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 Office Action is in reply to Applicants’ correspondence of 06/25/2026.
Applicants’ remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any new grounds of rejection presented in this Office Action are necessitated by Applicants’ amendments. Any rejections or objections not reiterated herein have been withdrawn in light of the amendments to the claims or as discussed in this Office Action.
This Action is made FINAL.
Please Note: The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Election/Restrictions
In the reply filed on 09/19/2025 Applicants elected of the invention of Group 1 (methods comprising DNA amplification), and the particular combination of loci that are positions 13992930, 113993052, 113993142, 13993304 and 113993313 of chromosome 2. The election has been treated as an election without traverse (MPEP § 818.01(a)), as set forth on page 2 of the Office Action of 01/06/2026.
As set forth in the interview summary of 06/29/2026, the Examiner has agreed to extend the examination of the elected combination of markers to include position 113994578 of chr2 (cg00422909).
Claims 2-10, 28-36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 09/19/2025.
Withdrawn Claim Rejections – Improper Markush Group
The rejection of claims for containing an improper Markush grouping of alternatives, as set forth on pages 3-4 of the Office Action of 01/06/2026, is withdrawn in light of the amendments to the claims.
Withdrawn Claim Rejections - 35 USC § 102 and 103
The rejections of claims under 35 USC 102 and 103, as set forth on pages 4-7 of the Office Action of 01/06/2026, are withdrawn in light of the amendments to the claims.
New Claim Rejections - 35 USC § 103
Necessitated by Amendments
Claim(s) 1 is/are rejected under 35 U.S.C. 103 as being unpatentable over Finer et al (2016), including the Supplementary Information in view of Husquin et al (2018), including the Additional files, and Homo sapiens chromosome 2, GRCh37.p13 Primary Assembly (2013).
Regarding the methods of the rejected claims, Finer et al teaches the analysis of genomic DNA from whole blood samples (e.g.: p.3, left col), including the treatment of the DNA with bisulfite to generate bisulfite modified DNA (e.g.: p.3, right col) and the amplification of the modified DNA with a primer pair that includes positions 13992930 (cg21550016), 113993052 (cg07772999), 113993142 (cg19083407), 13993304 (cg07594247) and 113993313 (cg 17445212) of chromosome 2 and quantifying methylation at the positions of the PAX8 gene locus (e.g.: p.3, right col: Forward and reverse primers (one of them being biotinylated) flanking the region of interest were designed using the Pyromark Assay Design v2.0.1.15 software and used with Platinum Taq DNA Polymerase to amplify 20 ng of BS-converted DNA. Quantitative short read sequencing of amplified BS-DNA was performed…). See also page 4 - Targeted DNA methylation analysis, and p.5, right col (Quantitative methylation values derived from the 450k array at PAX8 were validated against a BS-pyrosequencing amplicon targeted to 8 CpG sites overlying and adjacent to the metastable epiallele), and Supplementary table 3.
Finer et al does not exemplify the analysis of methylation at position 113994578 of chr2 (cg00422909). However, the analysis of CpG methylation in the PAX8 gene, including the CpG dinucleotide identified as cg00422909 was known in the prior art and is taught by Husquin et al.
Relevant to the instantly rejected claim, Husquin et al teaches the analysis of CpG methylation in the human genome to identify CpGs whose levels of DNA methylation were associated with regulation of immune gene expression (eQTMs). Husquin et al provides the results of genes and particular CpGs with methylation associated with immune gene regulation, the results provide CpG dinucleotides in the PAX8 gene locus including: cg21550016; cg07772999; cg19083407; cg07594247; cg17445212; and cg00422909 (Table S4a).
It would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to have applied the known prior art methods of CpG methylation analysis of Finer et al to the PAX8 CpGs associated with immune gene regulation as taught by Husquin et al. Where Husquin et al teaches methods of detecting CpG methylation (e.g.: p.11 – DNA methylation profiling and data normalization), and teaches the particular CpGs in the PAX8 gene including: cg21550016; cg07772999; cg19083407; cg07594247; cg17445212; and cg00422909, the use of the particular methods of Finer et al would be the simple substitution of one known method for another with predictable results. The skilled artisan would have a reasonable expectation of success where Finer et al teaches that assay reagents for CpGs of interests are designed using available software, and Homo sapiens chromosome 2, GRCh37.p13 Primary Assembly provides the sequence of the genomic locus of the PAX8 gene required for creating primers for analysis using bisulfite converted genomic DNA.
Claim(s) 27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Finer et al (2016), including the Supplementary Information in view of Husquin et al (2018), including the Additional files, and Homo sapiens chromosome 2, GRCh37.p13 Primary Assembly (2013), as applied to claim 1 above and further in view of Mikeska et al (2011).
Finer et al in view of Husquin et al and the Homo sapiens chromosome 2 sequence disclosure renders obvious the method of claim 1.
Additionally relevant to the instant rejection of claim 27, Finer et al recites using Platinum Taq DNA Polymerase to amplify 20 ng of BS-converted DNA, but does not explicitly disclose repeated steps of heating and cooling, as recited in claim 27.
However, such steps were typically used in the analysis of DNA methylation using bisulphite pyrosequencing, and are taught by Mikeska et al (e.g.: p.43 – 3.3. Bisulphite-Specific PCR).
It would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to have used the methods of Mikeska et al in the analysis of BS-converted DNA rendered obvious by Finer et al in view of Husquin et al and the Homo sapiens chromosome 2 sequence disclosure. The skilled artisan would have been motivated to use the methods of Mikeska et al, and would have had a reasonable expectation of success, based on the expressed teaching of Mikeska et al that such methods provide accurate quantitative information pertaining to DNA methylation in a sample.
Conclusion
No claim is allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. The dissertation of Carmen-Andrea Holz (2009) teaches the analysis of CpG islands in the PAX8 gene (e.g.: p.40-52), and teaches methylation in ‘CpG- Island 2’ which is relevant to the CpGs in chromosome 2 of the instant claims. The UCSC Genome Browser on Human (GRCh37/hg19) results of chr2:113,994,523-113,994,602 show that the location and sequence context of cg00422909 in the PAX8 gene at position 113,994,578 of human chromosome 2 in the GRCh37/hg19 build.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHEN THOMAS KAPUSHOC whose telephone number is (571)272-3312. The examiner can normally be reached M-F, 8am-5pm.
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Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683
