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 16-29 and 31-39 are pending. Claims 33-35 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1-15 and 30 are canceled. Claims 16, 28, and 36-37 are amended. Claims 38-39 are new. Claims 16-29, 31-32, and 36-39 are currently under examination.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/19/25 has been entered.
Priority
The instant application 17/604,182 filed on 10/15/21 is 371 of PCT/EP2020/060517 filed on 4/15/20 and claims foreign priority to application EP19382290.5 filed on 4/15/19. The priority date is determined to be 4/15/19.
Response to Arguments
Applicant’s arguments, see pages 9-12, filed 12/19/25, with respect to the rejections of claims 16-29, 31-32, and 36-37 under 35 USC 101 have been fully considered and are found unpersuasive, and the 101 rejections documented in the Final mailed 6/25/25 have been revised to address claim amendments and new claims 38-39 filed 12/19/25 in this Final Office Action. More detailed responses to Applicant’s arguments are provided at the end of each maintained rejection.
Applicant’s arguments, see pages 12-16, filed 12/5/25, with respect to the rejections of claims 16-29, 31-32, and 36-37 under 35 USC 102 and 103 have been fully considered and are found persuasive. Therefore, the rejections documented in the Final mailed 6/25/25 have been withdrawn. However, upon further consideration, new grounds of 103 rejections necessitated by claim amendments and new claims 38-39 filed 12/19/25 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 16-29, 31-32, and 36-39 remain/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 rejection is revised/updated in response to claim amendments filed 12/5/25.
Step 1: The claims are directed to the statutory category of a process.
Step 2A, prong one: The claim recites a judicial exception.
The instant claims recite a law of nature. The claims set forth “a method for determining the methylation status of the LINC00473 gene in a liquid biopsy obtained from a patient suspected of having a colorectal cancer and/or a pre-cancerous stage thereof.” This type of correlation between the methylation status of LINC00473 (phenotype) and colorectal cancer (genotype) is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo. See MPEP 2106.04(b).
The instant claims recite abstract ideas. The claims are drawn to “(b) determining the level of methylation of the LINC00473 gene based on results”, and “(c) comparing the level of methylation of the LINC00473 gene”. Claim 28 similarly recites abstract ideas through “(b) determining that the methylation level of the LINC00473 is higher”. These “determining” and “comparing” steps are carried out in the mind after “performing a sequencing or amplification reaction,” and are considered abstract ideas that are mental processes. See MPEP 2106.04(a)(2)(III).
Claim 18 recites elevated LINC00473 methylation levels are indicative of colorectal cancer, introducing an additional natural phenomenon judicial exception.
Step 2A, prong two: The judicial exception is not integrated into a practical application.
The claims do NOT recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exceptions.
These judicial exceptions are not integrated into a practical application because there are no elements in the claims that integrate the law of nature and/or abstract idea. The claims end with the judicial exception.
Claim 16 recites extra-solution and data-gathering limitations to obtain the methylation status through specific promoter regions and primer sequences, and are considered pre-solution and data-gathering activity. The primers are used to generate the data for the judicial exceptions of the natural correlation between methylation status and colorectal cancer and mental processes. Furthermore, claim 17 sets forth extra-solution and data-gathering methodology comprised within the sequencing or amplification step. Claim 18 does not provide additional limitations beyond the judicial exception. Claim 19 recites sample limitations unrelated to the judicial exception. Claims 20-21 and 31-32 recite the limitation of the pre-cancerous stages being colorectal adenomas and advanced colorectal adenomas, which are unrelated to the judicial exceptions. Claims 22-25 recite specific genomic positions for determining LINC00473 methylation status. These steps are not considered to integrate the judicial exceptions into a practical application because they merely add insignificant extra-solution activity (data gathering) to the judicial exception. 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)).
Claims 26-27 and 29 recite imaging techniques and colonoscopy to identify colorectal cancer and/or a precancerous stage. These limitations are unrelated to the judicial exceptions and do not integrate the judicial exceptions so as to practically apply the judicial exceptions.
Claims 36-37 recite primer limitations that are considered extra-solution and data-gathering in regards to performing the sequencing or amplification reaction. The primers are used to generate the data for the judicial exceptions of the natural correlation between methylation status and colorectal cancer and mental processes.
Claims 38-39 recite limitations to the sensitivity and specificity of the method and are unrelated to the judicial exceptions.
Step 2B: The claim does not provide an inventive concept.
