 rejections). Additionally, claimed SEQ ID NO: 4 methylation level has been determined before (see Markowitz et al. 2018 (WO 2018/009535 A1; FOR citation N in PTO-892 filed 11/17/25)).
For the reasons set forth above, claims 18-24, 29-33, and 35-36 are not directed to patent eligible subject matter.
Claim Rejections - 35 USC § 103
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.
Claims 18-24, 29-33, and 35-36 are rejected under 35 U.S.C. 103 as being unpatentable over Markowitz et al. (2018; WO 2018/009535 A1; FOR citation N in PTO-892 filed 11/17/25) in view of Olek et al. (2017; US 9,719,131 B2; USPat citation A in PTO-892 filed 11/17/25).
This new 103 rejection is necessitated by claim amendments filed 2/17/26.
(i) Markowitz et al. teaches limitations relevant to claim 18.
Relevant to claim 18, Markowitz et al. Abstract teaches “The disclosure provides methods for identifying genomic loci (e.g., vimentin and/or SqBEl8) that are differentially methylated in metaplasias (e.g., Barrett's esophagus) and/or neoplastic cancers (e.g., esophageal cancers). Identification of methylated genomic loci has numerous uses, including for example, to characterize disease risk, to predict responsiveness to therapy, to noninvasively diagnose subjects and to treat subjects determined to have gastrointestinal metaplasias and/or neoplasias.”
Further relevant to claim 18, Markowitz et al. teaches "In certain aspects, the application provides assays and methods using any of the informative loci, or bisulfite converted methylated or unmethylated sequences thereof, disclosed herein. In some embodiments, the informative loci comprise a sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to any of the sequences of SEQ ID NOs: … 5137-5531…" (page 56, lines 8-12). It is noted that Markowitz et al. SEQ ID NO: 5349 has 100% nucleotide similarity to the instantly claimed SEQ ID NO: 4 (see below excerpt).
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Further relevant to claim 18, Markowitz et al. teaches “In certain aspects, the present disclosure is based in part on the discovery of particular human genomic DNA regions (also referred to herein as informative loci or patches) in which the cytosines within CpG dinucleotides are differentially methylated in esophageal neoplasia compared to normal human tissues” (page 2, paragraph 1).
Further relevant to claim 18, Markowitz et al. teaches “For example, detecting esophageal neoplasia may select the patient to undergo therapies that include, but are not limited, to resection of the neoplasia (via endoscopic resection or surgical resection), ablation of the neoplasia, chemotherapy, or radiation therapy” (last sentence of page 30 continued to page 31).
(ii) Markowitz et al. is silent to SEQ ID NO: 34-36 and 43-48 (relevant to claims 18-24), sample treatment (claim 29), sample limitations (claims 30-33), and tumor limitations (claims 35-36). However, these limitations were known in the prior art and taught by Olek et al.
Relevant to claim 18, Olek et al. Title teaches "METHOD FOR DETERMINING THE DEGREE OF METHYLATION OF DEFINED CYTOSINES IN GENOMIC DNA IN THE SEQUENCE CONTEXT OF 5'-CPG-3'".
Further relevant to claim 18, Olek et al. teaches "The subject of the present invention is a kit comprising a reagent containing bisulfite, primer oligonucleotides for the production of the amplified products and/or preferably oligonucleotides immobilized to a solid phase as well as instructions for conducting the method according to the invention. The primer oligonucleotides and the immobilized oligonucleotides, as described above, are derived from the Seq. IDs 1 to 40712" (column 11, lines 25-32).
Further relevant to claim 18, and additionally relevant to claims 19-24, Olek et al. SEQ ID NO: 28481 has 100% nucleotide similarity to SEQ ID NO: 34-36 and 43-48. See below excerpts of alignments from ABSS sequence search results against the Issued Patents Database (NPL citation U in PTO-892 filed 11/17/25 for SEQ ID NO: 4 and 43-45; and NPL citation U in associated PTO-892 for SEQ ID NO: 34-36 and 46-48).
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Relevant to claims 18-24, Olek et al. SEQ ID NO: 28481 is 686 nucleotides long, and includes the claimed SEQ ID NOs. The skilled artisan would recognize that the Olek et al. longer sequence disclosure would encompass the claimed shorter SEQ ID NOs. Olek et al. teaches “It is particularly preferred according to the invention that the DNA treatment in step a) is conducted with a solution of a bisulfite (=hydrogen sulfite, disulfite). A method is also particularly preferred, in which oligonucleotides are used for the amplification, which comprise a sequence segment of a chemically pretreated DNA which is at least 18 bases long according to one of the Seq. ID 1 to Seq. ID 40712. It is assured that primers complementary to the bisulfite-treated DNA are used, which can amplify regulatory regions (CpG islands) which can then be investigated with respect to methylation” (column 9, lines 36-46).
In the below excerpt, the instantly claimed SEQ ID NOs correspond to a subset of a finite number of CpG islands which can be amplified within the Olek et al. SEQ ID NO: 28481. The skilled artisan would recognize that differential CpG methylation amplification primers and probes would have to be designed from a finite number of possibilities within this region, further restricted by known primer design limitations (secondary structure, methylation sensitivity, melting temperature, etc.). Thus, the skilled artisan would recognize that the Olek et al. “primers complementary to the bisulfite-treated DNA are used, which can amplify regulatory regions (CpG islands) which can then be investigated with respect to methylation” “derived from the Seq. IDs 1 to 40712” would obviously include instantly claimed SEQ ID NO: 34-36 and 43-48.
