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 .
Prosecution Note
Please note that since the previous Office action, the application has been transferred to Examiner Leverett.
Priority
This application filed 03/03/2023 is a National Stage entry of PCT/US2021/049078, with an International Filing Date of 09/03/2021, and claims priority from Provisional Application 63074836, filed 09/04/2020. The claims are therefore examined as filed on 09/04/2020, the effective filing date. In future actions, the effective filing date of one or more claims may change, due to amendments to the claims, or further review of the priority application(s).
Election/Restrictions
Claims 1-11 and 13-26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/04/2025.
Applicant’s election without traverse of claim 12, the species “cg19693031” as the sequence complimentary to the oligonucleotide primer, and the species “rs1153188” for the sequence of an SNP complimentary to the nucleic acid primer, in the reply filed on 12/04/2025, is acknowledged.
Claim Status
Claims 12-16, 18, 20, and 27-35 are pending.
Claims 13-16, 18 and 20 are withdrawn.
Claims 12 and 27-35 are directed to the elected invention.
Claims 1-11, 17, 19, 21-26 are cancelled.
Claims 12 and 27-35 are examined.
Claims 12 and 27-35 are rejected.
Information Disclosure Statement
The Information Disclosure Statements are in compliance with the provisions of 37 CFR 1.97. Accordingly, all references have been considered.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claim Rejection
Claims 12 and 27-35 are rejected under 35 U.S.C. 103 as being unpatentable over DOGAN 2019 (US 20190264286 A1, as cited on the IDS filed 10/13/2023) in view of FLORATH 2016 “Type 2 diabetes and leucocyte DNA methylation: an epigenome-wide association study in over 1,500 older adults” and ZEGGINI 2008 “Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes.”
Claim Interpretation and Scope and Contents of Prior Art
Claim 12 recites the limitation of a method of determining the presence of biomarkers associated with diabetes in a biological sample from a subject, comprising: (a) providing a first portion of the biological sample and a second portion of the biological sample, wherein the nucleic acid from at least the first portion is bisulfite converted; and (b) contacting the first portion of the biological sample with a first oligonucleotide primer at least 8 nucleotides in length that is complementary to a sequence that comprises a first CpG dinucleotide at a GC locus, or a second CpG dinucleotide in linkage disequilibrium with the first CpG dinucleotide at a GC locus wherein the linkage disequilibrium has a value of R>0.3, wherein the first nucleic acid primer detects a methylated or unmethylated CpG dinucleotide, and where the sequence is cg19693031 (as elected).
With respect to this limitation, DOGAN teaches methods and kits for detecting the presence of biomarkers in a biological sample from a subject (Abstract) where portions (aliquots) of the sample sequence are provided from the sample and bisulfate-converted, and contacting a first portion of the sample with a first oligonucleotide primer at least 8 nucleotides in length complimentary to a sequence that comprises a methylated or unmethylated CpG dinucleotide [0021-22]. Further, while DOGAN primarily teaches these methods and kits specifically for detecting predisposition for cardiovascular disease, it also indicates that such methods could also be used in detecting biomarkers for diabetes [0212, 427].
DOGAN does not teach that the CpG dinucleotide is specifically cg19693031. However, FLORATH teaches that site cg19693031 is associated with diabetes, and that methylation levels decrease at this site with increasing fasting glucose (Abstract, pg 135). It would be obvious to one of ordinary skill in the art to substitute targeting of this site in the method in order to determine the presence of biomarkers associated with diabetes.
Claim 12 also recites the limitation of (c) contacting the second portion of the biological sample with a nucleic acid primer at least 8 nucleotides in length that is complementary to a DNA sequence or a bisulfite- converted DNA sequence of a first SNP or a second SNP in linkage disequilibrium with a first SNP, wherein the linkage disequilibrium has a value of R>0.3, and where the SNP is rs1153188 (as elected).
With respect to this limitation, DOGAN teaches contacting the second portion/aliquot of the sample with a nucleic acid primer at least 8 nucleotides in length that is complementary to an SNP sequence [0022], or an SNP in linkage disequilibrium with a value of R>0.3 [028].