In addition to the judicial exceptions, the claims require providing a liquid biopsy “sample of plasma, blood or serum” (claim 19) for “converting DNA in the liquid biopsy to bisulfite-converted DNA (bis-DNA)” (claim 17) and “performing the sequencing or amplification reaction of the LINC00473 gene” (claims 16 and 17). Claims 22-25 recite determining LINC00473 methylation status within specific genomic positions. These steps do NOT amount to significantly more because they simply append well understood, routine, and conventional activities previously known in the art to the judicial exceptions.
Claims 16 and 36 recitation of primer sequence limitations are not inventive. SEQ ID NOs: 1-9 show homology to the promoter region of LINC00473, with deviations that the skilled artisan would consider as within the bounds of routine primer optimization (see Clustal Omega alignment; Ramalho-Carvalho et al. (2018). Chapter 23. “Methylation-Specific PCR”. In: Tost, J. (eds) DNA Methylation Protocols. Methods in Molecular Biology, vol 1708. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7481-8_23; and Fackler et al. (2018). Chapter 24. “Quantitation of DNA Methylation by Quantitative Multiplex Methylation-Specific PCR (QM-MSP) Assay”. In: Tost, J. (eds) DNA Methylation Protocols. Methods in Molecular Biology, vol 1708. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7481-8_24).
Additionally, the teachings in the specification demonstrate the well understood, routine, conventional nature of the additional elements because it teaches that the additional elements are commercially available. For example, the specification teaches the following:
Page 14, lines 18-22:
EXAMPLE 1.7.
BISULFITE CONVERSION OF CIRCULATING DNA.
For DNA bisulfite conversion, 15-50 ng of circulating DNA were used, and conversion was performed with EZ DNA Methylation-Lightning Kit (Zymo Research) according to manufacturer's recommendations following these thermocycling steps: 98°C 8 min, 54°C 60 min and 4°C.
Page 16, lines 6-16:
One of the CpGs (chr6: 166402416) contained in the sequence amplified (amplicon) by real-time PCR corresponds with the CpG termed cg08886973 according to the Infinium Human Methylation 450K and Infinium MethylationEPIC assays (Illumina), which are microarray assays able to detect the methylation status of more than 450,000 and 850,000 CpGs, respectively. These microarrays are also able to detect other CpGs from the LINC00473 promoter identified as cg06545143 (chr6: 166402638) and cg21306006 (chr6: 166402081) that are located, respectively, 162 nucleotides upstream and 282 nucleotides downstream the amplicon of LINC00473 analyzed in this study. The three CpGs included in this type of microarray assays (cg06545143, cg08886973, cg21306006) are located in the TSS 1500 promoter region of LINC00473, which is the region of the promoter between 200 and 1500 nucleotides upstream its transcription start site (TSS).
Claim 19 recites the limitation that the “liquid biopsy is a sample of plasma, blood or serum.” This recitation does not amount to significantly more than the judicial exception because it was understood prior to the applicant’s invention that methylation assays could be performed upon plasma samples, as evidenced by the eponymous work of Lin et al. (2015; “Clinical Relevance of Plasma DNA Methylation in Colorectal Cancer Patients Identified by Using a Genome-Wide High-Resolution Array”; NPL citation U in PTO-892 filed 1/17/25).
Further, it is noted that 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.
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);
Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. 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);
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);
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
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
Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247.
Although claim 29 recites the limitation of colonoscopy fulfilling the imaging step, this specific imaging technique is conventional (see Rex et al. 2017, NPL citation 6 on IDS filed 2/28/2022; page 1017, column 1, paragraph 2 “Colonoscopy is generally the test of choice for diagnostic examinations”). As such, this limitation does not provide any inventive element beyond the judicial exception.
For the reasons set forth above, claims 16-29 and 31-39 are not directed to patent eligible subject matter.
Applicant’s Arguments
Applicant argues that the amendment including specific recitations of SEQ ID NOs 4-7 and specificity of 100% “satisfy the requirements of 35 U.S.C. § 101” as they are “a specific combination of four non-natural primers” and “provides a technological improvement in the field of molecular diagnostics” through the increased sensitivity and specificity as compared to current methods (Remarks 12/19/25, pages 11-12).
