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 111-116, 118-124, and 126-130 are pending and currently under examination. Claims 1-110, 117, and 125 are cancelled. Claims 111, 118, and 124 are amended. Claims 128-130 are new.
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 2/24/26 has been entered.
Priority
The instant application 17/921,711 filed on 10/27/22 is a 371 US national phase of PCT/US2021/030638 filed on 5/4/21, and claims domestic priority to provisional application 63/019,753 filed on 5/4/20. The priority date is determined to be 5/4/20.
Response to Arguments
Applicant’s arguments, see pages 6-7, filed 2/24/26, with respect to the rejections of claims 111-116, 118-124, and 126-127 under 35 USC 103 have been fully considered and are found persuasive. Therefore, the rejections documented in the Final mailed 12/1/25 have been withdrawn. However, upon further consideration, new grounds of rejections necessitated by claim amendments and new claims 128-130 are made in this Non-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 111-116, 118-124, and 126-130 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 and new claims 128-130 filed 2/24/26.
Step 1: The claim is directed to the statutory category of a process.
Step 2A, prong one: The claim recites a judicial exception.
Claim 111 recitations of “characterizing” and “determining”; and claim 118 recitation of “detecting presence or absence” are all abstract ideas. These limitations are abstract mental processes (see MPEP 2106.04(a)). The abstract mental processes of characterizing, determining, and detecting are concepts performed in the human mind.
Additionally, the claims are directed towards laws of nature and natural phenomena through the correlations of gene methylation levels (genotype) and melanoma (phenotype). Claims 118 and 123 correlations of gene methylation characterization and melanoma are considered laws of nature and natural phenomena (see MPEP 2106.04(b)).
Step 2A, prong two: The judicial exception is not integrated into a practical application.
Claims 111-116, 118-124, and 126-130 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)).
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 characterizing melanoma sample gene methylation levels are not inventive (Regan et al. 2012; WO 2012/109500 A2; and Mueller et al. 2017; WO 2017/201606 A1; FOR citation N in PTO-892 filed 7/15/25).
For the reasons set forth above, claims 111-116, 118-124, and 126-130 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 111-116, 118-124, and 126-128 are rejected under 35 U.S.C. 103 as being unpatentable over Regan et al. (2012; WO 2012/109500 A2).
Relevant to claim 111, Regan et al. teaches “In another aspect, methods are provided herein for analyzing nucleic acid methylation status” (paragraph 0091).
Relevant to claims 111-113, Regan et al. teaches “In one method to identify methylated cytosines, bisulfite treatment is used to convert cytosines to uracils; methylated cytosines, however, are protected. Subsequent PCR converts uracil to a thymidine, resulting in a different sequence output for the same region of interest. Alternatively, conversion of C->T through bisulfite treatment can change the melting temperature of the amplicon, which can be measured through melting curve analysis post amplification” (paragraph 00226).
Relevant to claims 111 and 128, Regan et al. teaches that “The target sequence can be a gene. For example, the gene can be… A2M” (paragraph 00301).
It is noted that MAX.chr1.110627096-110627364 corresponds to LINC01397, which has a RefSeq Accession of NM_000014.6 encoding for A2M (see below screen grabs from UCSC Genome Browser).
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Relevant to claim 114, Regan et al. paragraphs 00305-00306 teach “The methods described herein can make use of nucleic acid amplification… Examples of PCR techniques that can be used include, but are not limited to… multiplex fluorescent PCR (MF-PCR)”.
Relevant to claim 115, Regan et al. teaches “One or more methylation sensitive restriction enzymes can be used in the methods, compositions, and kits provided herein” (paragraph 00229).
Relevant to claim 116, Regan et al. paragraph 00290 teaches that the sample is a stool sample, a urine sample, a plasma sample, a blood sample.
Relevant to claim 118, Regan et al. teaches “The methods described herein can be used for diagnosing or prognosing a disorder or disease” (paragraph 00369). Regan et al. further teaches “The sample can be from a subject who has a specific disease, disorder, or condition, or is suspected of having (or at risk of having) a specific disease, disorder or condition. For example, the sample can be from a cancer patient, a patient suspected of having cancer, or a patient at risk of having cancer. The cancer can be, e.g.… melanoma” (paragraph 00288).
Relevant to claim 119, Regan et al. teaches that beta-actin can be a housekeeping gene that “can be used as reference in the methods described herein” (paragraph 00209).
Relevant to claim 120, Regan et al. teaches “A milepost assay can be used to determine methylation status of a CpG island” (paragraph 00220).
Relevant to claim 121, Regan et al. teaches “CpG islands can be common in the 5' region of human genes, including in promoter sequences” (paragraph 00221).
Relevant to claim 122, Regan et al. teaches “The methylation status of a CpG island can be measured over a period of time (e.g., in samples taken at different time points, e.g., days, months, years)” (paragraph 00224).