DOGAN does not teach that the SNP is specifically rs1153188. However, ZEGGINI teaches that SNP rs1153188 variants are associated with type 2 diabetes (Table 2, pg 624 col 1). It would be obvious to one of ordinary skill in the art to substitute targeting of this SNP in the method in order to determine the presence of biomarkers associated with diabetes.
Claim 12 further recites the limitation wherein the percentage of methylation of the CpG dinucleotide at the GC locus cg19693031, and the identity of the nucleotide in the first SNP rs1153188, or the second SNP in linkage disequilibrium with the first SNP are biomarkers associated with diabetes in the subject.
With respect to this limitation, DOGAN teaches its methods could also be used in detecting biomarkers for diabetes [0212, 427], but does not specifically teach that the percentage of methylation at cg19693031 and the identity of the nucleotide at SNP rs1153188 are biomarkers associated with diabetes. However, However, FLORATH teaches that methylation at site cg19693031 is associated with diabetes (Abstract, pg 135), and ZEGGINI teaches that SNP rs1153188 variants are associated with type 2 diabetes (Table 2, pg 624 col 1).
Claim 27 recites the limitation wherein the first oligonucleotide primer detects the unmethylated CpG dinucleotide. With respect to this limitation, DOGAN teaches that the first oligonucleotide primer can detect the unmethylated CpG dinucleotide [0020].
Claim 28 recites the limitation wherein the first oligonucleotide primer detects the methylated CpG dinucleotide. With respect to this limitation, DOGAN teaches that the first oligonucleotide primer can detect the methylated CpG dinucleotide [0020].
Claim 29 recites the limitation wherein the first oligonucleotide primer comprises one or more nucleotide analogs. With respect to this limitation, DOGAN teaches that the oligonucleotide primer can include one or more nucleotide analogs [0170].
Claim 30 recites the limitation wherein the first oligonucleotide primer comprises one or more synthetic or non-natural nucleotides. With respect to this limitation, DOGAN teaches that the oligonucleotide primer can include one or more synthetic or non-natural nucleotides [0170].
Claim 31 recites the limitation wherein the first oligonucleotide primer is bound to a solid substrate. With respect to this limitation, DOGAN teaches that the primers can be bound to a solid substrate [019, 137, 151].
Claim 32 recites the limitation wherein the solid substrate is a polymer, glass, semiconductor, paper, metal, gel or hydrogel. With respect to this limitation, DOGAN teaches that the solid substrate is a polymer, glass, semiconductor, paper, metal, gel or hydrogel [0138].
Claim 33 recites the limitation wherein the solid substrate is a microarray or microfluidics card. With respect to this limitation, DOGAN teaches that the solid substrate is a microarray [0139] or microfluidics card [0171].
Claim 34 recites the limitation wherein the first oligonucleotide primer comprises a detectable label. With respect to this limitation, DOGAN teaches that the primers can be labeled with one or more detectable labels [0172].
Claim 35 recites the limitation wherein the biological sample is a saliva sample. With respect to this limitation, DOGAN teaches that that biological sample is a saliva sample [0023].
Resolving Ordinary Skill in the Art and Obviousness Rationale
A teaching, suggestion, or motivation in the prior art would have led one of ordinary skill in the art to modify or combine the prior art to arrive at the claimed invention. Specifically, a person of ordinary skill in testing for diabetes biomarkers would have been motivated to combine the teachings of DOGAN with the teachings of FLORATH and ZEGGINI, in order to achieve the claimed invention, because the CpG sites and SNP variants identified in FLORATH and ZEGGINI, respectively, are shown to be associated with diabetes, and determining the presence of these biomarkers in a sample would therefore help to identify the presence or risk of diabetes in a subject. A person of ordinary skill would reasonably expect success from combining these teachings, as the CpG sites and SNP variants identified in FLORATH and ZEGGINI, respectively, can be substituted in place of those used in the methods of DOGAN, such that the primers detect them as diabetes biomarkers. Therefore, the claims at issue would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention as there is both a reason to modify or combine the prior art, and a reasonable expectation of success (see MPEP 2143.02 (I)).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARY C LEVERETT whose telephone number is (571)272-5494. The examiner can normally be reached 8:00am - 5:00pm M-Th.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Karlheinz R. Skowronek can be reached at (571) 272-9047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MARY C LEVERETT/Examiner, Art Unit 1687
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