Response to Applicant’s Arguments
The Examiner respectfully disagrees with the amended claims satisfying the requirements of 35 U.S.C. § 101. Clustal alignment of SEQ ID NOs 4-9 to the LINC00473 promoter region demonstrates 100% alignment of SEQ ID NOs 5 and 7. Additionally, the 8 nucleotides of SEQ ID NO 4 and 9 nucleotides of SEQ ID NO 6 in the 5’ termini deviating from the natural sequence of the LINC00473 promoter region are within the bounds of routine primer optimization by the skilled artisan (see Clustal Omega alignment; Ramalho-Carvalho et al. (2018). Chapter 23. “Methylation-Specific PCR”. In: Tost, J. (eds) DNA Methylation Protocols. Methods in Molecular Biology, vol 1708. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7481-8_23; and Fackler et al. (2018). Chapter 24. “Quantitation of DNA Methylation by Quantitative Multiplex Methylation-Specific PCR (QM-MSP) Assay”. In: Tost, J. (eds) DNA Methylation Protocols. Methods in Molecular Biology, vol 1708. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7481-8_24).
Ramalho-Carvalho et al. teaches “Primer design is a common challenge for all PCR-based methods used to analyze bisulfite-converted DNA and it is a critical step to accurately determine the methylation status of a gene promoter [citation]. After bisulfite modification, the two strands of DNA are no longer complementary. Thus, strand-specific primers must be used for PCR amplification. Because any strand can be selected for methylation studies, it is possible to design suitable primers for one strand when the other does not allow for appropriate primer design” (first paragraph of section “3.3 Primer Design” on pages 457 – 460).
Fackler et al. section 3.1 Primer Design teaches manual design of primers for Quantitative Multiplex Methylation-Specific PCR (QM-MSP), obviating methods and reasons for the skilled artisan to optimize primer designs (pages 476 – 478).
See below 103 rejection for expanded explanations regarding primer optimizations.
Additionally, Fackler et al. Abstract on Quantitative Multiplex Methylation-Specific PCR (QM-MSP) teaches “For the gene panel, the highest level of normal DNA methylation above which a sample would be called positive is derived by using Receiver Operating Characteristic (ROC), maximizing assay specificity and sensitivity to distinguish between normal/benign versus tumor DNA” (page 473).
This teaching indicates that, in addition to careful primer optimization, methylation-specific PCR is commonly capable of 100% sensitivity.
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 16-19, 22-25, 36, and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Lange et al. (2012; “Genome-Scale Discovery of DNA-Methylation Biomarkers for Blood-Based Detection of Colorectal Cancer”. PLoS ONE 7(11): e50266; https://doi.org/10.1371/journal.pone.0050266; NPL citation V in PTO-892 filed on 1/17/25), in view of Diaz-Lagares et al. (2016; “Epigenetic inactivation of the p53-induced long noncoding RNA TP53 target 1 in human cancer”. Proc. Natl. Acad. Sci. U.S.A. 113 (47) E7535-E7544, https://doi.org/10.1073/pnas.1608585113; NPL citation 1 in IDS filed 3/11/2024), Illumina Infinium HumanMethylation450K spreadsheet (HumanMethylation450 v1.2 Manifest File; May 23, 2013; NPL citation W in PTO-892 filed 1/17/25), Ramalho-Carvalho et al. (2018; Chapter 23. “Methylation-Specific PCR”. In: Tost, J. (eds) DNA Methylation Protocols. Methods in Molecular Biology, vol 1708. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7481-8_23), and Fackler et al. (2018; Chapter 24. “Quantitation of DNA Methylation by Quantitative Multiplex Methylation-Specific PCR (QM-MSP) Assay”. In: Tost, J. (eds) DNA Methylation Protocols. Methods in Molecular Biology, vol 1708. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7481-8_24).
This rejection is necessitated by claim amendments filed 12/19/25.
(i) Lange et al. teaches limitations relevant to claims 16 and 19.
Relevant to claims 16 and 19, Lange et al. Abstract teaches “We employed a genome-scale marker discovery method to identify and verify candidate DNA methylation biomarkers for blood-based detection of colorectal cancer… DNA methylation data were generated by the Illumina Infinium HumanMethylation27 and the HumanMethylation450 platforms, which determine the methylation status of 27,578 and 482,421 CpG sites respectively.”
(ii) Lange et al. is silent to specifics regarding LINC00473 methylation, relevant to claims 16-18, and 22-25. However, these limitations were known in the prior art and taught by Diaz-Lagares et al.
Relevant to claims 16-18, Diaz-Lagares et al. teaches that the Illumina Infinium HumanMethylation450 Bead Chip detects LINC00473 methylation (Fig. 1A) within bisulfite-converted DNA, and that there is “≥70% change in the CpG methylation level between the cancer cell line HCT-116 compared with the demethylated DKO cell line and the normal colon cell line” (page E7536: last line of column 2 – page E7537: first two lines of column 1).