Relevant to claim 123, Regan et al. teaches “The methods described herein can be used for diagnosing or prognosing a disorder or disease” (paragraph 00369). Regan et al. further teaches “The sample can be from a subject who has a specific disease, disorder, or condition, or is suspected of having (or at risk of having) a specific disease, disorder or condition. For example, the sample can be from a cancer patient, a patient suspected of having cancer, or a patient at risk of having cancer. The cancer can be, e.g.… melanoma” (paragraph 00288).
Relevant to claim 124, Regan et al. teaches “Provided herein are kits for carrying out the methods of the provided invention. The kits can comprise one or more restriction enzymes, devices, buffers, reagents, and instructions for use. A kit can comprise a restriction enzyme, a buffer, a salt, and instructions for use. A kit can comprise one or more primers and one or more probes” (paragraph 00431). It is noted above that Regan et al. provides for bisulfite reagents and PCR of the one or more genes listed in claim 111.
Relevant to claim 126, Regan et al. paragraphs 00285-00287 provide for sample collection. Taken with the above teachings relevant to claim 124, the skilled artisan would find it obvious that the kit would include a sample collector for obtaining a sample as it would fall under the Regan et al. disclosure of “devices” used for “carrying out the methods of the provided invention.”
Relevant to claim 127, Regan et al. paragraph 00293 teaches “Nucleic acids can be extracted from a sample by means available to one of ordinary skill in the art.” Taken with the above teachings relevant to claim 124, the skilled artisan would find it obvious that the kit would include a reagent for isolating a nucleic acid from the sample as it would fall under the Regan et al. disclosure of “reagents” used for “carrying out the methods of the provided invention.”
Regan 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 multiplex PCR, primer design, bisulfite-treatment, and kits — for a method of characterizing a sample, to arrive at compositions "yielding no more than one would expect from such an arrangement."
Claims 129-130 are rejected under 35 U.S.C. 103 as being unpatentable over Regan et al. (2012; WO 2012/109500 A2), as applied to claims 111-116, 118-124, and 126-128 above, and further in view of Mueller et al. (2017; WO 2017/201606 A1; FOR citation N in PTO-892 filed 7/15/25).
The teachings of Regan et al. are applied to instantly rejected claims 129-130 as they were previously applied to claims 111-116, 118-124, and 126-128 as rendering obvious a method for characterizing a sample. Regan et al. is silent to specifics regarding FLJ22536. However, these limitations were known in the prior art and taught by Mueller et al.
Mueller et al. Abstract teaches “The method utilizes detection of adjacent methylation signals within a single sequencing read as the basic positive tumour signal, thereby decreasing false positives. The method comprises extracting DNA from a cell-free sample obtained from a subject, bisulphite converting the DNA, amplifying regions methylated in cancer (e.g., CpG islands, CpG shores, and/or CpG shelves), generating sequencing reads, and detecting tumour signals. To increase sensitivity, biased primers designed based on bisulphite converted methylated sequences can be used. Target methylated regions can be selected from a pre-validated set according to the specific aim of the test. Absolute number, proportion, and/or distribution of tumour signals may be used for tumour detection or classification."
Relevant to claims 129-130, Mueller et al. teaches FLJ22536 as a gene target within their methodology (paragraph 00204 and Table 2).
Although Regan et al. is silent to the Mueller et al. FLJ22536 gene target, this limitation would be prima facie obvious to the skilled artisan. It is noted that Regan et al. and Mueller et al. are analogous disclosures to the instant methylation analyses performed within cancerous samples.
The skilled artisan would have been motivated to combine the analogous art. Mueller et al. teaches that “Fig. 2 depicts a schematic for amplification of target regions. Multiple regions from across the human genome have been identified as being differentially methylated in the DNA from various types of tumours compared to the normal DNA from a variety of different tissues. These regions can be fairly extensive spanning 100s to 1000s of base pairs of DNA. These target regions (black boxes, bottom) exhibit coordinated methylation where most or all of the CpG dinucleotides in these regions are methylated in tumour tissue with little or no methylation in normal tissues. As shown in Fig. 2, when sequencing across these regions (arrows) multiple CpG residues are seen to be methylated together in the tumour creating a concordant signal identifiable as being tumour specific. By targeting multiple PCR-amplified probes across individual regions (middle) and across the entire genome (top) large numbers of probes can be designed with the advantage that with more probes comes greater sensitivity due to the greater likelihood of detecting a tumour specific fragment in a given sample” (paragraph 00153).
Thus, the skilled artisan would have been motivated to include the Mueller et al. FLJ22536 gene target within the Regan et al. methodology because Mueller et al. teaches that the FLJ22536 gene target has been identified as being differentially methylated in tumor-specific samples. The skilled artisan would have a reasonable expectation of success based on the disclosures of Regan et al., and further in view of Mueller et al., as discussed in the preceding paragraphs.
Conclusion
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/SARAH JANE KENNEDY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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