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Relevant to claim 29, Olek et al. teaches "In this method in the first step, a genomic DNA sample is on the two classes of oligonucleotides as a consequence of treated in such a way that except for the 5-methylcytosine bases, all cytosine bases are converted to uracil. This chemical treatment is preferably conducted with the solution of a bisulfite (=hydrogen sulfite, disulfite)" (column 11, lines 39-43).
Relevant to claims 30 and 32-33, Olek et al. teaches "The method is preferred according to the invention, whereby the genomic DNA sample has been obtained from cell lines, blood, sputum, stool, urine, cerebrospinal fluid, tissue embedded in paraffin, for example, tissue from eyes, intestine, kidney, brain, heart, prostate, lung, breast or liver, histological slides or all other possible combinations thereof" (column 10, line 65 - column 11, line 3).
Relevant to claim 31, Olek et al. teaches "An increased methylation of the CpG islands was established in bladder cancer [citation]" (column 3, lines 41-46).
Thus, although Olek et al. does not include bladder tissue explicitly within the exemplary tissues, the skilled artisan would find this limitation obvious because Olek et al. teaches that "An increased methylation of the CpG islands was established in bladder cancer [citation]" (column 3, lines 41-46). Thus, the skilled artisan would find it obvious to use bladder tissue samples within methylation assays, and be motivated to do so as a result of the field acknowledging that bladder cancer has established increased methylation of the CpG islands.
Relevant to claim 35, Olek et al. teaches "The method is preferred according to the invention, whereby the genomic DNA sample has been obtained from cell lines, blood, sputum, stool, urine, cerebrospinal fluid, tissue embedded in paraffin, for example, tissue from eyes, intestine, kidney, brain, heart, prostate, lung, breast or liver, histological slides or all other possible combinations thereof" (column 10, line 65 - column 11, line 3).
Further relevant to claim 35, Olek et al. teaches "The use of a method according to the invention is preferred for the diagnosis and/or prognosis of adverse events for patients or individuals, whereby these adverse events belong to at least one of the following categories: … cancer diseases …" (column 11, lines 4-8).
The skilled artisan would recognize that the urothelium is the lining of the urinary tract, which includes the renal pelvis (in the kidneys), ureters, bladder, and urethra (Cleveland Clinic definition). Therefore, the skilled artisan would recognize that the Olek et al.-disclosed kidney tissue samples and cancer diseases would obviously read on claim 35 urothelial tumor.
Relevant to claim 36, Olek et al. teaches "The use of a method according to the invention is preferred for the diagnosis and/or prognosis of adverse events for patients or individuals, whereby these adverse events belong to at least one of the following categories: … cancer diseases …" (column 11, lines 4-8).
Further relevant to claim 36, Olek et al. teaches "An increased methylation of the CpG islands was established in bladder cancer [citation]" (column 3, lines 41-46).
Thus, although Olek et al. does not include bladder cancer explicitly within the broad "cancer diseases", the skilled artisan would find this limitation obvious because Olek et al. teaches that "An increased methylation of the CpG islands was established in bladder cancer". Thus, the skilled artisan would find it obvious to use bladder tissue samples within methylation assays, and be motivated to do so as a result of the field acknowledging that bladder cancer has established increased methylation of the CpG islands.
(iii) Although Markowitz et al. does not explicitly teach Olek et al. SEQ ID NO: 34-36 and 43-48, sample treatment, and sample/tumor limitations, it would have been prima facie obvious to the skilled artisan. It is noted that Markowitz et al. and Olek et al. are analogous disclosures to the instant methylation-level detection.
The skilled artisan would be motivated the analogous art. Although the Markowitz et al. disclosure highlights esophageal cancers, the skilled artisan would find the Markowitz et al. teachings applicable to the instant invention because Markowitz et al. teaches "The term 'neoplasia' as used herein refers to an abnormal growth of tissue. As used herein, the term 'neoplasia' may be used to refer to cancerous and non-cancerous tumors…" (page 13, 14-15). Markowitz et al. Abstract teaches "The disclosure provides methods for identifying genomic loci… that are differentially methylated in… neoplastic cancers".
Markowitz et al. identified SEQ ID NO: 5349 (~ instantly claimed SEQ ID NO: 4) as an informative locus, and teaches that “informative loci are used as molecular markers to distinguish between healthy cells and neoplastic cells (e.g., cancer cells)" (page 56, lines 24-26). Thus, the skilled artisan would be motivated to assay the Markowitz et al. locus within the Olek et al. methodology because Markowitz et al. identifies it as a cancer-distinguishing methylation locus and Olek et al. is directed towards the “METHOD FOR DETERMINING THE DEGREE OF METHYLATION OF DEFINED CYTOSINES IN GENOMIC DNA IN THE SEQUENCE CONTEXT OF 5'-CPG-3'” (Title).
The skilled artisan would have a reasonable expectation of success based on the disclosure of Markowitz et al. in view of Olek et al., as discussed in preceding paragraphs.
Conclusion
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.
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/SARAH JANE KENNEDY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682