Relevant to claims 16 and 22-24, Diaz-Lagares et al. Supplementary Table 1 teaches that C6orf176 (LINC00473) has “a CpG island in the promoter region included in the Infinium HumanMethylation450 microarray” at chr6:166401526-166402659. Additionally, Diaz-Lagares et al. Supplementary Table 2 teaches that LINC00473 has been “identified using the DNA methylation microarray approach” with the CpG island chr6:166401526-166402659.
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Relevant to claims 22-25, Illumina Infinium HumanMethylation450K Manifest File teaches that LINC00473 methylation can be assayed with the Bead Chip at several positions and CpG within the promoter region. Claim 25 specific CpG with their corresponding claim 24 loci are bolded in the excerpt included below.
(iii) Lange et al., Diaz-Lagares et al., and the Illumina Manifest File are silent to exact sequence matches to a primer having the nucleotide sequence as set forth in SEQ ID NO:4-9 relevant to claims 16 and 36, and sensitivity/specificity relevant to claims 16, 36, and 38. However, these limitations were known in the prior art and taught by Ramalho-Carvalho et al. and Fackler et al.
Relevant to claims 16 and 36, Clustal alignment of SEQ ID NOs 4-9 to the LINC00473 promoter region demonstrates 100% alignment of SEQ ID NOs 5 and 7. The skilled artisan would find it obvious to design primers in this region consisting of these homologous sequences, since Diaz-Lagares et al. and Illumina teach CpG content within this promoter region.
Further relevant to claims 16 and 36, the non-homologous 5’ termini of SEQ ID NOs 4, 6, and 8-9 deviating from the natural sequence of the LINC00473 promoter region would be considered as within the bounds of routine primer optimization by the skilled artisan.
This routine primer optimization is taught by Ramalho-Carvalho et al. and Fackler et al.
Relevant to claims 16, 36, and 38, Ramalho-Carvalho et al. teaches “Primer design is a common challenge for all PCR-based methods used to analyze bisulfite-converted DNA and it is a critical step to accurately determine the methylation status of a gene promoter [citation]. After bisulfite modification, the two strands of DNA are no longer complementary. Thus, strand-specific primers must be used for PCR amplification. Because any strand can be selected for methylation studies, it is possible to design suitable primers for one strand when the other does not allow for appropriate primer design” (first paragraph of section “3.3 Primer Design” on pages 457 – 460).
Further relevant to claims 16, 36, and 38, Ramalho-Carvalho et al. further teaches “primers designed for amplification of bisulfite-converted DNA frequently have multiple annealing sites, leading to alternative unspecific amplicons, and are more prone to primer-dimer formation (see Note 4)” (last sentence of page 457 continued to page 458).
Further relevant to claims 16, 36, and 38, Ramalho-Carvalho et al. further teaches “Moreover, aberrant DNA methylation (hypomethylation and hypermethylation) has been reported for many pathologies, including cancer… MSP [methylation-specific PCR] allows for highly sensitive detection (detection level of 0.1% of the alleles, with full specificity) of locus-specific DNA methylation, using PCR amplification of bisulfite-converted DNA” (page 448).
Further relevant to claims 16, 36, and 38, Ramalho-Carvalho et al. further teaches “Nevertheless, MSP has been modified to allow for quantification of methylated alleles of a single region among unmethylated DNA (real-time quantitative MSP, QMSP) (see also Chapters 24 and 25)” (page 449).
Further relevant to claims 16, 36, and 38, Ramalho-Carvalho et al. further teaches “The QMSP assay allows for the quantification of methylated alleles of a given region among unmethylated DNA. The sensitivity of QMSP is very similar to conventional MSP (1:1000–1:10,000)” (page 462).
Further relevant to claims 16, 36, and 38, Fackler et al. Abstract on Quantitative Multiplex Methylation-Specific PCR (QM-MSP) teaches “For the gene panel, the highest level of normal DNA methylation above which a sample would be called positive is derived by using Receiver Operating Characteristic (ROC), maximizing assay specificity and sensitivity to distinguish between normal/benign versus tumor DNA” (page 473).
Further relevant to claims 16, 36, and 38, Fackler et al. section 3.1 Primer Design teaches manual design of primers for QM-MSP, obviating methods and reasons for the skilled artisan to optimize primer designs (pages 476 – 478), including fusion with fluorophores (page 478).
Further relevant to claims 16, 36, and 38, Fackler et al. Abstract on Quantitative Multiplex Methylation-Specific PCR (QM-MSP) teaches “For the gene panel, the highest level of normal DNA methylation above which a sample would be called positive is derived by using Receiver Operating Characteristic (ROC), maximizing assay specificity and sensitivity to distinguish between normal/benign versus tumor DNA” (page 473).
This teaching indicates that, in addition to careful primer optimization, methylation-specific PCR is commonly capable of high sensitivity and specificity.
(iv) Although Lange et al. does not teach the limitations of Diaz-Lagares et al., Illumina, Ramalho-Carvalho et al., and Fackler et al. it would have been prima facie obvious to the skilled artisan. It is noted that Lange et al., Diaz-Lagares et al., Illumina, Ramalho-Carvalho et al., and Fackler et al. are all analogous to the instant molecular biology methodology.
The skilled artisan would have been motivated to combine the analogous disclosures. The skilled artisan would have been motivated to modify the detection method of Lange et al. to include the LINC00473 methylation assessment of Diaz-Lagares et al. because the Illumina Infinium HumanMethylation450K microarray includes several genomic loci able to quantify the gene’s methylation levels. The microarray previously demonstrated success with determining LINC00473 methylation within colorectal cancer, as shown by Diaz-Lagares et al. Additionally, the skilled artisan would have been motivated to perform the routine primer optimizations of Ramalho-Carvalho et al. and Fackler et al., resulting in “maximizing assay specificity and sensitivity to distinguish between normal/benign versus tumor DNA” (Fackler et al. Abstract).
The skilled artisan would have a reasonable expectation of success based on the disclosures of Lange et al. in view of Diaz-Lagares et al., Illumina, Ramalho-Carvalho et al., and Fackler et al., as discussed in preceding paragraphs.
Claims 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over Lange et al. (2012; “Genome-Scale Discovery of DNA-Methylation Biomarkers for Blood-Based Detection of Colorectal Cancer”. PLoS ONE 7(11): e50266; https://doi.org/10.1371/journal.pone.0050266; NPL citation V in PTO-892 filed on 1/17/25), in view of Diaz-Lagares et al. (2016; “Epigenetic inactivation of the p53-induced long noncoding RNA TP53 target 1 in human cancer”. Proc. Natl. Acad. Sci. U.S.A. 113 (47) E7535-E7544, https://doi.org/10.1073/pnas.1608585113; NPL citation 1 in IDS filed 3/11/2024), Illumina Infinium HumanMethylation450K spreadsheet (HumanMethylation450 v1.2 Manifest File; May 23, 2013; NPL citation W in PTO-892 filed 1/17/25), Ramalho-Carvalho et al. (2018; Chapter 23. “Methylation-Specific PCR”. In: Tost, J. (eds) DNA Methylation Protocols. Methods in Molecular Biology, vol 1708. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7481-8_23), and Fackler et al. (2018; Chapter 24. “Quantitation of DNA Methylation by Quantitative Multiplex Methylation-Specific PCR (QM-MSP) Assay”. In: Tost, J. (eds) DNA Methylation Protocols. Methods in Molecular Biology, vol 1708. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7481-8_24), as applied to claims 16-19, 22-25, 36, and 38 above, and further in view of Molloy et al. (US 2014/0315203 Al, USPGPub citation 1 in IDS filed 07/02/2024). The teachings of Lange et al. in view of Diaz-Lagares et al., Illumina, Ramalho-Carvalho et al., and Fackler et al. are applied to instantly rejected claims 20-21 as they were previously applied to claims 16-19, 22-25, 36, and 38.
Regarding claims 20-21: following the discussions of claims 16-19, 22-25, 36, and 38, modified Lange et al. differs from the instant claims in that they do not teach detection within pre-cancerous stages of colorectal or advanced colorectal adenomas. However, these limitations were known in the prior art and taught by Molloy et al.
Molloy et al. teaches a diagnostic method for detecting DNA methylation status within colorectal cancer biological samples (Abstract), such as blood samples (Specification 0090). Molloy et al. further teaches that the method “extends to the assessment of an individual’s predisposition to the development of a neoplasm, such as an adenoma or carcinoma” (Specification 0092).
It would have been prima facie obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of modified Lange et al. to include the ability to assess the pre-cancerous stages of Molloy et al. A skilled artisan would be motivated to modify the detection method of modified Lange et al. to include the pre-cancerous stages of Molloy et al. because “early detection of colorectal cancer greatly improves the prognosis” (Molloy et al., Specification 0016) and “diagnostic methods that result in early detection of malignant or even premalignant disease could have considerable clinical benefits, reducing mortality and morbidity of patients with colorectal cancer” (Lange et al., Introduction, page 1, columns 1-2). Thus, the teachings of Lange et al. in view of Diaz-Lagares et al., Illumina, Ramalho-Carvalho et al., and Fackler et al., and further in view of Molloy et al. render the methylation assessments of pre-cancerous colorectal obvious with reasonable expectation of success, as discussed in preceding paragraphs.
Claims 26-29, 31-32, 37, and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Lange et al. (2012; “Genome-Scale Discovery of DNA-Methylation Biomarkers for Blood-Based Detection of Colorectal Cancer”. PLoS ONE 7(11): e50266; https://doi.org/10.1371/journal.pone.0050266; NPL citation V in PTO-892 filed on 1/17/25), in view of Diaz-Lagares et al. (2016; “Epigenetic inactivation of the p53-induced long noncoding RNA TP53 target 1 in human cancer”. Proc. Natl. Acad. Sci. U.S.A. 113 (47) E7535-E7544, https://doi.org/10.1073/pnas.1608585113; NPL citation 1 in IDS filed 3/11/2024), Illumina Infinium HumanMethylation450K spreadsheet (HumanMethylation450 v1.2 Manifest File; May 23, 2013; NPL citation W in PTO-892 filed 1/17/25), Ramalho-Carvalho et al. (2018; Chapter 23. “Methylation-Specific PCR”. In: Tost, J. (eds) DNA Methylation Protocols. Methods in Molecular Biology, vol 1708. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7481-8_23), Fackler et al. (2018; Chapter 24. “Quantitation of DNA Methylation by Quantitative Multiplex Methylation-Specific PCR (QM-MSP) Assay”. In: Tost, J. (eds) DNA Methylation Protocols. Methods in Molecular Biology, vol 1708. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7481-8_24), and Molloy et al. (US 2014/0315203 Al, USPGPub citation 1 in IDS filed 07/02/2024), as applied to claims 20-21 above, and further in view of Rex et al. (2017; “Colorectal Cancer Screening: Recommendations for Physicians and Patients From the U.S. Multi-Society Task Force on Colorectal Cancer”. Am J Gastroenterol. 2017 Jul;112(7):1016-1030. doi: 10.1038/ajg.2017.174; NPL citation 6 in IDS filed 02/28/2022; NPL citation 6 in IDS filed 2/28/22).
The teachings of Lange et al. in view of Diaz-Lagares et al., Illumina, Ramalho-Carvalho et al., and Fackler et al., and further in view of Molloy et al. are applied to instantly rejected claims 26-29, 31-32, 37, and 39 as they were previously applied to claims 20-21.
Lange et al. in view of Diaz-Lagares et al., Illumina, Ramalho-Carvalho et al., and Fackler et al., and Molloy et al. renders obvious assessing pre-cancerous colorectal and advanced colorectal adenomas for LINC00473 methylation.
Modified Lange et al. does not provide performing imaging techniques, such as colonoscopy, to identify colorectal cancer and/or a pre-cancerous stage. However, these limitations were known in the prior art and taught by Rex et al.
Rex et al. teaches that “colonoscopy is generally the test of choice for diagnostic examinations” of colorectal cancer (page 1017, column 1, paragraph 2, last sentence).
It would have been prima facie obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have included an imaging technique such as colonoscopy to identify colorectal cancer and/or a pre-cancerous stage in addition to the methylation assessments rendered obvious by Lange et al. in view of Diaz-Lagares et al., Illumina, Ramalho-Carvalho et al., and Fackler et al., and Molloy et al. The skilled artisan would be motivated to include the imaging technique and colonoscopy because Molloy et al. teaches that “a colonoscopy has the advantage that if polyps are found during the procedure they can be removed immediately” (Specification 0021). Thus, assessing LINC00473 methylation within pre-cancerous stages as rendered obvious by the methods of Lange et al. in view of Diaz-Lagares et al., Illumina, Ramalho-Carvalho et al., and Fackler et al., and Molloy et al. would include a colonoscopy, since Rex et al. teaches that it is “the test of choice for diagnostic examinations.” The skilled artisan would have a reasonable expectation of success given the teachings of Lange et al. in view of Diaz-Lagares et al., Illumina, Ramalho-Carvalho et al., and Fackler et al., and Molloy et al., and further in view of Rex et al., as discussed in preceding paragraphs.
Conclusion
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/SARAH JANE KENNEDY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682